Compuestos tipo alcaloides quinolínicos y limonoides (triterpenos) sintéticos con potencial anti-leishmania: una aproximación al mecanismo de acción

La leishmaniasis es una enfermedad parasitaria antropozoonótica, causada por el protozoario del género Leishmania spp. y transmitida por el mosquito del genero Lutzomya. Dentro de las formas clínicas de la enfermedad, la cutánea, constituye la manifestación mas frecuente en el mundo, y corresponde a...

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Autores:: Torres Súarez, Francy Elaine

Tipo de recurso:: Doctoral thesis

Fecha de publicación:: 2021

Institución:: Universidad Nacional de Colombia

Repositorio:: Universidad Nacional de Colombia

Idioma:: spa

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network_acronym_str	UNACIONAL2
network_name_str	Universidad Nacional de Colombia
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dc.title.spa.fl_str_mv	Compuestos tipo alcaloides quinolínicos y limonoides (triterpenos) sintéticos con potencial anti-leishmania: una aproximación al mecanismo de acción
dc.title.translated.eng.fl_str_mv	Synthetic quinoline alkaloid and limonoid (triterpene) -type compounds with anti-leishmania potential: an approach to the mechanism of action
title	Compuestos tipo alcaloides quinolínicos y limonoides (triterpenos) sintéticos con potencial anti-leishmania: una aproximación al mecanismo de acción
spellingShingle	Compuestos tipo alcaloides quinolínicos y limonoides (triterpenos) sintéticos con potencial anti-leishmania: una aproximación al mecanismo de acción 610 - Medicina y salud 540 - Química y ciencias afines::547 - Química orgánica Alcaloides Triterpenos Enfermedades de la piel Infecciones Leishmaniasis Mecanismo de acción Tratamiento Alcaloides quinolínicos Triterpenoides Leishmaniasis Treatment Quinoline alkaloids Triterpenoids Action mechanism
title_short	Compuestos tipo alcaloides quinolínicos y limonoides (triterpenos) sintéticos con potencial anti-leishmania: una aproximación al mecanismo de acción
title_full	Compuestos tipo alcaloides quinolínicos y limonoides (triterpenos) sintéticos con potencial anti-leishmania: una aproximación al mecanismo de acción
title_fullStr	Compuestos tipo alcaloides quinolínicos y limonoides (triterpenos) sintéticos con potencial anti-leishmania: una aproximación al mecanismo de acción
title_full_unstemmed	Compuestos tipo alcaloides quinolínicos y limonoides (triterpenos) sintéticos con potencial anti-leishmania: una aproximación al mecanismo de acción
title_sort	Compuestos tipo alcaloides quinolínicos y limonoides (triterpenos) sintéticos con potencial anti-leishmania: una aproximación al mecanismo de acción
dc.creator.fl_str_mv	Torres Súarez, Francy Elaine
dc.contributor.advisor.none.fl_str_mv	Delgado Murcia, Lucy Gabriela
dc.contributor.author.none.fl_str_mv	Torres Súarez, Francy Elaine
dc.contributor.researchgroup.spa.fl_str_mv	Grupo de Investigación en Inmunotoxicología
dc.subject.ddc.spa.fl_str_mv	610 - Medicina y salud 540 - Química y ciencias afines::547 - Química orgánica
topic	610 - Medicina y salud 540 - Química y ciencias afines::547 - Química orgánica Alcaloides Triterpenos Enfermedades de la piel Infecciones Leishmaniasis Mecanismo de acción Tratamiento Alcaloides quinolínicos Triterpenoides Leishmaniasis Treatment Quinoline alkaloids Triterpenoids Action mechanism
dc.subject.lemb.none.fl_str_mv	Alcaloides Triterpenos Enfermedades de la piel Infecciones
dc.subject.proposal.spa.fl_str_mv	Leishmaniasis Mecanismo de acción Tratamiento Alcaloides quinolínicos Triterpenoides
dc.subject.proposal.eng.fl_str_mv	Leishmaniasis Treatment Quinoline alkaloids Triterpenoids Action mechanism
description	La leishmaniasis es una enfermedad parasitaria antropozoonótica, causada por el protozoario del género Leishmania spp. y transmitida por el mosquito del genero Lutzomya. Dentro de las formas clínicas de la enfermedad, la cutánea, constituye la manifestación mas frecuente en el mundo, y corresponde a más del 90% de los casos resportados en Colombia y en el mundo. Una de las dificultades más evidentes en el control de esta enfermedad, ha sido el tratamiento, el cual además de haber reportado pérdida de eficacia, presenta efectos adversos, largos esquemas de tratamiento y formas de administración de baja adherencia por parte del paciente, que generan el abandono del mismo y la generación de cepas resistentes. Por esta razón, la búsqueda de alternativas terapéuticas de aplicación tópica constituye una necesidad de alta prioridad, para disminuir el problema de salud pública que conlleva esta enfermedad. De este modo, en estudios previos realizados en el Grupo de Investigación en Inmunotoxicologia se identificaron dos moléculas de origen vegetal con propiedades antileishmaniales, correspondientes a alcaloides quinolínicos (N-metil-8-metoxiflindersina) y triterpenoides de tipo limonoide (11α,19β-dihidroxi-7-acetoxi-7-deoxoichangina), con efecto directo frente al parásito y propiedades inmunoduladoras en células humanas infectadas por el parásito; sin embargo, el origen (a partir de material vegetal de Raputia heptaphylla) y las dificultades que conllevan la extracción y la purificación, conllevó al diseño de estrategias para encontrar moléculas con características estructurales afines, bajo el principio de propiedades similares (PPS). Entre los hallazgos mas relevantes obtenidos en este trabajo, se encuentran los resultados obtenidos con compuestos de origen sintético y análogos a las moléculas naturales, los cuales fueron seleccionados por medio de estrategias In silico: triterpenoides [ácido oleanólico (5), glicirrizato de amonio (7) y ácido 18B-glicirretínico (8)] y alcaloides quinolínicos [1,2,3,4-tetrahidro-(benzo)-3-qinolin-ol (13) y 2-amino-8-hidroxiquinolina (19)] los cuales presentaron actividad anti-leishmanial In vitro [sobre promastigotes (13 y 19) y amastigotes intracelulares de L. (V.) panamensis (5, 7, 8, 13 y 19)] e In vivo [promoviendo la cura clínica (entre un 20% (8), 33,3% (13) y 50% (19) los animales cicatrizan completamente la lesión) y mejoría clínica (100% (5), 80% (7), 60% (8), 66,6% (13) y 33.3% (19), reducción en al menos un 20% el tamaño de la lesión), de los animales tratados con los compuestos, administrados de forma tópica]. De acuerdo con los efectos de cada compuesto, se propusieron modelos de aproximación al modo de acción de cada molécula. Los triterpenoides 5 y 7 mostraron característica de pro-fármacos (actividad evidente sobre la foma amastigote en MdMhu infectados), pero con afectaciones diferenciales en el amastigote intracelular para el triterpenoide 5 [causa muerte de tipo necrosis (presencia de membranas hinchadas o alteradas, acidocalcisomas y daño nuclear)] y saponina 7 [(afinidad por la mitocondria de MdMhu y parásitos (causando en Leishmania spp. estrés celular, la parición de acidocalcisomas e hinchamiento de membranas celulares)]. El triterpenoide 8 indujo el incremento diferencial de NO, a través de la modulación de iNOS vía NF-kB en macrófagos infectados y modificaciones en los amastigotes (citoquinesis alterada y señales de apoptosis). Se resaltan los hallazgos de los compuestos alcaloides (13 y 19), los cuales fueron activos frente a los dos estadios del parásito (promastigotes y amastigotes). El alcaloide 13, actúa sobre reservas de lípidos y componentes de membrana [(reflejado en el aumento de cuerpos lipídicos y vacuolas parasitóforas comunales en MdMhu)], causando el estrés celular de los parásitos (presencia de acidocalcisomas y citoquinesis alterada) y la disminución de la carga parasitaria en estas células, induciendo el aumento temprano de ROS en MI, contribuyendo así con el control temprano del parásito. Mientras que el efecto del compuesto 19 está dirigido hacia la modulación de procesos de generación de energía y respiración oxidativa (producción de especies reactivas en promastigotes y despolarización de la mitocondria), los cuales conducen a los parásitos a la muerte de tipo apoptosis (hinchamiento de membranas celulares, presencia de acidocalcisomas y distribución anormal de cromatina) y que se asocian con la expresión diferencial de proteínas (spots) en amastigotes expuestos al alcaloide; mientras que en las células hospederas infectadas, se induce apoptosis, mostrando la selectividad del compuesto. Estos resultados permiten soportar nuestro modelo de búsqueda de compuestos, en donde a partir de moléculas de difícil obtención (origen vegetal), se pueden encontrar antileishmaniales promisorios. Se destaca, que para cada molécula antiparasitaria encontrada en este proyecto, se identificó un posible modo de acción en el modelo de células primarias, así como su efectividad terapéutica en un modelo In vivo; estos hallazgos contribuyen al entendimiento de la forma de actuación de este tipo de compuestos y abre el camino para la optimización y tratamiento de la leishmaniasis cutánea en el país.
publishDate	2021
dc.date.accessioned.none.fl_str_mv	2021-05-21T15:53:35Z
dc.date.available.none.fl_str_mv	2021-05-21T15:53:35Z
dc.date.issued.none.fl_str_mv	2021-05
dc.type.spa.fl_str_mv	Trabajo de grado - Doctorado
dc.type.driver.spa.fl_str_mv	info:eu-repo/semantics/doctoralThesis
dc.type.version.spa.fl_str_mv	info:eu-repo/semantics/acceptedVersion
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dc.type.content.spa.fl_str_mv	Text
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dc.identifier.uri.none.fl_str_mv	https://repositorio.unal.edu.co/handle/unal/79547
dc.identifier.instname.spa.fl_str_mv	Universidad Nacional - Sede Medellín
dc.identifier.reponame.spa.fl_str_mv	Repositorio Institucional Universidad Nacional de Colombia
dc.identifier.repourl.spa.fl_str_mv	https://repositorio.unal.edu.co/
url	https://repositorio.unal.edu.co/handle/unal/79547 https://repositorio.unal.edu.co/
identifier_str_mv	Universidad Nacional - Sede Medellín Repositorio Institucional Universidad Nacional de Colombia
dc.language.iso.spa.fl_str_mv	spa
language	spa
dc.relation.references.spa.fl_str_mv	WHO. Number of cases of cutaneous leishmaniasis reported Data by country. Global Health Observatory data repository. 2019. PAHO. Leishmaniasis: Epidemiological Report of the Americass No 7 - Março, 2019. Informe de Leishmanioses No 7. 2019. Valderrama L, McMahon-Pratt D, Navas C, Saravia NG, Segura I, Valencia AZ, et al. Heterogeneity, geographic distribution, and pathogenicity of serodemes of Leishmania viannia in Colombia. Am J Trop Med Hyg. 2017; Herrera G, Barragán N, Luna N, Martínez D, De Martino F, Medina J, et al. An interactive database of Leishmania species distribution in the Americas. Sci Data. 2020 Dec 1;7(1). Instituto Nacional de Salud. Lineamientos para la atención clínica de Leishmaniasis en Colombia. Bogotá; 2018. Singh N, Mishra BB, Bajpai S, Singh RK, Tiwari VK. Natural product based leads to fight against leishmaniasis. Bioorg. Med. Chem. 2014. Torres-Guerrero E, Quintanilla-Cedillo MR, Ruiz-Esmenjaud J, Arenas R. Leishmaniasis: a review. F1000Research. 2017; Croft SL, Olliaro P. Leishmaniasis chemotherapy-challenges and opportunities. Clinical Microbiology and Infection. 2011. Garnier T, Croft SL. Topical treatment for cutaneous leishmaniasis. Current Opinion in Investigational Drugs. 2002. Ghorbani M, Farhoudi R. Leishmaniasis in humans: Drug or vaccine therapy? Drug Des. Devel. Ther. 2018. Le Pape P. Development of new antileishmanial drugs--current knowledge and future prospects. J Enzyme Inhib Med Chem. 2008;23(October):708–18. Chrzanowska M, Grajewska A, Rozwadowska MD. Asymmetric Synthesis of Isoquinoline Alkaloids: 2004–2015. Chem Rev [Internet]. 2016 Oct 12 [cited 2017 Dec 10];116(19):12369–465. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27680197 Granados-Falla D, Gomez-Galindo A, Daza A, Robledo S, Coy-Barrera C, Cuca L, et al. Seco-limonoid derived from Raputia heptaphylla promotes the control of cutaneous leishmaniasis in hamsters (Mesocricetus auratus). Parasitology. 2016; Coy Barrera CA, Coy Barrera ED, Granados Falla DS, Delgado Murcia G, Cuca Suarez LE. seco-limonoids and quinoline alkaloids from Raputia heptaphylla and their antileishmanial activity. Chem Pharm Bull (Tokyo) [Internet]. 