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J Med Chem. 2014 Aug 14;57(15):6572-82. doi: 10.1021/jm500833f. Epub 2014 Jul 16.

Diarylthiazole: an antimycobacterial scaffold potentially targeting PrrB-PrrA two-component system.

Author information

1
Department of Medicinal Chemistry, IMED Infection, AstraZeneca , Bellary Road, Hebbal, Bangalore 560024, India.

Abstract

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.

PMID:
24967731
DOI:
10.1021/jm500833f
[Indexed for MEDLINE]

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