Journal of Medicinal Chemistry p. 6572 - 6582 (2014)
Update date:2022-09-26
Topics:
Bellale, Eknath
Naik, Maruti
Vb, Varun
Ambady, Anisha
Narayan, Ashwini
Ravishankar, Sudha
Ramachandran, Vasanthi
Kaur, Parvinder
McLaughlin, Robert
Whiteaker, James
Morayya, Sapna
Guptha, Supreeth
Sharma, Sreevalli
Raichurkar, Anandkumar
Awasthy, Disha
Achar, Vijayshree
Vachaspati, Prakash
Bandodkar, Balachandra
Panda, Manoranjan
Chatterji, Monalisa
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.
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