2011 [cited 2017 Dec 8];59(7):855–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21720036 Granados Falla DS. Determinación de la actividad leishmanicida e inmunomoduladora de compuestos naturales derivados de Raputia heptaphylla (Familia Rutaceae) como posible alternativa terapeutica frente a la leishmaniosis cutánea. Ph. D. Thesis [Internet]. Universidad Nacional de Colombia; 2013. Available from: http://www.bdigital.unal.edu.co/11036/ Silva GL, Lee I-S, Kinghorn AD. Special Problems with the Extraction of Plants. In 1998. Tiuman TS, Santos AO, Ueda-Nakamura T, Filho BPD, Nakamura C V. Recent advances in leishmaniasis treatment. International Journal of Infectious Diseases. 2011. Loedige M. Design and Synthesis of Novel Antileishmanial Compounds. Int J Med Chem. 2015; Zulfiqar B, Shelper TB, Avery VM. Leishmaniasis drug discovery: recent progress and challenges in assay development. Vol. 22, Drug Discovery Today. Elsevier Ltd; 2017. p. 1516–31. Sereno D, Cordeiro da Silva A, Mathieu-Daude F, Ouaissi A. Advances and perspectives in Leishmania cell based drug-screening procedures. Parasitology International. 2007. Monge-Maillo B, López-Vélez R. Therapeutic options for old world cutaneous leishmaniasis and new world cutaneous and mucocutaneous leishmaniasis. Drugs. 2013. Chatelain E, Ioset JR. Drug discovery and development for neglected diseases: The DNDi model. Drug Design, Development and Therapy. 2011. Maggiora G, Vogt M, Stumpfe D, Bajorath J. Molecular Similarity in Medicinal Chemistry. J Med Chem [Internet]. 2014 Apr 24 [cited 2017 Dec 8];57(8):3186–204. Available from: http://pubs.acs.org/doi/10.1021/jm401411z De Almeida MC, Vilhena V, Barral A, Barral-Netto M. Leishmanial Infection: Analysis of its First Steps. A Review. Vol. 98, Mem . Inst. Oswaldo Cruz. 2003. p. 861–70. Palatnik-De-Sousa CB, Day MJ. One Health: The global challenge of epidemic and endemic leishmaniasis. Parasites and Vectors. 2011. Alvar J, Vélez ID, Bern C, Herrero M, Desjeux P, Cano J, et al. Leishmaniasis worldwide and global estimates of its incidence. Vol. 7, PLoS ONE. 2012. Desjeux P. Focus: Leishmaniasis. Nat Rev Microbiol. 2004; Nylén S, Eidsmo L. Tissue damage and immunity in cutaneous leishmaniasis. Parasite Immunology. 2012. Reveiz L, Maia-Elkhoury ANS, Nicholls RS, Sierra Romero GA, Yadon ZE. Interventions for American Cutaneous and Mucocutaneous Leishmaniasis: A Systematic Review Update. PLoS One. 2013; Scotti MT, Scotti L, Ishiki H, Ribeiro FF, Cruz RMD da, Oliveira MP de, et al. Natural Products as a Source for Antileishmanial and Antitrypanosomal Agents. Comb Chem High Throughput Screen [Internet]. 2016 [cited 2017 Dec 10];19(7):537–53. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27682867 Vannier-Santos M, Martiny A, Souza W. Cell Biology of Leishmania spp.: Invading and Evading. Curr Pharm Des. 2005; Burza S, Croft SL, Boelaert M. Leishmaniasis. The Lancet. 2018. Epidemiological situation W. WHO \| Epidemiological situation. WHO. 2017. Karimkhani C, Wanga V, Coffeng LE, Naghavi P, Dellavalle RP, Naghavi M. Global burden of cutaneous leishmaniasis: A cross-sectional analysis from the Global Burden of Disease Study 2013. Lancet Infect Dis. 2016; Pan American Health Organization. Leishmaniasis: Epidemiological Report in the Americas. Washington, DC PAHO. 2019; WHO. WHO: Weekly epidemiological record: Global leishmaniasis update, 2006-2015, a turning point in leishmaniasis surveillance. World Heal Organ. 2017; Salgado-Almario J, Hernández CA, Ovalle-Bracho C. Geographical distribution of Leishmania species in Colombia, 1985-2017. Biomedica. 2019; Ramírez JD, Hernández C, León CM, Ayala MS, Flórez C, González C. Taxonomy, diversity, temporal and geographical distribution of Cutaneous Leishmaniasis in Colombia: A retrospective study. Sci Rep. 2016; Zarean M, Maraghi S, Hajjaran H, Mohebali M, Feiz-Hadad MH, Assarehzadegan MA. Comparison of proteome profiling of two sensitive and resistant field iranian isolates of leishmania major to glucantime® by 2-dimensional electrophoresis. Iran J Parasitol. 2015; Ponte-Sucre A, Gamarro F, Dujardin JC, Barrett MP, López-Vélez R, García-Hernández R, et al. Drug resistance and treatment failure in leishmaniasis: A 21st century challenge. PLoS Negl Trop Dis. 2017. Baiocco P, Colotti G, Franceschini S, Ilari A. Molecular basis of antimony treatment in Leishmaniasis. J Med Chem. 2009; De Menezes JP, Saraiva EM, Da Rocha-Azevedo B. The site of the bite: Leishmania interaction with macrophages, neutrophils and the extracellular matrix in the dermis. Vol. 9, Parasites and Vectors. BioMed Central Ltd.; 2016. Podinovskaia M, Descoteaux A. Leishmania and the macrophage: A multifaceted interaction. Future Microbiol. 2015. Novais FO, Scott P. Immunology of Leishmaniasis. In: Encyclopedia of Immunobiology. 2016. Liese J, Schleicher U, Bogdan C. The innate immune response against Leishmania parasites. Immunobiology. 2008; Fidalgo LM, Gille L. Mitochondria and trypanosomatids: Targets and drugs. Pharmaceutical Research. 2011. Wheeler RJ, Gluenz E, Gull K. The cell cycle of Leishmania: Morphogenetic events and their implications for parasite biology. Mol Microbiol. 2011; Ivens AC, Peacock CS, Worthey EA, Murphy L, Aggarwal G, Berriman M, et al. The genome of the kinetoplastid parasite, Leishmania major. Science (80- ). 2005; Mougneau E, Bihl F, Glaichenhaus N. Cell biology and immunology of Leishmania. Immunol. Rev. 2011. Kima PE. The amastigote forms of Leishmania are experts at exploiting host cell processes to establish infection and persist. International Journal for Parasitology. 2007. Aulner N, Danckaert A, Rouault-Hardoin E, Desrivot J, Helynck O, Commere PH, et al. High Content Analysis of Primary Macrophages Hosting Proliferating Leishmania Amastigotes: Application to Anti-leishmanial Drug Discovery. PLoS Negl Trop Dis. 2013; Torres, Henry Jay Forman M, Torres M. Signaling by the Respiratory Burst in Macrophages. IUBMB Life [Internet]. 2001 Jun 1 [cited 2018 May 10];51(6):365–71. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11758804 Van Assche T, Deschacht M, Da Luz RAI, Maes L, Cos P. Leishmania-macrophage interactions: Insights into the redox biology. Free Radic. Biol. Med. 2011. Christine Hsiao CH, Ueno N, Shao JQ, Schroeder KR, Moore KC, Donelson JE, et al. The effects of macrophage source on the mechanism of phagocytosis and intracellular survival of Leishmania. Microbes Infect. 2011; Séguin O, Descoteaux A. Leishmania, the phagosome, and host responses: The journey of a parasite. Cell Immunol. 2016; Cecílio P, Pérez-Cabezas B, Santarém N, Maciel J, Rodrigues V, da Silva AC. Deception and manipulation: The arms of Leishmania, a successful parasite. Front. Immunol. 2014. Naderer T, Vince JE, McConville MJ. Surface determinants of Leishmania parasites and their role in infectivity in the mammalian host. Curr Mol Med. 2004; De Oliveira CI, Brodskyn CI. The immunobiology of Leishmania braziliensis infection. Frontiers in Immunology. 2012. Ameen M. Cutaneous leishmaniasis: Advances in disease pathogenesis, diagnostics and therapeutics. Clinical and Experimental Dermatology. 2010. Bosque F, Saravia NG, Valderrama L, Milon G. Distinct innate and acquired immune responses to Leishmania in putative susceptible and resistant human populations endemically exposed to L. (Viannia) panamensis infection. Scand J Immunol. 2000; Oliveira WN, Ribeiro LE, Schrieffer A, Machado P, Carvalho EM, Bacellar O. The role of inflammatory and anti-inflammatory cytokines in the pathogenesis of human tegumentary leishmaniasis. Cytokine. 2014; Andrews KT, Fisher G, Skinner-Adams TS. Drug repurposing and human parasitic protozoan diseases. Int. J. Par: Drugs and Drug Resistance. 2014. Oliveira LF, Schubach AO, Martins MM, Passos SL, Oliveira R V., Marzochi MC, et al. Systematic review of the adverse effects of cutaneous leishmaniasis treatment in the New World. Acta Tropica. 2011. Balasegaram M, Ritmeijer K, Lima MA, Burza S, Ortiz Genovese G, Milani B, et al. Liposomal amphotericin B as a treatment for human leishmaniasis. Expert Opin Emerg Drugs. 2012; Sundar S, Chakravarty J. Leishmaniasis: an update of current pharmacotherapy. Expert Opin Pharmacother. 2012; Barrett MP, Croft SL. Management of trypanosomiasis and leishmaniasis. British Medical Bulletin. 2012. Navas A, Vargas DA, Freudzon M, McMahon-Pratt D, Saravia NG, Gómez MA. Chronicity of dermal leishmaniasis caused by Leishmania panamensis is associated with parasite-mediated induction of chemokine gene expression. Infect Immun. 2014; Nassif PW, De Mello TFP, Navasconi TR, Mota CA, Demarchi IG, Aristides SMA, et al. Safety and efficacy of current alternatives in the topical treatment of cutaneous leishmaniasis: A systematic review. Parasitology. 2017. Aguiar MG, Pereira AMM, Fernandes AP, Ferreira LAM. Reductions in skin and systemic parasite burdens as a combined effect of topical paromomycin and oral miltefosine treatment of mice experimentally infected with Leishmania (Leishmania) amazonensis. Antimicrob Agents Chemother. 2010; Seeberger J, Daoud S, Pammer J. Transient effect of topical treatment of cutaneous leishmaniasis with imiquimod. In: International Journal of Dermatology. 2003. Mitra A, Wu Y. Topical delivery for the treatment of psoriasis. Expert Opinion on Drug Delivery. 2010. Manderson L. Neglected Diseases of Poverty. Medical Anthropology: Cross Cultural Studies in Health and Illness. 2012; Ogungbe IV, Setzer WN. The Potential of secondary metabolites from plants as drugs or leads against protozoan neglected diseases-Part III: In-Silico molecular docking investigations. Vol. 21, Molecules. 2016. Alqahtani A, Hamid K, Kam A, Wong KH, Abdelhak Z, Razmovski-Naumovski V, et al. The Pentacyclic Triterpenoids in Herbal Medicines and Their Pharmacological Activities in Diabetes and Diabetic Complications. Curr Med Chem. 2013; Begum S, Ayub A, Qamar Zehra S, Shaheen Siddiqui B, Iqbal Choudhary M, Samreen. Leishmanicidal triterpenes from Lantana camara. Chem Biodivers. 2014; Quinn RJ, Carroll AR, Pham NB, Baron P, Palframan ME, Suraweera L, et al. Developing a drug-like natural product library. J Nat Prod. 2008; Mishra BB, Singh RK, Srivastava A, Tripathi VJ, Tiwari VK. Fighting against Leishmaniasis: search of alkaloids as future true potential anti-Leishmanial agents. Mini Rev Med Chem [Internet]. 2009 Jan [cited 2017 Dec 10];9(1):107–23. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19149664 Rohloff J, Hymete A, Tariku Y. Plant-derived natural products for the treatment of leishmaniasis. In: Studies in Natural Products Chemistry. 2013. T.J. Schmidt, S.A. Khalid, A.J. Romanha, T.MA. Alves, M.W. Biavatti, R. Brun, et al. The Potential of Secondary Metabolites from Plants as Drugs or Leads Against Protozoan Neglected Diseases - Part I. Curr Med Chem [Internet]. 2012;19(14):2128–75. Available from: http://www.eurekaselect.com/openurl/content.php?genre=article&issn=0929-8673&volume=19&issue=14&spage=2128 Xu R, Fazio GC, Matsuda SPT. On the origins of triterpenoid skeletal diversity. Phytochemistry. 2004. 81. Kuttan G, Pratheeshkumar P, Manu KA, Kuttan R. Inhibition of tumor progression by naturally occurring terpenoids. Pharm Biol [Internet]. 2011 Oct 21 [cited 2017 Dec 8];49(10):995–1007. Available from: http://www.tandfonline.com/doi/full/10.3109/13880209.2011.559476 Roy A, Saraf S. Limonoids: overview of significant bioactive triterpenes distributed in plants kingdom. Biol Pharm Bull [Internet]. 2006 Feb [cited 2017 Dec 8];29(2):191–201. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16462017 Steverding D, Sidjui LS, Ferreira ÉR, Ngameni B, Folefoc GN, Mahiou-Leddet V, et al. Trypanocidal and leishmanicidal activity of six limonoids. Journal of Natural Medicines. 2020. Yamamoto ES, Campos BLS, Jesus JA, Laurenti MD, Ribeiro SP, Kallás EG, et al. The effect of ursolic acid on leishmania (Leishmania) amazonensis is related to programed cell death and presents therapeutic potential in experimental cutaneous leishmaniasis. PLoS One. 2015;10(12). Coy C, Coy E, Granados D, Delgado G, Cuca L. Seco-limonoids and quinoline alkaloids from Raputia heptaphylla and their antileishmanial activity. Chem Pharm Bull (Tokyo). 2011; Oliveira I dos S da S, Moragas Tellis CJ, Chagas M do S dos S, Behrens MD, Calabrese K da S, Abreu-Silva AL, et al. Carapa guianensis Aublet (Andiroba) Seed Oil: Chemical Composition and Antileishmanial Activity of Limonoid-Rich Fractions . Biomed Res Int. 2018; Gupta P, Ukil A, Das PK. Bioactive Component of Licorice as an Antileishmanial Agent. In: Biological Activities and Action Mechanisms of Licorice Ingredients. 