ABSTRACT
The widespread emergence of Plasmodium falciparum (Pf) strains resistant to frontline agents has fuelled the search for fast-acting agents with novel mechanism of action. Here, we report the discovery and optimization of novel antimalarial compounds, the triaminopyrimidines (TAPs), which emerged from a phenotypic screen against the blood stages of Pf. The clinical candidate (compound 12) is efficacious in a mouse model of Pf malaria with an ED99 <30 mg kg(-1) and displays good in vivo safety margins in guinea pigs and rats. With a predicted half-life of 36 h in humans, a single dose of 260 mg might be sufficient to maintain therapeutic blood concentration for 4-5 days. Whole-genome sequencing of resistant mutants implicates the vacuolar ATP synthase as a genetic determinant of resistance to TAPs. Our studies highlight the potential of TAPs for single-dose treatment of Pf malaria in combination with other agents in clinical development.
Subject(s)
Antimalarials/pharmacology , Plasmodium falciparum/drug effects , Pyrimidines/pharmacology , Amines/pharmacology , Animals , Drug Evaluation, Preclinical , Drug Resistance, Microbial , Guinea Pigs , Half-Life , RatsABSTRACT
Diarylthiazole (DAT), a hit from diversity screening, was found to have potent antimycobacterial activity against Mycobacterium tuberculosis (Mtb). In a systematic medicinal chemistry exploration, we demonstrated chemical opportunities to optimize the potency and physicochemical properties. The effort led to more than 10 compounds with submicromolar MICs and desirable physicochemical properties. The potent antimycobacterial activity, in conjunction with low molecular weight, made the series an attractive lead (antibacterial ligand efficiency (ALE)>0.4). The series exhibited excellent bactericidal activity and was active against drug-sensitive and resistant Mtb. Mutational analysis showed that mutations in prrB impart resistance to DAT compounds but not to reference drugs tested. The sensor kinase PrrB belongs to the PrrBA two component system and is potentially the target for DAT. PrrBA is a conserved, essential regulatory mechanism in Mtb and has been shown to have a role in virulence and metabolic adaptation to stress. Hence, DATs provide an opportunity to understand a completely new target system for antimycobacterial drug discovery.
Subject(s)
Antitubercular Agents/chemistry , Bacterial Proteins/metabolism , Mycobacterium tuberculosis/drug effects , Protein Kinases/metabolism , Thiazoles/chemistry , Animals , Antitubercular Agents/chemical synthesis , Antitubercular Agents/pharmacology , Bacterial Proteins/genetics , Drug Resistance, Bacterial , High-Throughput Screening Assays , Humans , Mice , Microbial Sensitivity Tests , Mutation , Mycobacterium tuberculosis/genetics , Mycobacterium tuberculosis/isolation & purification , Polymorphism, Single Nucleotide , Protein Kinases/genetics , Small Molecule Libraries , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/pharmacologyABSTRACT
Alpha,alpha-disubstituted acetamides undergo oxidative dehomologation to give one-carbon-shorter ketones when reacted with a hypervalent iodine (lambda(5)) reagent in combination with tetraethylammonium bromide (TEAB) in various solvents. In further studies, one such combination of a hypervalent iodine (lambda(5)) reagent, o-iodoxybenzoic acid, and TEAB has been established as a new, mild, efficient, and general method for the transformation.
