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

• Main Authors: Miguel Quiliano, Adela Mendoza, Kim Y. Fong, Adriana Pabón, Nathan E. Goldfarb, Isabelle Fabing, Ariane Vettorazzi, Adela López de Cerain, Ben M. Dunn, Giovanny Garavito, David W. Wright, Eric Deharo, Silvia Pérez-Silanes, Ignacio Aldana, Silvia Galiano
• Format: Article
• Language: English
• Published: Elsevier 2016-12-01
• Series: International Journal for Parasitology: Drugs and Drug Resistance
• Subjects: Antimalarial; Antiplasmodial; Arylamino alcohol; Plasmepsin II enzyme; Hemozoin inhibition; Mannich reaction
• Online Access: http://www.sciencedirect.com/science/article/pii/S2211320716300446

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.