2017. Dinesh N, Neelagiri S, Kumar V, Singh S. Glycyrrhizic acid attenuates growth of Leishmania donovani by depleting ergosterol levels. Exp Parasitol. 2017;176:21–9. Melo TS, Gattass CR, Soares DC, Cunha MR, Ferreira C, Tavares MT, et al. Oleanolic acid (OA) as an antileishmanial agent: Biological evaluation and in silico mechanistic insights. Parasitol Int. 2016;65(3):227–37. Torres-Santos EC, Lopes D, Rodrigues Oliveira R, Carauta JPP, Bandeira Falcao CA, Kaplan MAC, et al. Antileishmanial activity of isolated triterpenoids from Pourouma guianensis. Phytomedicine. 2004; Alakurtti S, Bergström P, Sacerdoti-Sierra N, Jaffe CL, Yli-Kauhaluoma J. Anti-leishmanial activity of betulin derivatives. J Antibiot (Tokyo). 2010; Das A, Jawed JJ, Das MC, Sandhu P, De UC, Dinda B, et al. Antileishmanial and immunomodulatory activities of lupeol, a triterpene compound isolated from Sterculia villosa. Int J Antimicrob Agents. 2017; Sousa MC, Varandas R, Santos RC, Santos-Rosa M, Alves V, Salvador JAR. Antileishmanial activity of semisynthetic lupane triterpenoids betulin and betulinic acid derivatives: Synergistic effects with miltefosine. PLoS One. 2014; Dinesh N, Neelagiri S, Kumar V, Singh S. Glycyrrhizic acid attenuates growth of Leishmania donovani by depleting ergosterol levels. Exp Parasitol. 2017; Ukil A, Biswas A, Das T, Das PK. 18 -Glycyrrhetinic Acid Triggers Curative Th1 Response and Nitric Oxide Up-Regulation in Experimental Visceral Leishmaniasis Associated with the Activation of NF- B. J Immunol. 2014; Gupta P, Das PK, Ukil A. Antileishmanial effect of 18β-glycyrrhetinic acid is mediated by toll-like receptor-dependent canonical and noncanonical p38 activation. Antimicrob Agents Chemother. 2015; Aniszewski T. Alkaloid chemistry. In: Alkaloids. 2015. Calla-Magariños J, Quispe T, Giménez A, Freysdottir J, Troye-Blomberg M, Fernández C. Quinolinic Alkaloids from G alipea longiflora Krause Suppress Production of Proinflammatory Cytokines in vitro and Control Inflammation in vivo upon Leishmania Infection in Mice. Scand J Immunol [Internet]. 2013 Jan [cited 2017 Dec 10];77(1):30–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23126625 Ferreira ME, Rojas de Arias A, Yaluff G, de Bilbao NV, Nakayama H, Torres S, et al. Antileishmanial activity of furoquinolines and coumarins from Helietta apiculata. Phytomedicine. 2010;17(5):375–8. Nakayama H, Desrivot J, Bories C, Franck X, Figadère B, Hocquemiller R, et al. In vitro and in vivo antileishmanial efficacy of a new nitrilquinoline against Leishmania donovani. Biomed Pharmacother. 2007; Paloque L, Verhaeghe P, Casanova M, Castera-Ducros C, Dumètre A, Mbatchi L, et al. Discovery of a new antileishmanial hit in 8-nitroquinoline series. Eur J Med Chem. 2012; Sasidharan S, Chen Y, Saravanan D, Sundram KM, Yoga Latha L. Extraction, isolation and characterization of bioactive compounds from plants’ extracts. African J Tradit Complement Altern Med. 2011; Coimbra ES, Antinarelli LMR, Silva NP, Souza IO, Meinel RS, Rocha MN, et al. Quinoline derivatives: Synthesis, leishmanicidal activity and involvement of mitochondrial oxidative stress as mechanism of action. Chem Biol Interact. 2016; Tempone AG, Melo Pompeu Da Silva AC, Brandt CA, Scalzaretto Martinez F, Borborema SET, Barata Da Silveira MA, et al. Synthesis and antileishmanial activities of novel 3-substituted quinolines. Antimicrob Agents Chemother. 2005; Calixto SL, Glanzmann N, Xavier Silveira MM, da Trindade Granato J, Gorza Scopel KK, Torres de Aguiar T, et al. Novel organic salts based on quinoline derivatives: The in vitro activity trigger apoptosis inhibiting autophagy in Leishmania spp. Chem Biol Interact. 2018 Sep 25;293:141–51. Fournet A, Barrios AA, Munoz V, Hocquemiller R, Cave A, Bruneton J. 2-Substituted quinoline alkaloids as potential antileishmanial drugs. Antimicrob Agents Chemother. 1993; Fournet A, Gantier JC, Gautheret A, Leysalles L, Munos MH, Mayrargue J, et al. The activity of 2-substituted quinoline alkaloids in BALB/c mice infected with leishmania donovani. J Antimicrob Chemother. 1994; Gopinath VS, Pinjari J, Dere RT, Verma A, Vishwakarma P, Shivahare R, et al. Design, synthesis and biological evaluation of 2-substituted quinolines as potential antileishmanial agents. Eur J Med Chem. 2013; de Mello TFP, Bitencourt HR, Pedroso RB, Aristides SMA, Lonardoni MVC, Silveira TGV. Leishmanicidal activity of synthetic chalcones in Leishmania (Viannia) braziliensis. Exp Parasitol. 2014; Coimbra ES, Libong D, Cojean S, Saint-Pierre-Chazalet M, Solgadi A, Le Moyec L, et al. Mechanism of interaction of sitamaquine with Leishmania donovani. J Antimicrob Chemother. 2010; Singh N, Kumar M, Singh RK. Leishmaniasis: Current status of available drugs and new potential drug targets. Asian Pac J Trop Med. 2012;5(6):485–97. Bhattacharjee S, Bhattacharjee A, Majumder S, Majumdar SB, Majumdar S. Glycyrrhizic acid suppresses cox-2-mediated anti-inflammatory responses during Leishmania donovani infection. J Antimicrob Chemother. 2012; Biswas A, Bhattacharya A, Vij A, Das PK. Role of leishmanial acidocalcisomal pyrophosphatase in the cAMP homeostasis in phagolysosome conditions required for intra-macrophage survival. Int J Biochem Cell Biol. 2017; Zhang C, Liu Z, Zheng Y, Geng Y, Han C, Shi Y, et al. Glycyrrhetinic Acid Functionalized Graphene Oxide for Mitochondria Targeting and Cancer Treatment In Vivo. Small [Internet]. 2017 Dec 4 [cited 2017 Dec 8];1703306. Available from: http://www.ncbi.nlm.nih.gov/pubmed/29205852 Haghshenas V, Fakhari S, Mirzaie S, Rahmani M, Farhadifar F, Pirzadeh S, et al. Glycyrrhetinic Acid inhibits cell growth and induces apoptosis in ovarian cancer a2780 cells. Adv Pharm Bull [Internet]. 2014 Oct [cited 2018 Sep 12];4(Suppl 1):437–41. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25364659 Dueñas-Romero AM, Loiseau PM, Saint-Pierre-Chazalet M. Interaction of sitamaquine with membrane lipids of Leishmania donovani promastigotes. Biochim Biophys Acta - Biomembr. 2007; Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Advanced Drug Delivery Reviews. 2012. Walters WP, Murcko A, Murcko MA. Recognizing molecules with drug-like properties. Curr Opin Chem Biol. 1999; World Health Organization (WHO). Control de la leishmaniasis. Ser Inf técnicos. 2010; Matsson P, Kihlberg J. How Big Is Too Big for Cell Permeability? Journal of Medicinal Chemistry. 2017; Vraka C, Mijailovic S, Fröhlich V, Zeilinger M, Klebermass EM, Wadsak W, et al. Expanding LogP: Present possibilities. Nucl Med Biol. 2018; Nikaido H. Preventing drug access to targets: Cell surface permeability barriers and active efflux in bacteria. Semin Cell Dev Biol. 2001; Caridha D, Vesely B, van Bocxlaer K, Arana B, Mowbray CE, Rafati S, et al. Route map for the discovery and pre-clinical development of new drugs and treatments for cutaneous leishmaniasis. International Journal for Parasitology: Drugs and Drug Resistance. 2019. Franc I, Lipinski A, Feeney PJ. Lipinski Rule, AdvDrugDelivRev 1997. Adv Drug Deliv Rev. 1997; Bajusz D, Rácz A, Héberger K. Why is Tanimoto index an appropriate choice for fingerprint-based similarity calculations? J Cheminform [Internet]. 2015 Dec 20 [cited 2017 Dec 8];7(1):20. Available from: http://www.jcheminf.com/content/7/1/20 Kogej T, Engkvist O, Blomberg N, Muresan S. Multifingerprint based similarity searches for targeted class compound selection. J Chem Inf Model. 2006; Coy Barrera CA, Coy Barrera ED, Granados Falla DS, Delgado Murcia G, Cuca Suarez LE. seco-Limonoids and Quinoline Alkaloids from Raputia heptaphylla and Their Antileishmanial Activity. Chem Pharm Bull (Tokyo). 2011; Holliday. Grouping of Coefficients for the Calculation of Inter-Molecular Similarity and Dissimilarity using 2D Fragment Bit-Strings. Comb Chem High Throughput Screen. 2002; Bajusz D, Rácz A, Héberger K. Why is Tanimoto index an appropriate choice for fingerprint-based similarity calculations? J Cheminform. 2015; Bender A, Jenkins JL, Scheiber J, Sukuru SCK, Glick M, Davies JW. How similar are similarity searching methods? A principal component analysis of molecular descriptor space. J Chem Inf Model. 2009; Martin YC, Kofron JL, Traphagen LM. Do structurally similar molecules have similar biological activity? J Med Chem. 2002; Eckert H, Bajorath J. Molecular similarity analysis in virtual screening: foundations, limitations and novel approaches. Drug Discovery Today. 2007. Kerns EH, Di L. Drug-like Properties: Concepts, Structure Design and Methods. Drug-like Properties: Concepts, Structure Design and Methods. 2008. Liu X, Testa B, Fahr A. Lipophilicity and its relationship with passive drug permeation. Pharmaceutical Research. 2011. Raney SG, Franz TJ, Lehman PA, Lionberger R, Chen ML. Pharmacokinetics-Based Approaches for Bioequivalence Evaluation of Topical Dermatological Drug Products. Clinical Pharmacokinetics. 2015. Guo Y, Shen H. pKa, Solubility, and Lipophilicity. In: Opt in Drug Dis. 2009. Lipinski CA. Drug-like properties and the causes of poor solubility and poor permeability. J Pharmacol Toxicol Methods. 2000; Carvajal MT, Yalkowsky S. Effect of pH and Ionic Strength on the Solubility of Quinoline: Back-to-Basics. AAPS PharmSciTech [Internet]. 2019 Apr 25;20(3):124. Available from: http://link.springer.com/10.1208/s12249-019-1336-9 Ačimovič J, Rozman D. Steroidal triterpenes of cholesterol synthesis. Molecules. 2013. Böttger S, Melzig MF. The influence of saponins on cell membrane cholesterol. Bioorganic Med Chem. 2013; Sahu T, Patel T, Sahu S, Gidwani B. Skin Cream as Topical Drug Delivery System: A Review. J Pharm Biol Sci. 2016; Pulido SA, Muñoz DL, Restrepo AM, Mesa C V., Alzate JF, Vélez ID, et al. Improvement of the green fluorescent protein reporter system in Leishmania spp. for the in vitro and in vivo screening of antileishmanial drugs. Acta Trop. 2012; Pérez-Flórez M, Ocampo CB, Valderrama-Ardila C, Alexander N. Spatial modeling of cutaneous leishmaniasis in the Andean region of Colombia. Mem Inst Oswaldo Cruz. 2016; Robledo SM, Carrillo LM, Daza A, Restrepo AM, Muñoz DL, Tobón J, et al. Cutaneous Leishmaniasis in the dorsal skin of hamsters: A useful model for the screening of antileishmanial drugs. J Vis Exp. 2012; García E, Coa JC, Otero E, Carda M, Vélez ID, Robledo SM, et al. Synthesis and antiprotozoal activity of furanchalcone–quinoline, furanchalcone–chromone and furanchalcone–imidazole hybrids. Med Chem Res. 2018; Osorio EJ, Robledo SM, Bastida J. Chapter 2 Alkaloids with Antiprotozoal Activity. Alkaloids: Chemistry and Biology. 2008. Meza C, Muñoz DL, Echeverry MCM, Vélez ID, Robledo SM, Mesa C V, et al. Susceptibilidad in vitro a infección por difiere según tipo de macrófagos. Salud UIS. 2010; Mears ER, Modabber F, Don R, Johnson GE. A Review: The Current In Vivo Models for the Discovery and Utility of New Anti-leishmanial Drugs Targeting Cutaneous Leishmaniasis. Vol. 9, PLoS Neglected Tropical Diseases. Public Library of Science; 2015. Corpas-López V, Merino-Espinosa G, López-Viota M, Gijón-Robles P, Morillas-Mancilla MJ, López-Viota J, et al. Topical Treatment of Leishmania tropica Infection Using (-)-α-Bisabolol Ointment in a Hamster Model: Effectiveness and Safety Assessment. J Nat Prod. 2016; Gomes-Silva A, Valverde JG, Ribeiro-Romão RP, Plácido-Pereira RM, Da-Cruz AM. Golden hamster (Mesocricetus auratus) as an experimental model for Leishmania (Viannia) braziliensis infection. Parasitology. 2013; Zurada JM, Kriegel D, Davis IC. Topical treatments for hypertrophic scars. J Am Acad Dermatol. 2006; Herrera G, Barragán N, Luna N, Martínez D, De Martino F, Medina J, et al. An interactive database of Leishmania species distribution in the Americas. Sci Data. 2020; Ministerio de la protección Social. Guía para la atención clínica integral del paciente con leishmaniasis. Colombia; 2010 p. 58. Ukil A, Kar S, Srivastav S, Ghosh K, Das PK. Curative effect of 18β-glycyrrhetinic acid in experimental visceral leishmaniasis depends on phosphatase-dependent modulation of cellular MAP kinases. PLoS One. 2011; da Silva EC, Dias Rayol C, Lys Medeiros P, Figueiredo RCBQ, Piuvezan MR, Brabosa-Filho JM, et al. Antileishmanial Activity of Warifteine: A Bisbenzylisoquinoline Alkaloid Isolated from Cissampelos sympodialis Eichl. (Menispermaceae). Sci World J [Internet]. 