ABSTRACT
Antimalarial drugs have thus far been chiefly derived from two sources-natural products and synthetic drug-like compounds. Here we investigate whether antimalarial agents with novel mechanisms of action could be discovered using a diverse collection of synthetic compounds that have three-dimensional features reminiscent of natural products and are underrepresented in typical screening collections. We report the identification of such compounds with both previously reported and undescribed mechanisms of action, including a series of bicyclic azetidines that inhibit a new antimalarial target, phenylalanyl-tRNA synthetase. These molecules are curative in mice at a single, low dose and show activity against all parasite life stages in multiple in vivo efficacy models. Our findings identify bicyclic azetidines with the potential to both cure and prevent transmission of the disease as well as protect at-risk populations with a single oral dose, highlighting the strength of diversity-oriented synthesis in revealing promising therapeutic targets.
Subject(s)
Antimalarials/chemical synthesis , Antimalarials/pharmacology , Azetidines/therapeutic use , Drug Discovery , Life Cycle Stages/drug effects , Malaria, Falciparum/drug therapy , Plasmodium falciparum/drug effects , Plasmodium falciparum/growth & development , Animals , Antimalarials/administration & dosage , Antimalarials/therapeutic use , Azabicyclo Compounds/administration & dosage , Azabicyclo Compounds/chemical synthesis , Azabicyclo Compounds/pharmacology , Azabicyclo Compounds/therapeutic use , Azetidines/administration & dosage , Azetidines/adverse effects , Azetidines/pharmacology , Cytosol/enzymology , Disease Models, Animal , Female , Liver/drug effects , Liver/parasitology , Macaca mulatta/parasitology , Malaria, Falciparum/prevention & control , Malaria, Falciparum/transmission , Male , Mice , Phenylalanine-tRNA Ligase/antagonists & inhibitors , Phenylurea Compounds/administration & dosage , Phenylurea Compounds/chemical synthesis , Phenylurea Compounds/pharmacology , Phenylurea Compounds/therapeutic use , Plasmodium falciparum/cytology , Plasmodium falciparum/enzymology , SafetyABSTRACT
With increasing emergence of multi-drug resistant infections, there is a dire need for new classes of compounds that act through unique mechanisms. In this work, we describe the discovery and optimization of a novel series of inhibitors of bacterial methionine aminopeptidase (MAP). Through a high-throughput screening campaign, one azepinone amide hit was found that resembled the native peptide substrate and possessed moderate biochemical potency against three bacterial isozymes. X-ray crystallography was used in combination with substrate-based design to direct the rational optimization of analogs with sub-micromolar potency. The novel compounds presented here represent potent broad-spectrum biochemical inhibitors of bacterial MAP and have the potential to lead to the development of new medicines to combat serious multi-drug resistant infections.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Escherichia coli/drug effects , Methionyl Aminopeptidases/antagonists & inhibitors , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Azepines/chemistry , Crystallography, X-Ray , Drug Design , Enzyme Activation/drug effects , Enzyme Inhibitors/chemistry , Escherichia coli/enzymology , Humans , Inhibitory Concentration 50 , Models, Molecular , Structure-Activity RelationshipABSTRACT
In an ongoing effort to develop novel and potent nonnucleoside HIV-1 reverse transcriptase (RT) inhibitors that are effective against the wild type (WT) virus and clinically observed mutants, 1,2-bis-substituted benzimidazoles were synthesized and tested. Optimization of the N1 and C2 positions of benzimidazole led to the development of 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-methylbenzimidazole (1) (IC50 = 0.2 microM, EC50 = 0.44 microM, and TC50 >/= 100 against WT). This paper describes how substitution on the benzimidazole ring profoundly affects activity. Substituents at the benzimidazole C4 dramatically enhanced potency, while at C5 or C6 substituents were generally detrimental or neutral to activity, respectively. A 7-methyl analogue did not inhibit HIV-1 RT. Determination of the crystal structure of 1 bound to RT provided the basis for accurate modeling of additional analogues, which were synthesized and tested. Several derivatives were nanomolar inhibitors of wild-type virus and were effective against clinically relevant HIV-1 mutants.
