4-substituted (1,2,5-oxadiazol-3-yl)benzamides and -benzene sulfonamides as antiplasmodial agents.

The 1,2,5-oxadiazol MMV665805 from Medicines for Malaria Venture's Malaria Box Project is the lead compound of herein presented study. It exhibits very promising activity against the blood stages of the strain NF54 of Plasmodium falciparum. Twenty-five new derivates were prepared by replacing the initial left-hand side 3,4-diethoxyphenyl ring as well as introducing various benzamido and benzenesulfonamido substituents in position 3 of the furazan. Thereby, an insightful series of valuable structure-activity-relationships was elaborated. Compounds were furthermore analyzed for their compliance with Lipinski's rules for drug-likeness. Additionally, passive permeability was determined experimentally. A 3-amino-N-[4-(3,4-diethoxyphenyl)-1,2,5-oxadiazol-3-yl]benzamide not only complies perfectly with Lipinski's rules, most notably, it possessed excellent antiplasmodial activity against the chloroquine-sensitive strain P. falciparum NF 54 (IC50 = 0.035 μM). Furthermore, it is nearly nontoxic for rat L-6 cells (IC50 = 186.2 μM) resulting in a marvelous selectivity index of 5319.