2012;2012:1–5. Available from: http://www.hindawi.com/journals/tswj/2012/516408/ Chanquia SN, Larregui F, Puente V, Labriola C, Lombardo E, García Liñares G. Synthesis and biological evaluation of new quinoline derivatives as antileishmanial and antitrypanosomal agents. Bioorg Chem. 2019; Di L, Kerns EH. Drug-Like Properties: Concepts, Structure Design and Methods from ADME to Toxicity Optimization. Drug-Like Properties: Concepts, Structure Design and Methods from ADME to Toxicity Optimization. 2016. Olekhnovitch R, Bousso P. Induction, Propagation, and Activity of Host Nitric Oxide: Lessons from Leishmania Infection. Vol. 31, Trends in Parasitology. 2015. p. 653–64. Teixeira MJ, Teixeira CR, Andrade BB, Barral-Netto M, Barral A. Chemokines in host–parasiteinteractions in leishmaniasis. Trends Parasitol [Internet]. 2006 Jan [cited 2019 Oct 14];22(1):32–40. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16310413 Maspi N, Abdoli A, Ghaffarifar F. Pro- and anti-inflammatory cytokines in cutaneous leishmaniasis: a review. Pathogens and Global Health. 2016. 161. Brodskyn CI, DeKrey GK, Titus RG. Influence of costimulatory molecules on immune response to Leishmania major by human cells in vitro. Infect Immun. 2001; Park MC, Kim D, Lee Y, Kwon HJ. CD83 expression induced by CpG-DNA stimulation in a macrophage cell line RAW 264.7. BMB Rep. 2013; Shio MT, Hassani K, Isnard A, Ralph B, Contreras I, Gomez MA, et al. Host Cell Signalling and Leishmania Mechanisms of Evasion. J Trop Med [Internet]. 2012 [cited 2017 Dec 8];2012:1–14. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22131998 Kumar S, Bawa S, Gupta H. Biological Activities of Quinoline Derivatives. Mini-Reviews Med Chem. 2010; Yamamoto ES, Campos BLS, Jesus JA, Laurenti MD, Ribeiro SP, Kallás EG, et al. The effect of ursolic acid on leishmania (Leishmania) amazonensis is related to programed cell death and presents therapeutic potential in experimental cutaneous leishmaniasis. PLoS One. 2015; Baltina LA. Chemical modification of glycyrrhizic acid as a route to new bioactive compounds for medicine. Curr Med Chem [Internet]. 2003 Jan [cited 2017 Dec 8];10(2):155–71. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12570715 Ríos JL. Effects of triterpenes on the immune system. Journal of Ethnopharmacology. 2010. Marquez-Martin A, Puerta RD La, Fernandez-Arche A, Ruiz-Gutierrez V, Yaqoob P. Modulation of cytokine secretion by pentacyclic triterpenes from olive pomace oil in human mononuclear cells. Cytokine. 2006; Atri C, Guerfali FZ, Laouini D. Role of human macrophage polarization in inflammation during infectious diseases. International Journal of Molecular Sciences. 2018. Oh HM, Lee S, Park YN, Choi EJ, Choi JY, Kim JA, et al. Ammonium glycyrrhizinate protects gastric epithelial cells from hydrogen peroxide-induced cell death. Exp Biol Med. 2009; Schröfelbauer B, Raffetseder J, Hauner M, Wolkerstorfer A, Ernst W, Szolar OHJ. Glycyrrhizin, the main active compound in liquorice, attenuates pro-inflammatory responses by interfering with membrane-dependent receptor signalling. Biochem J. 2015; Jeong HG, Kim JY. Induction of inducible nitric oxide synthase expression by 18β-glycyrrhetinic acid in macrophages. FEBS Lett. 2002; Herrera G, Teherán A, Pradilla I, Vera M, Ramírez JD. Geospatial-temporal distribution of Tegumentary Leishmaniasis in Colombia (2007–2016). PLoS Negl Trop Dis. 2018; Guillon J, Forfar I, Mamani-Matsuda M, Desplat V, Saliège M, Thiolat D, et al. Synthesis, analytical behaviour and biological evaluation of new 4-substituted pyrrolo[1,2-a]quinoxalines as antileishmanial agents. Bioorganic Med Chem. 2007; Kesherwani V, Sodhi A. Differential activation of macrophages in vitro by lectin Concanavalin A, Phytohemagglutinin and Wheat germ agglutinin: Production and regulation of nitric oxide. Nitric Oxide [Internet]. 2007 Mar 1 [cited 2019 Oct 13];16(2):294–305. Available from: https://www.sciencedirect.com/science/article/pii/S1089860306004526?via%3Dihub Tur J, Vico T, Lloberas J, Zorzano A, Celada A. Macrophages and Mitochondria: A Critical Interplay Between Metabolism, Signaling, and the Functional Activity. In: Advances in Immunology. 2017. Titus RG, Dekrey GK, Morris R V., Soares MBP. Interleukin-6 deficiency influences cytokine expression in susceptible BALB mice infected with Leishmania major but does not alter the outcome of disease. Infect Immun. 2001; Gomes CM, Ávila LR, Pinto SA, Duarte FB, Pereira LIA, Abrahamsohn IA, et al. Leishmania braziliensis amastigotes stimulate production of IL-1β, IL-6, IL-10 and TGF-β by peripheral blood mononuclear cells from nonendemic area healthy residents. Parasite Immunol. 2014; Suarez ET, Granados-Falla DS, Robledo SM, Murillo J, Upegui Y, Delgado G. Antileishmanial activity of synthetic analogs of the naturally occurring quinolone alkaloid N-methyl-8-methoxyflindersin. PLoS One [Internet]. 2020 [cited 2020 Dec 28];15(12):e0243392. Available from: https://dx.plos.org/10.1371/journal.pone.0243392 Macedo-Silva ST de, Oliveira Silva TLA de, Urbina JA, Souza W de, Rodrigues JCF. Antiproliferative, Ultrastructural, and Physiological Effects of Amiodarone on Promastigote and Amastigote Forms of Leishmania amazonensis . Mol Biol Int. 2011; Saka HA, Valdivia R. Emerging Roles for Lipid Droplets in Immunity and Host-Pathogen Interactions. Annu Rev Cell Dev Biol. 2012; Walpole GFW, Grinstein S, Westman J. The role of lipids in host-pathogen interactions. IUBMB Life. 2018; Rabhi S, Rabhi I, Trentin B, Piquemal D, Regnault B, Goyard S, et al. Lipid droplet formation, their localization and dynamics during leishmania major macrophage infection. PLoS One. 2016; Remmerie A, Scott CL. Macrophages and lipid metabolism. Cell Immunol. 2018; DaMata JP, Mendes BP, Maciel-Lima K, Menezes CAS, Dutra WO, Sousa LP, et al. Distinct Macrophage Fates after in vitro Infection with Different Species of Leishmania: Induction of Apoptosis by Leishmania (Leishmania) amazonensis, but Not by Leishmania (Viannia) guyanensis. Afrin F, editor. PLoS One [Internet]. 2015 Oct 29 [cited 2019 Oct 14];10(10):e0141196. Available from: https://dx.plos.org/10.1371/journal.pone.0141196 LeFurgey A, Gannon M, Blum J, Ingram P. Leishmania donovani amastigotes mobilize organic and inorganic osmolytes during regulatory volume decrease. J Eukaryot Microbiol. 2005; Robertson GS, LaCasse EC, Holcik M. Programmed Cell Death. In: Pharmacology. 2009. Perrotta I, Carito V, Russo E, Tripepi S, Aquila S, Donato G. Macrophage autophagy and oxidative stress: an ultrastructural and immunoelectron microscopical study. Oxid Med Cell Longev [Internet]. 2011 Sep 13 [cited 2019 Oct 14];2011:282739. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21922037 Miranda K, Docampo R, Grillo O, Franzen A, Attias M, Vercesi A, et al. Dynamics of polymorphism of acidocalcisomes in Leishmania parasites. Histochem Cell Biol. 2004; Holzmuller P, Bras-Goncalves R, Lemesre J-L. Phenotypical characteristics, biochemical pathways, molecular targets and putative role of nitric oxide-mediated programmed cell death in Leishmania. Parasitology [Internet]. 2006 Mar 3 [cited 2019 Oct 14];132(S1):S19–32. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17018162 Harris J, Deen N, Zamani S, Hasnat MA. Mitophagy and the release of inflammatory cytokines. Mitochondrion [Internet]. 2017 Oct 26 [cited 2017 Dec 8]; Available from: http://www.ncbi.nlm.nih.gov/pubmed/29107116 Cyrino LT, Araújo AP, Joazeiro PP, Vicente CP, Giorgio S. In vivo and in vitro Leishmania amazonensis infection induces autophagy in macrophages. Tissue Cell. 2012; Real F, Mortara RA. The diverse and dynamic nature of leishmania parasitophorous vacuoles studied by multidimensional imaging. PLoS Negl Trop Dis. 2012; Castro R, Scott K, Jordan T, Evans B, Craig J, Peters EL, et al. THE ULTRASTRUCTURE OF THE PARASITOPHOROUS VACUOLE FORMED BY LEISHMANIA MAJOR. J Parasitol. 2007; Burchmore RJS, Barrett MP. Life in vacuoles - Nutrient acquisition by Leishmania amastigotes. International Journal for Parasitology. 2001. Real F, Mortara RA. The diverse and dynamic nature of leishmania parasitophorous vacuoles studied by multidimensional imaging. PLoS Negl Trop Dis. 2012 Feb;6(2). Borges VM, Lopes UG, De Souza W, Vannier-Santos MA. Cell structure and cytokinesis alterations in multidrug-resistant Leishmania (Leishmania) amazonensis. Parasitol Res. 2005; Britta EA, Scariot DB, Falzirolli H, Ueda-Nakamura T, Silva CC, Filho BPD, et al. Cell death and ultrastructural alterations in Leishmania amazonensis caused by new compound 4-Nitrobenzaldehyde thiosemicarbazone derived from S-limonene. BMC Microbiol. 2014; Daina A, Michielin O, Zoete V. SwissTargetPrediction: updated data and new features for efficient prediction of protein targets of small molecules. Nucleic Acids Res. 2019; Walker J, Vasquez JJ, Gomez MA, Drummelsmith J, Burchmore R, Girard I, et al. Identification of developmentally-regulated proteins in Leishmania panamensis by proteome profiling of promastigotes and axenic amastigotes. Mol Biochem Parasitol. 2006; Akpunarlieva S, Weidt S, Lamasudin D, Naula C, Henderson D, Barrett M, et al. Integration of proteomics and metabolomics to elucidate metabolic adaptation in Leishmania. J Proteomics [Internet]. 2017 Feb 23 [cited 2017 Dec 12];155:85–98. Available from: http://www.sciencedirect.com/science/article/pii/S1874391916305267?via%3Dihub Hajjaran H, Mohammadi Bazargani M, Mohebali M, Burchmore R, Salekdeh GH, Kazemi-Rad E, et al. Comparison of the proteome profiling of iranian isolates of leishmania tropica, l. Major and l. infantum by two-dimensional electrophoresis (2-DE) and mass-spectrometry. Iran J Parasitol. 2015; Wheeler RJ, Gluenz E, Gull K. The cell cycle of Leishmania: Morphogenetic events and their implications for parasite biology. Mol Microbiol. 2011; Pescher P, Blisnick T, Bastin P, Späth GF. Quantitative proteome profiling informs on phenotypic traits that adapt Leishmania donovani for axenic and intracellular proliferation. Cell Microbiol. 2011; Handman E, Bullen DVR. Interaction of Leishmania with the host macrophage. Trends in Parasitology. 2002. Coimbra ES, Antinarelli LMR, Silva NP, Souza IO, Meinel RS, Rocha MN, et al. Quinoline derivatives: Synthesis, leishmanicidal activity and involvement of mitochondrial oxidative stress as mechanism of action. Chem Biol Interact. 2016; Brobey RKB, Mei FC, Cheng X, Soong L. Comparative two-dimensional gel electrophoresis maps for promastigotes of Leishmania amazonensis and Leishmania major. Brazilian J Infect Dis. 2006;
