Exploring the scope of new arylamino alcohol derivatives: Synthesis, antimalarial evaluation, toxicological studies, and target exploration

ABSTRACT: Synthesis of new 1-aryl-3-substituted propanol derivatives followed by structure-activity relationship, in silico drug-likeness, cytotoxicity, genotoxicity, in silico metabolism, in silico pharmacophore modeling, and in vivo studies led to the identification of compounds 22 and 23 with significant in vitro antiplasmodial activity against drug sensitive (D6 IC50 ≤ 0.19 μM) and multidrug resistant (FCR-3 IC50 ≤ 0.40 μM and C235 IC50 ≤ 0.28 μM) strains of Plasmodium falciparum. Adequate selectivity index and absence of genotoxicity was also observed. Notably, compound 22 displays excellent parasitemia reduction (98 ± 1%), and complete cure with all treated mice surviving through the entire period with no signs of toxicity. One important factor is the agreement between in vitro potency and in vivo studies. Target exploration was performed; this chemotype series exhibits an alternative antimalarial mechanism.

• Autores: Pabón Vidal, Adriana Lucía; Quiliano, Miguel; Mendoza, Adela; Fong, Kim; Goldfarb, Nathan; Fabing, Isabelle; Vettorazzi, Ariane; López de Cerain, Adela; Dunn, Ben; Garavito, Giovanny; Wright, David; DeHaro, Eric; Pérez Silanes, Silvia; Aldana, Ignacio; Galiano, Silvia
• Tipo de recurso: Article of investigation
• Fecha de publicación: 2016
• Institución: Universidad de Antioquia
• Repositorio: Repositorio UdeA
• Idioma: eng
• OAI Identifier: oai:bibliotecadigital.udea.edu.co:10495/32004
• Acceso en línea: https://hdl.handle.net/10495/32004
• Palabra clave: Drug-Related Side Effects and Adverse Reactions; Antimaláricos; Antimalarials; Amino Alcoholes; Amino Alcohols; Modelos Animales de Enfermedad; Disease Models, Animal; Concentración 50 Inhibidora; Inhibitory Concentration 50; Malaria Falciparum; Malaria, Falciparum; Plasmodium falciparum; Relación Estructura-Actividad; Structure-Activity Relationship; Resultado del Tratamiento; Treatment Outcome; Análisis de Supervivencia; Survival Analysis; Ratones; Mice; http://id.nlm.nih.gov/mesh/D064420
• Rights: openAccess
• License: http://creativecommons.org/licenses/by-nc-nd/2.5/co/