ABSTRACT
Malaria continues to be a major global health problem, being particularly devastating in the African population under the age of five. Artemisinin-based combination therapies (ACTs) are the first-line treatment recommended by the WHO to treat Plasmodium falciparum malaria, but clinical resistance against them has already been reported. As a consequence, novel chemotypes are urgently needed. Herein we report a novel, in vivo active, fast-acting antimalarial chemotype based on a benzimidazole core. This discovery is the result of a medicinal chemistry plan focused on improving the developability profile of an antichlamydial chemical class previously reported by our group.
Subject(s)
Antimalarials/chemical synthesis , Antimalarials/pharmacology , Benzamides/chemical synthesis , Benzamides/pharmacology , Benzimidazoles/chemistry , Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacology , Cell Proliferation/drug effects , Drug Design , Amides/chemical synthesis , Amides/pharmacokinetics , Amides/pharmacology , Animals , Antimalarials/pharmacokinetics , Benzamides/pharmacokinetics , Benzimidazoles/pharmacokinetics , Cells, Cultured , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Female , Humans , Malaria, Falciparum , Mice, Inbred NOD , Mice, SCID , Models, Molecular , Molecular Structure , Plasmodium falciparum , Structure-Activity Relationship , Tissue DistributionABSTRACT
Malaria is one of the deadliest infectious diseases in the world, with the eukaryotic parasite Plasmodium falciparum causing the most severe form of the disease. Discovery of new classes of antimalarial drugs has become an urgent task to counteract the increasing problem of drug resistance. Screening directly for compounds able to inhibit parasite growth in vitro is one of the main approaches the malaria research community is now pursuing for the identification of novel antimalarial drug leads. Very recently, thousands of compounds with potent activity against the parasite P. falciparum have been identified and information about their molecular descriptors, antiplasmodial potency, and cytotoxicity is publicly available. Now the challenges are how to identify the most promising chemotypes for further development and how best to progress these compounds through a lead optimization program to generate antimalarial drug candidates. We report here the first chemical series to be characterized from one of those screenings, a completely novel chemical class with the generic name cyclopropyl carboxamides that has never before been described as having antimalarial or other pharmacological activities. Cyclopropyl carboxamides are potent inhibitors of drug-sensitive and -resistant strains of P. falciparum in vitro and show in vivo oral efficacy in malaria mouse models. In the present work, we describe the biological characterization of this chemical family, showing that inhibition of their still unknown target has very favorable pharmacological consequences but the compounds themselves seem to select for resistance at a high frequency.