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spelling	Atribución-NoComercial-SinDerivadas 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccesshttp://purl.org/coar/access_right/c_abf2Delgado Murcia, Lucy Gabriela5a5d74a7f279e35695f243a887783c55Torres Súarez, Francy Elaine7ee0339982524041b59aa3bf2082348dGrupo de Investigación en Inmunotoxicología2021-05-21T15:53:35Z2021-05-21T15:53:35Z2021-05https://repositorio.unal.edu.co/handle/unal/79547Universidad Nacional - Sede MedellínRepositorio Institucional Universidad Nacional de Colombiahttps://repositorio.unal.edu.co/La leishmaniasis es una enfermedad parasitaria antropozoonótica, causada por el protozoario del género Leishmania spp. y transmitida por el mosquito del genero Lutzomya. Dentro de las formas clínicas de la enfermedad, la cutánea, constituye la manifestación mas frecuente en el mundo, y corresponde a más del 90% de los casos resportados en Colombia y en el mundo. Una de las dificultades más evidentes en el control de esta enfermedad, ha sido el tratamiento, el cual además de haber reportado pérdida de eficacia, presenta efectos adversos, largos esquemas de tratamiento y formas de administración de baja adherencia por parte del paciente, que generan el abandono del mismo y la generación de cepas resistentes. Por esta razón, la búsqueda de alternativas terapéuticas de aplicación tópica constituye una necesidad de alta prioridad, para disminuir el problema de salud pública que conlleva esta enfermedad. De este modo, en estudios previos realizados en el Grupo de Investigación en Inmunotoxicologia se identificaron dos moléculas de origen vegetal con propiedades antileishmaniales, correspondientes a alcaloides quinolínicos (N-metil-8-metoxiflindersina) y triterpenoides de tipo limonoide (11α,19β-dihidroxi-7-acetoxi-7-deoxoichangina), con efecto directo frente al parásito y propiedades inmunoduladoras en células humanas infectadas por el parásito; sin embargo, el origen (a partir de material vegetal de Raputia heptaphylla) y las dificultades que conllevan la extracción y la purificación, conllevó al diseño de estrategias para encontrar moléculas con características estructurales afines, bajo el principio de propiedades similares (PPS). Entre los hallazgos mas relevantes obtenidos en este trabajo, se encuentran los resultados obtenidos con compuestos de origen sintético y análogos a las moléculas naturales, los cuales fueron seleccionados por medio de estrategias In silico: triterpenoides [ácido oleanólico (5), glicirrizato de amonio (7) y ácido 18B-glicirretínico (8)] y alcaloides quinolínicos [1,2,3,4-tetrahidro-(benzo)-3-qinolin-ol (13) y 2-amino-8-hidroxiquinolina (19)] los cuales presentaron actividad anti-leishmanial In vitro [sobre promastigotes (13 y 19) y amastigotes intracelulares de L. (V.) panamensis (5, 7, 8, 13 y 19)] e In vivo [promoviendo la cura clínica (entre un 20% (8), 33,3% (13) y 50% (19) los animales cicatrizan completamente la lesión) y mejoría clínica (100% (5), 80% (7), 60% (8), 66,6% (13) y 33.3% (19), reducción en al menos un 20% el tamaño de la lesión), de los animales tratados con los compuestos, administrados de forma tópica]. De acuerdo con los efectos de cada compuesto, se propusieron modelos de aproximación al modo de acción de cada molécula. Los triterpenoides 5 y 7 mostraron característica de pro-fármacos (actividad evidente sobre la foma amastigote en MdMhu infectados), pero con afectaciones diferenciales en el amastigote intracelular para el triterpenoide 5 [causa muerte de tipo necrosis (presencia de membranas hinchadas o alteradas, acidocalcisomas y daño nuclear)] y saponina 7 [(afinidad por la mitocondria de MdMhu y parásitos (causando en Leishmania spp. estrés celular, la parición de acidocalcisomas e hinchamiento de membranas celulares)]. El triterpenoide 8 indujo el incremento diferencial de NO, a través de la modulación de iNOS vía NF-kB en macrófagos infectados y modificaciones en los amastigotes (citoquinesis alterada y señales de apoptosis). Se resaltan los hallazgos de los compuestos alcaloides (13 y 19), los cuales fueron activos frente a los dos estadios del parásito (promastigotes y amastigotes). El alcaloide 13, actúa sobre reservas de lípidos y componentes de membrana [(reflejado en el aumento de cuerpos lipídicos y vacuolas parasitóforas comunales en MdMhu)], causando el estrés celular de los parásitos (presencia de acidocalcisomas y citoquinesis alterada) y la disminución de la carga parasitaria en estas células, induciendo el aumento temprano de ROS en MI, contribuyendo así con el control temprano del parásito. Mientras que el efecto del compuesto 19 está dirigido hacia la modulación de procesos de generación de energía y respiración oxidativa (producción de especies reactivas en promastigotes y despolarización de la mitocondria), los cuales conducen a los parásitos a la muerte de tipo apoptosis (hinchamiento de membranas celulares, presencia de acidocalcisomas y distribución anormal de cromatina) y que se asocian con la expresión diferencial de proteínas (spots) en amastigotes expuestos al alcaloide; mientras que en las células hospederas infectadas, se induce apoptosis, mostrando la selectividad del compuesto. Estos resultados permiten soportar nuestro modelo de búsqueda de compuestos, en donde a partir de moléculas de difícil obtención (origen vegetal), se pueden encontrar antileishmaniales promisorios. Se destaca, que para cada molécula antiparasitaria encontrada en este proyecto, se identificó un posible modo de acción en el modelo de células primarias, así como su efectividad terapéutica en un modelo In vivo; estos hallazgos contribuyen al entendimiento de la forma de actuación de este tipo de compuestos y abre el camino para la optimización y tratamiento de la leishmaniasis cutánea en el país.Leishmaniasis is an anthroponotic parasitic disease, caused by the protozoan of the genus Leishmania spp. and transmitted by the mosquito of the genus Lutzomya. This disease has been classified as a neglected pathology by the WHO because its presence is established in tropical and sub-tropical areas and mainly in developing countries. Within the clinical forms of the disease, the cutaneous form constitutes the most frequent manifestation in the world, which corresponds to more than 90% of the cases reported in Colombia and the world. One of the most obvious difficulties in the control of this disease has been treated, which is accompanied by adverse effects, long treatment schedules, and forms of administration that are not very friendly to the patient, which generate the abandonment of treatment and the generation of resistant strains. For this reason, the search for therapeutic alternatives for topical application constitutes an imperative need to mitigate the public health problem that this disease entails. Thus, in previous studies carried out by the Immunotoxicology research group, two molecules with antileishmanial properties were identified, corresponding to quinolinic alkaloids (N-methyl-8-methoxyflindersine) and limonoid-type triterpenoids (11α, 19βdihydroxy-7- acetoxy-7-deoxoichangin), with direct effect against the parasite and immunomodulatory properties in human cells infected by the parasite; however, the origin (from Raputia heptaphylla plant material) and the difficulties involved in extraction and purification, led to the design of strategies to find molecules with similar structural characteristics, under the principle of similar properties (PPS). Among the most relevant findings obtained in this work, are the results obtained with the five compounds of synthetic origin and analogous to natural molecules (previously evaluated by the research group), which were selected through the In silico strategies: Triterpenoid compounds [oleanolic acid (5), ammonium glycyrrhizate (7) and 18B-glycyrrhetinic acid (8)] and quinolinic alkaloids [1,2,3,4-tetrahydro- (benzo) -3-qinolin-ol (13) and 2-amino-8- hydroxyquinoline (19); which presented anti-leishmanial activity In vitro [on promastigotes (13 and 19) and intracellular amastigotes of L. (V.) panamensis (5, 7, 8, 13 and 19)] and In vivo [promoting clinical cure (between 20% (8), 33.3% (13) and 50% (19) the animals completely heal the lesion) and clinical improvement (100% (5), 80% (7), 60% (8), 66,6% (13) and 33.3% (19), reduction of lesion size by at least 20%), of the animals treated with the compounds, administered topically]. Each synthetic antileishmanial compound showed evident effects in the model used, giving rise to models of approximation to its mode of action. Triterpenoids 5 and 7 showed prodrug activity [(Activity in the amastigote form), in addition to causing necrosis-type death in the intracellular parasite (presence of swollen or altered membranes, acidocalcisomes, and nuclear damage) by the compound 5, while saponin 7 had an evident affinity for the mitochondria of MdMhu and parasites (causing cellular stress, the calving of acidocalcisomes and swelling of cell membranes in Leishmania spp.)]. Triterpenoid 8 (synthetic pentacyclic) revealed immunomodulatory properties by inducing the differential increase in NO, through modulation of iNOS via NF-kB in infected macrophages and evident alterations in amastigotes (altered cytokinesis and apoptosis signals), possibly as an effect of NO. The findings of the alkaloid compounds (13 and 19) are highlighted, which had evident activity against the two stages of the parasite (promastigotes and amastigotes). The alkaloid 13 acts on lipid reserves and membrane components [(reflected in the increase of lipid bodies and communal parasitophorous vacuoles in MdMhu)], causing cellular stress of the parasites (presence of acidocalcisomes and altered cytokinesis) and the decrease of the parasite load in these cells inducing the early increase of ROS in MI, contributing to the early control of the parasite. The effect of compound 19 evidenced in intracellular promastigotes and amastigotes is directed towards the modulation of processes of energy generation and oxidative respiration (production of reactive species in promastigotes and depolarization of the mitochondria), which lead parasites to death of the type apoptosis (swelling of cell membranes, presence of acidocalcisomes and abnormal chromatin distribution) and that are associated with the differential expression of proteins (spots) in amastigotes exposed to the alkaloid; while in host cells, the induction of early apoptosis was differentially evidenced in infected cells, showing the selectivity of the compound. These results allow us to support our compound search model, where promising antileishmanial can be found from difficult-to-obtain molecules (plant origin). It should be noted that for each antiparasitic molecule found in this project, a possible mode of action was identified in the primary cell model, as well as its therapeutic effectiveness in an In vivo model; These findings contribute to the understanding of how this type of compound works and opens the way for the optimization and treatment of cutaneous leishmaniasis in the country.Ministerio de ciencia, tecnología e innovación de Colombia (Minciencias)DoctoradoDoctora en BiotecnologíaDesarrollo de alternativas terapéuticas frente a enfermedades tropicales210 páginasapplication/pdfspaUniversidad Nacional de Colombia - Sede MedellínMedellín - Ciencias - Doctorado en BiotecnologíaEscuela de biocienciasFacultad de CienciasMedellínUniversidad Nacional de Colombia - Sede Medellín610 - Medicina y salud540 - Química y ciencias afines::547 - Química orgánicaAlcaloidesTriterpenosEnfermedades de la pielInfeccionesLeishmaniasisMecanismo de acciónTratamientoAlcaloides quinolínicosTriterpenoidesLeishmaniasisTreatmentQuinoline alkaloidsTriterpenoidsAction mechanismCompuestos tipo alcaloides quinolínicos y limonoides (triterpenos) sintéticos con potencial anti-leishmania: una aproximación al mecanismo de acciónSynthetic quinoline alkaloid and limonoid (triterpene) -type compounds with anti-leishmania potential: an approach to the mechanism of actionTrabajo de grado - Doctoradoinfo:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/acceptedVersionhttp://purl.org/coar/resource_type/c_db06TextWHO. Number of cases of cutaneous leishmaniasis reported Data by country. Global Health Observatory data repository. 2019.PAHO. Leishmaniasis: Epidemiological Report of the Americass No 7 - Março, 2019. Informe de Leishmanioses No 7. 2019.Valderrama L, McMahon-Pratt D, Navas C, Saravia NG, Segura I, Valencia AZ, et al. Heterogeneity, geographic distribution, and pathogenicity of serodemes of Leishmania viannia in Colombia. Am J Trop Med Hyg. 2017;Herrera G, Barragán N, Luna N, Martínez D, De Martino F, Medina J, et al. An interactive database of Leishmania species distribution in the Americas. Sci Data. 2020 Dec 1;7(1).Instituto Nacional de Salud. Lineamientos para la atención clínica de Leishmaniasis en Colombia. Bogotá; 2018.Singh N, Mishra BB, Bajpai S, Singh RK, Tiwari VK. Natural product based leads to fight against leishmaniasis. Bioorg. Med. Chem. 2014.Torres-Guerrero E, Quintanilla-Cedillo MR, Ruiz-Esmenjaud J, Arenas R. Leishmaniasis: a review. F1000Research. 2017;Croft SL, Olliaro P. Leishmaniasis chemotherapy-challenges and opportunities. Clinical Microbiology and Infection. 2011.Garnier T, Croft SL. Topical treatment for cutaneous leishmaniasis. Current Opinion in Investigational Drugs. 2002.Ghorbani M, Farhoudi R. Leishmaniasis in humans: Drug or vaccine therapy? Drug Des. Devel. Ther. 2018.Le Pape P. Development of new antileishmanial drugs--current knowledge and future prospects. J Enzyme Inhib Med Chem. 2008;23(October):708–18.Chrzanowska M, Grajewska A, Rozwadowska MD. Asymmetric Synthesis of Isoquinoline Alkaloids: 2004–2015. Chem Rev [Internet]. 2016 Oct 12 [cited 2017 Dec 10];116(19):12369–465. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27680197Granados-Falla D, Gomez-Galindo A, Daza A, Robledo S, Coy-Barrera C, Cuca L, et al. Seco-limonoid derived from Raputia heptaphylla promotes the control of cutaneous leishmaniasis in hamsters (Mesocricetus auratus). Parasitology. 2016;Coy Barrera CA, Coy Barrera ED, Granados Falla DS, Delgado Murcia G, Cuca Suarez LE. seco-limonoids and quinoline alkaloids from Raputia heptaphylla and their antileishmanial activity. Chem Pharm Bull (Tokyo) [Internet]. 2011 [cited 2017 Dec 8];59(7):855–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21720036Granados Falla DS. Determinación de la actividad leishmanicida e inmunomoduladora de compuestos naturales derivados de Raputia heptaphylla (Familia Rutaceae) como posible alternativa terapeutica frente a la leishmaniosis cutánea. Ph. D. Thesis [Internet]. Universidad Nacional de Colombia; 2013. Available from: http://www.bdigital.unal.edu.co/11036/Silva GL, Lee I-S, Kinghorn AD. Special Problems with the Extraction of Plants. In 1998.Tiuman TS, Santos AO, Ueda-Nakamura T, Filho BPD, Nakamura C V. Recent advances in leishmaniasis treatment. International Journal of Infectious Diseases. 2011.Loedige M. Design and Synthesis of Novel Antileishmanial Compounds. Int J Med Chem. 2015;Zulfiqar B, Shelper TB, Avery VM. Leishmaniasis drug discovery: recent progress and challenges in assay development. Vol. 22, Drug Discovery Today. Elsevier Ltd; 2017. p. 1516–31.Sereno D, Cordeiro da Silva A, Mathieu-Daude F, Ouaissi A. Advances and perspectives in Leishmania cell based drug-screening procedures. Parasitology International. 2007.Monge-Maillo B, López-Vélez R. Therapeutic options for old world cutaneous leishmaniasis and new world cutaneous and mucocutaneous leishmaniasis. Drugs. 2013.Chatelain E, Ioset JR. Drug discovery and development for neglected diseases: The DNDi model. Drug Design, Development and Therapy. 2011.Maggiora G, Vogt M, Stumpfe D, Bajorath J. Molecular Similarity in Medicinal Chemistry. J Med Chem [Internet]. 2014 Apr 24 [cited 2017 Dec 8];57(8):3186–204. Available from: http://pubs.acs.org/doi/10.1021/jm401411zDe Almeida MC, Vilhena V, Barral A, Barral-Netto M. Leishmanial Infection: Analysis of its First Steps. A Review. Vol. 98, Mem . Inst. Oswaldo Cruz. 2003. p. 861–70.Palatnik-De-Sousa CB, Day MJ. One Health: The global challenge of epidemic and endemic leishmaniasis. Parasites and Vectors. 2011.Alvar J, Vélez ID, Bern C, Herrero M, Desjeux P, Cano J, et al. Leishmaniasis worldwide and global estimates of its incidence. Vol. 7, PLoS ONE. 2012.Desjeux P. Focus: Leishmaniasis. Nat Rev Microbiol. 2004;Nylén S, Eidsmo L. Tissue damage and immunity in cutaneous leishmaniasis. Parasite Immunology. 2012.Reveiz L, Maia-Elkhoury ANS, Nicholls RS, Sierra Romero GA, Yadon ZE. Interventions for American Cutaneous and Mucocutaneous Leishmaniasis: A Systematic Review Update. PLoS One. 2013;Scotti MT, Scotti L, Ishiki H, Ribeiro FF, Cruz RMD da, Oliveira MP de, et al. Natural Products as a Source for Antileishmanial and Antitrypanosomal Agents. Comb Chem High Throughput Screen [Internet]. 2016 [cited 2017 Dec 10];19(7):537–53. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27682867Vannier-Santos M, Martiny A, Souza W. Cell Biology of Leishmania spp.: Invading and Evading. Curr Pharm Des. 2005;Burza S, Croft SL, Boelaert M. Leishmaniasis. The Lancet. 2018.Epidemiological situation W. WHO \| Epidemiological situation. WHO. 2017.Karimkhani C, Wanga V, Coffeng LE, Naghavi P, Dellavalle RP, Naghavi M. Global burden of cutaneous leishmaniasis: A cross-sectional analysis from the Global Burden of Disease Study 2013. Lancet Infect Dis. 2016;Pan American Health Organization. Leishmaniasis: Epidemiological Report in the Americas. Washington, DC PAHO. 2019;WHO. WHO: Weekly epidemiological record: Global leishmaniasis update, 2006-2015, a turning point in leishmaniasis surveillance. World Heal Organ. 2017;Salgado-Almario J, Hernández CA, Ovalle-Bracho C. Geographical distribution of Leishmania species in Colombia, 1985-2017. Biomedica. 2019;Ramírez JD, Hernández C, León CM, Ayala MS, Flórez C, González C. Taxonomy, diversity, temporal and geographical distribution of Cutaneous Leishmaniasis in Colombia: A retrospective study. Sci Rep. 2016;Zarean M, Maraghi S, Hajjaran H, Mohebali M, Feiz-Hadad MH, Assarehzadegan MA. Comparison of proteome profiling of two sensitive and resistant field iranian isolates of leishmania major to glucantime® by 2-dimensional electrophoresis. Iran J Parasitol. 2015;Ponte-Sucre A, Gamarro F, Dujardin JC, Barrett MP, López-Vélez R, García-Hernández R, et al. Drug resistance and treatment failure in leishmaniasis: A 21st century challenge. PLoS Negl Trop Dis. 2017.Baiocco P, Colotti G, Franceschini S, Ilari A. Molecular basis of antimony treatment in Leishmaniasis. J Med Chem. 2009;De Menezes JP, Saraiva EM, Da Rocha-Azevedo B. The site of the bite: Leishmania interaction with macrophages, neutrophils and the extracellular matrix in the dermis. Vol. 9, Parasites and Vectors. BioMed Central Ltd.; 2016.Podinovskaia M, Descoteaux A. Leishmania and the macrophage: A multifaceted interaction. Future Microbiol. 2015.Novais FO, Scott P. Immunology of Leishmaniasis. In: Encyclopedia of Immunobiology. 2016.Liese J, Schleicher U, Bogdan C. The innate immune response against Leishmania parasites. Immunobiology. 2008;Fidalgo LM, Gille L. Mitochondria and trypanosomatids: Targets and drugs. Pharmaceutical Research. 2011.Wheeler RJ, Gluenz E, Gull K. The cell cycle of Leishmania: Morphogenetic events and their implications for parasite biology. Mol Microbiol. 2011;Ivens AC, Peacock CS, Worthey EA, Murphy L, Aggarwal G, Berriman M, et al. The genome of the kinetoplastid parasite, Leishmania major. Science (80- ). 2005;Mougneau E, Bihl F, Glaichenhaus N. Cell biology and immunology of Leishmania. Immunol. Rev. 2011.Kima PE. The amastigote forms of Leishmania are experts at exploiting host cell processes to establish infection and persist. International Journal for Parasitology. 2007.Aulner N, Danckaert A, Rouault-Hardoin E, Desrivot J, Helynck O, Commere PH, et al. High Content Analysis of Primary Macrophages Hosting Proliferating Leishmania Amastigotes: Application to Anti-leishmanial Drug Discovery. PLoS Negl Trop Dis. 2013;Torres, Henry Jay Forman M, Torres M. Signaling by the Respiratory Burst in Macrophages. IUBMB Life [Internet]. 2001 Jun 1 [cited 2018 May 10];51(6):365–71. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11758804Van Assche T, Deschacht M, Da Luz RAI, Maes L, Cos P. Leishmania-macrophage interactions: Insights into the redox biology. Free Radic. Biol. Med. 2011.Christine Hsiao CH, Ueno N, Shao JQ, Schroeder KR, Moore KC, Donelson JE, et al. The effects of macrophage source on the mechanism of phagocytosis and intracellular survival of Leishmania. Microbes Infect. 2011;Séguin O, Descoteaux A. Leishmania, the phagosome, and host responses: The journey of a parasite. Cell Immunol. 2016;Cecílio P, Pérez-Cabezas B, Santarém N, Maciel J, Rodrigues V, da Silva AC. Deception and manipulation: The arms of Leishmania, a successful parasite. Front. Immunol. 2014.Naderer T, Vince JE, McConville MJ. Surface determinants of Leishmania parasites and their role in infectivity in the mammalian host. Curr Mol Med. 2004;De Oliveira CI, Brodskyn CI. The immunobiology of Leishmania braziliensis infection. Frontiers in Immunology. 2012.Ameen M. Cutaneous leishmaniasis: Advances in disease pathogenesis, diagnostics and therapeutics. Clinical and Experimental Dermatology. 2010.Bosque F, Saravia NG, Valderrama L, Milon G. Distinct innate and acquired immune responses to Leishmania in putative susceptible and resistant human populations endemically exposed to L. (Viannia) panamensis infection. Scand J Immunol. 2000;Oliveira WN, Ribeiro LE, Schrieffer A, Machado P, Carvalho EM, Bacellar O. The role of inflammatory and anti-inflammatory cytokines in the pathogenesis of human tegumentary leishmaniasis. Cytokine. 2014;Andrews KT, Fisher G, Skinner-Adams TS. Drug repurposing and human parasitic protozoan diseases. Int. J. Par: Drugs and Drug Resistance. 2014.Oliveira LF, Schubach AO, Martins MM, Passos SL, Oliveira R V., Marzochi MC, et al. Systematic review of the adverse effects of cutaneous leishmaniasis treatment in the New World. Acta Tropica. 2011.Balasegaram M, Ritmeijer K, Lima MA, Burza S, Ortiz Genovese G, Milani B, et al. Liposomal amphotericin B as a treatment for human leishmaniasis. Expert Opin Emerg Drugs. 2012;Sundar S, Chakravarty J. Leishmaniasis: an update of current pharmacotherapy. Expert Opin Pharmacother. 2012;Barrett MP, Croft SL. Management of trypanosomiasis and leishmaniasis. British Medical Bulletin. 2012.Navas A, Vargas DA, Freudzon M, McMahon-Pratt D, Saravia NG, Gómez MA. Chronicity of dermal leishmaniasis caused by Leishmania panamensis is associated with parasite-mediated induction of chemokine gene expression. Infect Immun. 2014;Nassif PW, De Mello TFP, Navasconi TR, Mota CA, Demarchi IG, Aristides SMA, et al. Safety and efficacy of current alternatives in the topical treatment of cutaneous leishmaniasis: A systematic review. Parasitology. 2017.Aguiar MG, Pereira AMM, Fernandes AP, Ferreira LAM. Reductions in skin and systemic parasite burdens as a combined effect of topical paromomycin and oral miltefosine treatment of mice experimentally infected with Leishmania (Leishmania) amazonensis. Antimicrob Agents Chemother. 2010;Seeberger J, Daoud S, Pammer J. Transient effect of topical treatment of cutaneous leishmaniasis with imiquimod. In: International Journal of Dermatology. 2003.Mitra A, Wu Y. Topical delivery for the treatment of psoriasis. Expert Opinion on Drug Delivery. 2010.Manderson L. Neglected Diseases of Poverty. Medical Anthropology: Cross Cultural Studies in Health and Illness. 2012;Ogungbe IV, Setzer WN. The Potential of secondary metabolites from plants as drugs or leads against protozoan neglected diseases-Part III: In-Silico molecular docking investigations. Vol. 21, Molecules. 2016.Alqahtani A, Hamid K, Kam A, Wong KH, Abdelhak Z, Razmovski-Naumovski V, et al. The Pentacyclic Triterpenoids in Herbal Medicines and Their Pharmacological Activities in Diabetes and Diabetic Complications. Curr Med Chem. 2013;Begum S, Ayub A, Qamar Zehra S, Shaheen Siddiqui B, Iqbal Choudhary M, Samreen. Leishmanicidal triterpenes from Lantana camara. Chem Biodivers. 2014;Quinn RJ, Carroll AR, Pham NB, Baron P, Palframan ME, Suraweera L, et al. Developing a drug-like natural product library. J Nat Prod. 2008;Mishra BB, Singh RK, Srivastava A, Tripathi VJ, Tiwari VK. Fighting against Leishmaniasis: search of alkaloids as future true potential anti-Leishmanial agents. Mini Rev Med Chem [Internet]. 2009 Jan [cited 2017 Dec 10];9(1):107–23. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19149664Rohloff J, Hymete A, Tariku Y. Plant-derived natural products for the treatment of leishmaniasis. In: Studies in Natural Products Chemistry. 2013.T.J. Schmidt, S.A. Khalid, A.J. Romanha, T.MA. Alves, M.W. Biavatti, R. Brun, et al. The Potential of Secondary Metabolites from Plants as Drugs or Leads Against Protozoan Neglected Diseases - Part I. Curr Med Chem [Internet]. 2012;19(14):2128–75. Available from: http://www.eurekaselect.com/openurl/content.php?genre=article&issn=0929-8673&volume=19&issue=14&spage=2128Xu R, Fazio GC, Matsuda SPT. On the origins of triterpenoid skeletal diversity. Phytochemistry. 2004. 81. Kuttan G, Pratheeshkumar P, Manu KA, Kuttan R. Inhibition of tumor progression by naturally occurring terpenoids. Pharm Biol [Internet]. 2011 Oct 21 [cited 2017 Dec 8];49(10):995–1007. Available from: http://www.tandfonline.com/doi/full/10.3109/13880209.2011.559476Roy A, Saraf S. Limonoids: overview of significant bioactive triterpenes distributed in plants kingdom. Biol Pharm Bull [Internet]. 2006 Feb [cited 2017 Dec 8];29(2):191–201. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16462017Steverding D, Sidjui LS, Ferreira ÉR, Ngameni B, Folefoc GN, Mahiou-Leddet V, et al. Trypanocidal and leishmanicidal activity of six limonoids. Journal of Natural Medicines. 2020.Yamamoto ES, Campos BLS, Jesus JA, Laurenti MD, Ribeiro SP, Kallás EG, et al. The effect of ursolic acid on leishmania (Leishmania) amazonensis is related to programed cell death and presents therapeutic potential in experimental cutaneous leishmaniasis. PLoS One. 2015;10(12).Coy C, Coy E, Granados D, Delgado G, Cuca L. Seco-limonoids and quinoline alkaloids from Raputia heptaphylla and their antileishmanial activity. Chem Pharm Bull (Tokyo). 2011;Oliveira I dos S da S, Moragas Tellis CJ, Chagas M do S dos S, Behrens MD, Calabrese K da S, Abreu-Silva AL, et al. Carapa guianensis Aublet (Andiroba) Seed Oil: Chemical Composition and Antileishmanial Activity of Limonoid-Rich Fractions . Biomed Res Int. 2018;Gupta P, Ukil A, Das PK. Bioactive Component of Licorice as an Antileishmanial Agent. In: Biological Activities and Action Mechanisms of Licorice Ingredients. 2017.Dinesh N, Neelagiri S, Kumar V, Singh S. Glycyrrhizic acid attenuates growth of Leishmania donovani by depleting ergosterol levels. Exp Parasitol. 2017;176:21–9.Melo TS, Gattass CR, Soares DC, Cunha MR, Ferreira C, Tavares MT, et al. Oleanolic acid (OA) as an antileishmanial agent: Biological evaluation and in silico mechanistic insights. Parasitol Int. 2016;65(3):227–37.Torres-Santos EC, Lopes D, Rodrigues Oliveira R, Carauta JPP, Bandeira Falcao CA, Kaplan MAC, et al. Antileishmanial activity of isolated triterpenoids from Pourouma guianensis. Phytomedicine. 2004;Alakurtti S, Bergström P, Sacerdoti-Sierra N, Jaffe CL, Yli-Kauhaluoma J. Anti-leishmanial activity of betulin derivatives. J Antibiot (Tokyo). 2010;Das A, Jawed JJ, Das MC, Sandhu P, De UC, Dinda B, et al. Antileishmanial and immunomodulatory activities of lupeol, a triterpene compound isolated from Sterculia villosa. Int J Antimicrob Agents. 2017;Sousa MC, Varandas R, Santos RC, Santos-Rosa M, Alves V, Salvador JAR. Antileishmanial activity of semisynthetic lupane triterpenoids betulin and betulinic acid derivatives: Synergistic effects with miltefosine. PLoS One. 2014;Dinesh N, Neelagiri S, Kumar V, Singh S. Glycyrrhizic acid attenuates growth of Leishmania donovani by depleting ergosterol levels. Exp Parasitol. 2017;Ukil A, Biswas A, Das T, Das PK. 18 -Glycyrrhetinic Acid Triggers Curative Th1 Response and Nitric Oxide Up-Regulation in Experimental Visceral Leishmaniasis Associated with the Activation of NF- B. J Immunol. 2014;Gupta P, Das PK, Ukil A. Antileishmanial effect of 18β-glycyrrhetinic acid is mediated by toll-like receptor-dependent canonical and noncanonical p38 activation. Antimicrob Agents Chemother. 2015;Aniszewski T. Alkaloid chemistry. In: Alkaloids. 2015.Calla-Magariños J, Quispe T, Giménez A, Freysdottir J, Troye-Blomberg M, Fernández C. Quinolinic Alkaloids from G alipea longiflora Krause Suppress Production of Proinflammatory Cytokines in vitro and Control Inflammation in vivo upon Leishmania Infection in Mice. Scand J Immunol [Internet]. 2013 Jan [cited 2017 Dec 10];77(1):30–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23126625Ferreira ME, Rojas de Arias A, Yaluff G, de Bilbao NV, Nakayama H, Torres S, et al. Antileishmanial activity of furoquinolines and coumarins from Helietta apiculata. Phytomedicine. 2010;17(5):375–8.Nakayama H, Desrivot J, Bories C, Franck X, Figadère B, Hocquemiller R, et al. In vitro and in vivo antileishmanial efficacy of a new nitrilquinoline against Leishmania donovani. Biomed Pharmacother. 2007;Paloque L, Verhaeghe P, Casanova M, Castera-Ducros C, Dumètre A, Mbatchi L, et al. Discovery of a new antileishmanial hit in 8-nitroquinoline series. Eur J Med Chem. 2012;Sasidharan S, Chen Y, Saravanan D, Sundram KM, Yoga Latha L. Extraction, isolation and characterization of bioactive compounds from plants’ extracts. African J Tradit Complement Altern Med. 2011;Coimbra ES, Antinarelli LMR, Silva NP, Souza IO, Meinel RS, Rocha MN, et al. Quinoline derivatives: Synthesis, leishmanicidal activity and involvement of mitochondrial oxidative stress as mechanism of action. Chem Biol Interact. 2016;Tempone AG, Melo Pompeu Da Silva AC, Brandt CA, Scalzaretto Martinez F, Borborema SET, Barata Da Silveira MA, et al. Synthesis and antileishmanial activities of novel 3-substituted quinolines. Antimicrob Agents Chemother. 2005;Calixto SL, Glanzmann N, Xavier Silveira MM, da Trindade Granato J, Gorza Scopel KK, Torres de Aguiar T, et al. Novel organic salts based on quinoline derivatives: The in vitro activity trigger apoptosis inhibiting autophagy in Leishmania spp. Chem Biol Interact. 2018 Sep 25;293:141–51.Fournet A, Barrios AA, Munoz V, Hocquemiller R, Cave A, Bruneton J. 2-Substituted quinoline alkaloids as potential antileishmanial drugs. Antimicrob Agents Chemother. 1993;Fournet A, Gantier JC, Gautheret A, Leysalles L, Munos MH, Mayrargue J, et al. The activity of 2-substituted quinoline alkaloids in BALB/c mice infected with leishmania donovani. J Antimicrob Chemother. 1994;Gopinath VS, Pinjari J, Dere RT, Verma A, Vishwakarma P, Shivahare R, et al. Design, synthesis and biological evaluation of 2-substituted quinolines as potential antileishmanial agents. Eur J Med Chem. 2013;de Mello TFP, Bitencourt HR, Pedroso RB, Aristides SMA, Lonardoni MVC, Silveira TGV. Leishmanicidal activity of synthetic chalcones in Leishmania (Viannia) braziliensis. Exp Parasitol. 2014;Coimbra ES, Libong D, Cojean S, Saint-Pierre-Chazalet M, Solgadi A, Le Moyec L, et al. Mechanism of interaction of sitamaquine with Leishmania donovani. J Antimicrob Chemother. 2010;Singh N, Kumar M, Singh RK. Leishmaniasis: Current status of available drugs and new potential drug targets. Asian Pac J Trop Med. 2012;5(6):485–97.Bhattacharjee S, Bhattacharjee A, Majumder S, Majumdar SB, Majumdar S. Glycyrrhizic acid suppresses cox-2-mediated anti-inflammatory responses during Leishmania donovani infection. J Antimicrob Chemother. 2012;Biswas A, Bhattacharya A, Vij A, Das PK. Role of leishmanial acidocalcisomal pyrophosphatase in the cAMP homeostasis in phagolysosome conditions required for intra-macrophage survival. Int J Biochem Cell Biol. 2017;Zhang C, Liu Z, Zheng Y, Geng Y, Han C, Shi Y, et al. Glycyrrhetinic Acid Functionalized Graphene Oxide for Mitochondria Targeting and Cancer Treatment In Vivo. Small [Internet]. 2017 Dec 4 [cited 2017 Dec 8];1703306. Available from: http://www.ncbi.nlm.nih.gov/pubmed/29205852Haghshenas V, Fakhari S, Mirzaie S, Rahmani M, Farhadifar F, Pirzadeh S, et al. Glycyrrhetinic Acid inhibits cell growth and induces apoptosis in ovarian cancer a2780 cells. Adv Pharm Bull [Internet]. 2014 Oct [cited 2018 Sep 12];4(Suppl 1):437–41. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25364659Dueñas-Romero AM, Loiseau PM, Saint-Pierre-Chazalet M. Interaction of sitamaquine with membrane lipids of Leishmania donovani promastigotes. Biochim Biophys Acta - Biomembr. 2007;Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Advanced Drug Delivery Reviews. 2012.Walters WP, Murcko A, Murcko MA. Recognizing molecules with drug-like properties. Curr Opin Chem Biol. 1999;World Health Organization (WHO). Control de la leishmaniasis. Ser Inf técnicos. 2010;Matsson P, Kihlberg J. How Big Is Too Big for Cell Permeability? Journal of Medicinal Chemistry. 2017;Vraka C, Mijailovic S, Fröhlich V, Zeilinger M, Klebermass EM, Wadsak W, et al. Expanding LogP: Present possibilities. Nucl Med Biol. 2018;Nikaido H. Preventing drug access to targets: Cell surface permeability barriers and active efflux in bacteria. Semin Cell Dev Biol. 2001;Caridha D, Vesely B, van Bocxlaer K, Arana B, Mowbray CE, Rafati S, et al. Route map for the discovery and pre-clinical development of new drugs and treatments for cutaneous leishmaniasis. International Journal for Parasitology: Drugs and Drug Resistance. 2019.Franc I, Lipinski A, Feeney PJ. Lipinski Rule, AdvDrugDelivRev 1997. Adv Drug Deliv Rev. 1997;Bajusz D, Rácz A, Héberger K. Why is Tanimoto index an appropriate choice for fingerprint-based similarity calculations? J Cheminform [Internet]. 2015 Dec 20 [cited 2017 Dec 8];7(1):20. Available from: http://www.jcheminf.com/content/7/1/20Kogej T, Engkvist O, Blomberg N, Muresan S. Multifingerprint based similarity searches for targeted class compound selection. J Chem Inf Model. 2006;Coy Barrera CA, Coy Barrera ED, Granados Falla DS, Delgado Murcia G, Cuca Suarez LE. seco-Limonoids and Quinoline Alkaloids from Raputia heptaphylla and Their Antileishmanial Activity. Chem Pharm Bull (Tokyo). 2011;Holliday. Grouping of Coefficients for the Calculation of Inter-Molecular Similarity and Dissimilarity using 2D Fragment Bit-Strings. Comb Chem High Throughput Screen. 2002;Bajusz D, Rácz A, Héberger K. Why is Tanimoto index an appropriate choice for fingerprint-based similarity calculations? J Cheminform. 2015;Bender A, Jenkins JL, Scheiber J, Sukuru SCK, Glick M, Davies JW. How similar are similarity searching methods? A principal component analysis of molecular descriptor space. J Chem Inf Model. 2009;Martin YC, Kofron JL, Traphagen LM. Do structurally similar molecules have similar biological activity? J Med Chem. 2002;Eckert H, Bajorath J. Molecular similarity analysis in virtual screening: foundations, limitations and novel approaches. Drug Discovery Today. 2007.Kerns EH, Di L. Drug-like Properties: Concepts, Structure Design and Methods. Drug-like Properties: Concepts, Structure Design and Methods. 2008.Liu X, Testa B, Fahr A. Lipophilicity and its relationship with passive drug permeation. Pharmaceutical Research. 2011.Raney SG, Franz TJ, Lehman PA, Lionberger R, Chen ML. Pharmacokinetics-Based Approaches for Bioequivalence Evaluation of Topical Dermatological Drug Products. Clinical Pharmacokinetics. 2015.Guo Y, Shen H. pKa, Solubility, and Lipophilicity. In: Opt in Drug Dis. 2009.Lipinski CA. Drug-like properties and the causes of poor solubility and poor permeability. J Pharmacol Toxicol Methods. 2000;Carvajal MT, Yalkowsky S. Effect of pH and Ionic Strength on the Solubility of Quinoline: Back-to-Basics. AAPS PharmSciTech [Internet]. 2019 Apr 25;20(3):124. Available from: http://link.springer.com/10.1208/s12249-019-1336-9Ačimovič J, Rozman D. Steroidal triterpenes of cholesterol synthesis. Molecules. 2013.Böttger S, Melzig MF. The influence of saponins on cell membrane cholesterol. Bioorganic Med Chem. 2013;Sahu T, Patel T, Sahu S, Gidwani B. Skin Cream as Topical Drug Delivery System: A Review. J Pharm Biol Sci. 2016;Pulido SA, Muñoz DL, Restrepo AM, Mesa C V., Alzate JF, Vélez ID, et al. Improvement of the green fluorescent protein reporter system in Leishmania spp. for the in vitro and in vivo screening of antileishmanial drugs. Acta Trop. 2012;Pérez-Flórez M, Ocampo CB, Valderrama-Ardila C, Alexander N. Spatial modeling of cutaneous leishmaniasis in the Andean region of Colombia. Mem Inst Oswaldo Cruz. 2016;Robledo SM, Carrillo LM, Daza A, Restrepo AM, Muñoz DL, Tobón J, et al. Cutaneous Leishmaniasis in the dorsal skin of hamsters: A useful model for the screening of antileishmanial drugs. J Vis Exp. 2012;García E, Coa JC, Otero E, Carda M, Vélez ID, Robledo SM, et al. Synthesis and antiprotozoal activity of furanchalcone–quinoline, furanchalcone–chromone and furanchalcone–imidazole hybrids. Med Chem Res. 2018;Osorio EJ, Robledo SM, Bastida J. Chapter 2 Alkaloids with Antiprotozoal Activity. Alkaloids: Chemistry and Biology. 2008.Meza C, Muñoz DL, Echeverry MCM, Vélez ID, Robledo SM, Mesa C V, et al. Susceptibilidad in vitro a infección por difiere según tipo de macrófagos. Salud UIS. 2010;Mears ER, Modabber F, Don R, Johnson GE. A Review: The Current In Vivo Models for the Discovery and Utility of New Anti-leishmanial Drugs Targeting Cutaneous Leishmaniasis. Vol. 9, PLoS Neglected Tropical Diseases. Public Library of Science; 2015.Corpas-López V, Merino-Espinosa G, López-Viota M, Gijón-Robles P, Morillas-Mancilla MJ, López-Viota J, et al. Topical Treatment of Leishmania tropica Infection Using (-)-α-Bisabolol Ointment in a Hamster Model: Effectiveness and Safety Assessment. J Nat Prod. 2016;Gomes-Silva A, Valverde JG, Ribeiro-Romão RP, Plácido-Pereira RM, Da-Cruz AM. Golden hamster (Mesocricetus auratus) as an experimental model for Leishmania (Viannia) braziliensis infection. Parasitology. 2013;Zurada JM, Kriegel D, Davis IC. Topical treatments for hypertrophic scars. J Am Acad Dermatol. 2006;Herrera G, Barragán N, Luna N, Martínez D, De Martino F, Medina J, et al. An interactive database of Leishmania species distribution in the Americas. Sci Data. 2020;Ministerio de la protección Social. Guía para la atención clínica integral del paciente con leishmaniasis. Colombia; 2010 p. 58.Ukil A, Kar S, Srivastav S, Ghosh K, Das PK. Curative effect of 18β-glycyrrhetinic acid in experimental visceral leishmaniasis depends on phosphatase-dependent modulation of cellular MAP kinases. PLoS One. 2011;da Silva EC, Dias Rayol C, Lys Medeiros P, Figueiredo RCBQ, Piuvezan MR, Brabosa-Filho JM, et al. Antileishmanial Activity of Warifteine: A Bisbenzylisoquinoline Alkaloid Isolated from Cissampelos sympodialis Eichl. (Menispermaceae). Sci World J [Internet]. 2012;2012:1–5. Available from: http://www.hindawi.com/journals/tswj/2012/516408/Chanquia SN, Larregui F, Puente V, Labriola C, Lombardo E, García Liñares G. Synthesis and biological evaluation of new quinoline derivatives as antileishmanial and antitrypanosomal agents. Bioorg Chem. 2019;Di L, Kerns EH. Drug-Like Properties: Concepts, Structure Design and Methods from ADME to Toxicity Optimization. Drug-Like Properties: Concepts, Structure Design and Methods from ADME to Toxicity Optimization. 2016.Olekhnovitch R, Bousso P. Induction, Propagation, and Activity of Host Nitric Oxide: Lessons from Leishmania Infection. Vol. 31, Trends in Parasitology. 2015. p. 653–64.Teixeira MJ, Teixeira CR, Andrade BB, Barral-Netto M, Barral A. Chemokines in host–parasiteinteractions in leishmaniasis. Trends Parasitol [Internet]. 2006 Jan [cited 2019 Oct 14];22(1):32–40. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16310413Maspi N, Abdoli A, Ghaffarifar F. Pro- and anti-inflammatory cytokines in cutaneous leishmaniasis: a review. Pathogens and Global Health. 2016. 161. Brodskyn CI, DeKrey GK, Titus RG. Influence of costimulatory molecules on immune response to Leishmania major by human cells in vitro. Infect Immun. 2001;Park MC, Kim D, Lee Y, Kwon HJ. CD83 expression induced by CpG-DNA stimulation in a macrophage cell line RAW 264.7. BMB Rep. 2013;Shio MT, Hassani K, Isnard A, Ralph B, Contreras I, Gomez MA, et al. Host Cell Signalling and Leishmania Mechanisms of Evasion. J Trop Med [Internet]. 2012 [cited 2017 Dec 8];2012:1–14. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22131998Kumar S, Bawa S, Gupta H. Biological Activities of Quinoline Derivatives. Mini-Reviews Med Chem. 2010;Yamamoto ES, Campos BLS, Jesus JA, Laurenti MD, Ribeiro SP, Kallás EG, et al. The effect of ursolic acid on leishmania (Leishmania) amazonensis is related to programed cell death and presents therapeutic potential in experimental cutaneous leishmaniasis. PLoS One. 2015;Baltina LA. Chemical modification of glycyrrhizic acid as a route to new bioactive compounds for medicine. Curr Med Chem [Internet]. 2003 Jan [cited 2017 Dec 8];10(2):155–71. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12570715Ríos JL. Effects of triterpenes on the immune system. Journal of Ethnopharmacology. 2010.Marquez-Martin A, Puerta RD La, Fernandez-Arche A, Ruiz-Gutierrez V, Yaqoob P. Modulation of cytokine secretion by pentacyclic triterpenes from olive pomace oil in human mononuclear cells. Cytokine. 2006;Atri C, Guerfali FZ, Laouini D. Role of human macrophage polarization in inflammation during infectious diseases. International Journal of Molecular Sciences. 2018.Oh HM, Lee S, Park YN, Choi EJ, Choi JY, Kim JA, et al. Ammonium glycyrrhizinate protects gastric epithelial cells from hydrogen peroxide-induced cell death. Exp Biol Med. 2009;Schröfelbauer B, Raffetseder J, Hauner M, Wolkerstorfer A, Ernst W, Szolar OHJ. Glycyrrhizin, the main active compound in liquorice, attenuates pro-inflammatory responses by interfering with membrane-dependent receptor signalling. Biochem J. 2015;Jeong HG, Kim JY. Induction of inducible nitric oxide synthase expression by 18β-glycyrrhetinic acid in macrophages. FEBS Lett. 2002;Herrera G, Teherán A, Pradilla I, Vera M, Ramírez JD. Geospatial-temporal distribution of Tegumentary Leishmaniasis in Colombia (2007–2016). PLoS Negl Trop Dis. 2018;Guillon J, Forfar I, Mamani-Matsuda M, Desplat V, Saliège M, Thiolat D, et al. Synthesis, analytical behaviour and biological evaluation of new 4-substituted pyrrolo[1,2-a]quinoxalines as antileishmanial agents. Bioorganic Med Chem. 2007;Kesherwani V, Sodhi A. Differential activation of macrophages in vitro by lectin Concanavalin A, Phytohemagglutinin and Wheat germ agglutinin: Production and regulation of nitric oxide. Nitric Oxide [Internet]. 2007 Mar 1 [cited 2019 Oct 13];16(2):294–305. Available from: https://www.sciencedirect.com/science/article/pii/S1089860306004526?via%3DihubTur J, Vico T, Lloberas J, Zorzano A, Celada A. Macrophages and Mitochondria: A Critical Interplay Between Metabolism, Signaling, and the Functional Activity. In: Advances in Immunology. 2017.Titus RG, Dekrey GK, Morris R V., Soares MBP. Interleukin-6 deficiency influences cytokine expression in susceptible BALB mice infected with Leishmania major but does not alter the outcome of disease. Infect Immun. 2001;Gomes CM, Ávila LR, Pinto SA, Duarte FB, Pereira LIA, Abrahamsohn IA, et al. Leishmania braziliensis amastigotes stimulate production of IL-1β, IL-6, IL-10 and TGF-β by peripheral blood mononuclear cells from nonendemic area healthy residents. Parasite Immunol. 2014;Suarez ET, Granados-Falla DS, Robledo SM, Murillo J, Upegui Y, Delgado G. Antileishmanial activity of synthetic analogs of the naturally occurring quinolone alkaloid N-methyl-8-methoxyflindersin. PLoS One [Internet]. 2020 [cited 2020 Dec 28];15(12):e0243392. Available from: https://dx.plos.org/10.1371/journal.pone.0243392Macedo-Silva ST de, Oliveira Silva TLA de, Urbina JA, Souza W de, Rodrigues JCF. Antiproliferative, Ultrastructural, and Physiological Effects of Amiodarone on Promastigote and Amastigote Forms of Leishmania amazonensis . Mol Biol Int. 2011;Saka HA, Valdivia R. Emerging Roles for Lipid Droplets in Immunity and Host-Pathogen Interactions. Annu Rev Cell Dev Biol. 2012;Walpole GFW, Grinstein S, Westman J. The role of lipids in host-pathogen interactions. IUBMB Life. 2018;Rabhi S, Rabhi I, Trentin B, Piquemal D, Regnault B, Goyard S, et al. Lipid droplet formation, their localization and dynamics during leishmania major macrophage infection. PLoS One. 2016;Remmerie A, Scott CL. Macrophages and lipid metabolism. Cell Immunol. 2018;DaMata JP, Mendes BP, Maciel-Lima K, Menezes CAS, Dutra WO, Sousa LP, et al. Distinct Macrophage Fates after in vitro Infection with Different Species of Leishmania: Induction of Apoptosis by Leishmania (Leishmania) amazonensis, but Not by Leishmania (Viannia) guyanensis. Afrin F, editor. PLoS One [Internet]. 2015 Oct 29 [cited 2019 Oct 14];10(10):e0141196. Available from: https://dx.plos.org/10.1371/journal.pone.0141196LeFurgey A, Gannon M, Blum J, Ingram P. Leishmania donovani amastigotes mobilize organic and inorganic osmolytes during regulatory volume decrease. J Eukaryot Microbiol. 2005;Robertson GS, LaCasse EC, Holcik M. Programmed Cell Death. In: Pharmacology. 2009.Perrotta I, Carito V, Russo E, Tripepi S, Aquila S, Donato G. Macrophage autophagy and oxidative stress: an ultrastructural and immunoelectron microscopical study. Oxid Med Cell Longev [Internet]. 2011 Sep 13 [cited 2019 Oct 14];2011:282739. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21922037Miranda K, Docampo R, Grillo O, Franzen A, Attias M, Vercesi A, et al. Dynamics of polymorphism of acidocalcisomes in Leishmania parasites. Histochem Cell Biol. 2004; Holzmuller P, Bras-Goncalves R, Lemesre J-L. Phenotypical characteristics, biochemical pathways, molecular targets and putative role of nitric oxide-mediated programmed cell death in Leishmania. Parasitology [Internet]. 2006 Mar 3 [cited 2019 Oct 14];132(S1):S19–32. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17018162Harris J, Deen N, Zamani S, Hasnat MA. Mitophagy and the release of inflammatory cytokines. Mitochondrion [Internet]. 2017 Oct 26 [cited 2017 Dec 8]; Available from: http://www.ncbi.nlm.nih.gov/pubmed/29107116Cyrino LT, Araújo AP, Joazeiro PP, Vicente CP, Giorgio S. In vivo and in vitro Leishmania amazonensis infection induces autophagy in macrophages. Tissue Cell. 2012;Real F, Mortara RA. The diverse and dynamic nature of leishmania parasitophorous vacuoles studied by multidimensional imaging. PLoS Negl Trop Dis. 2012;Castro R, Scott K, Jordan T, Evans B, Craig J, Peters EL, et al. THE ULTRASTRUCTURE OF THE PARASITOPHOROUS VACUOLE FORMED BY LEISHMANIA MAJOR. J Parasitol. 2007;Burchmore RJS, Barrett MP. Life in vacuoles - Nutrient acquisition by Leishmania amastigotes. International Journal for Parasitology. 2001.Real F, Mortara RA. The diverse and dynamic nature of leishmania parasitophorous vacuoles studied by multidimensional imaging. PLoS Negl Trop Dis. 2012 Feb;6(2).Borges VM, Lopes UG, De Souza W, Vannier-Santos MA. Cell structure and cytokinesis alterations in multidrug-resistant Leishmania (Leishmania) amazonensis. Parasitol Res. 2005;Britta EA, Scariot DB, Falzirolli H, Ueda-Nakamura T, Silva CC, Filho BPD, et al. Cell death and ultrastructural alterations in Leishmania amazonensis caused by new compound 4-Nitrobenzaldehyde thiosemicarbazone derived from S-limonene. BMC Microbiol. 2014;Daina A, Michielin O, Zoete V. SwissTargetPrediction: updated data and new features for efficient prediction of protein targets of small molecules. Nucleic Acids Res. 2019;Walker J, Vasquez JJ, Gomez MA, Drummelsmith J, Burchmore R, Girard I, et al. Identification of developmentally-regulated proteins in Leishmania panamensis by proteome profiling of promastigotes and axenic amastigotes. Mol Biochem Parasitol. 2006;Akpunarlieva S, Weidt S, Lamasudin D, Naula C, Henderson D, Barrett M, et al. Integration of proteomics and metabolomics to elucidate metabolic adaptation in Leishmania. J Proteomics [Internet]. 2017 Feb 23 [cited 2017 Dec 12];155:85–98. Available from: http://www.sciencedirect.com/science/article/pii/S1874391916305267?via%3DihubHajjaran H, Mohammadi Bazargani M, Mohebali M, Burchmore R, Salekdeh GH, Kazemi-Rad E, et al. Comparison of the proteome profiling of iranian isolates of leishmania tropica, l. Major and l. infantum by two-dimensional electrophoresis (2-DE) and mass-spectrometry. Iran J Parasitol. 2015;Wheeler RJ, Gluenz E, Gull K. The cell cycle of Leishmania: Morphogenetic events and their implications for parasite biology. Mol Microbiol. 2011;Pescher P, Blisnick T, Bastin P, Späth GF. Quantitative proteome profiling informs on phenotypic traits that adapt Leishmania donovani for axenic and intracellular proliferation. Cell Microbiol. 2011;Handman E, Bullen DVR. Interaction of Leishmania with the host macrophage. Trends in Parasitology. 2002.Coimbra ES, Antinarelli LMR, Silva NP, Souza IO, Meinel RS, Rocha MN, et al. Quinoline derivatives: Synthesis, leishmanicidal activity and involvement of mitochondrial oxidative stress as mechanism of action. Chem Biol Interact. 2016;Brobey RKB, Mei FC, Cheng X, Soong L. Comparative two-dimensional gel electrophoresis maps for promastigotes of Leishmania amazonensis and Leishmania major. Brazilian J Infect Dis. 2006;“Compuestos triterpenoides y alcaloides quinolínicos con actividad antileishma-nia: Una aproximación al mecanismo de acción” :Código No.11017775819. Convocatoria Salud-No.777-20182Convocatoria Doctorados nacionales 2015-No.727Ministerio de ciencia y tecnologíaMinisterio de ciencia, tecnología e innovación de Colombia (Minciencias)LICENSElicense.txtlicense.txttext/plain; charset=utf-83964https://repositorio.unal.edu.co/bitstream/unal/79547/1/license.txtcccfe52f796b7c63423298c2d3365fc6MD51CC-LICENSElicense_rdflicense_rdfapplication/rdf+xml; charset=utf-8805https://repositorio.unal.edu.co/bitstream/unal/79547/3/license_rdf4460e5956bc1d1639be9ae6146a50347MD53ORIGINAL1018406263.2021.pdf1018406263.2021.pdfTesis de Doctorado en Biotecnologíaapplication/pdf4770732https://repositorio.unal.edu.co/bitstream/unal/79547/4/1018406263.2021.pdf2a4384f43d3e2b7d984e70790da6bc07MD54THUMBNAIL1018406263.2021.pdf.jpg1018406263.2021.pdf.jpgGenerated Thumbnailimage/jpeg5326https://repositorio.unal.edu.co/bitstream/unal/79547/5/1018406263.2021.pdf.jpg6347a5da02e990e40ee7f35715334ebbMD55unal/79547oai:repositorio.unal.edu.co:unal/795472024-07-10 23:21:42.469Repositorio Institucional Universidad Nacional de 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