title: Diarylthiazole: an antimycobacterial scaffold potentially targeting PrrB-PrrA two-component system.
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.
authors: Department of Medicinal Chemistry, IMED Infection, AstraZeneca , Bellary Road, Hebbal, Bangalore 560024, India.
authors: Eknath
authors: E
authors: Bellale
authors: Maruti
authors: M
authors: Naik
authors: Varun
authors: V
authors: V B
authors: Anisha
authors: A
authors: Ambady
authors: Ashwini
authors: A
authors: Narayan
authors: Sudha
authors: S
authors: Ravishankar
authors: Vasanthi
authors: V
authors: Ramachandran
authors: Parvinder
authors: P
authors: Kaur
authors: Robert
authors: R
authors: McLaughlin
authors: James
authors: J
authors: Whiteaker
authors: Sapna
authors: S
authors: Morayya
authors: Supreeth
authors: S
authors: Guptha
authors: Sreevalli
authors: S
authors: Sharma
authors: Anandkumar
authors: A
authors: Raichurkar
authors: Disha
authors: D
authors: Awasthy
authors: Vijayshree
authors: V
authors: Achar
authors: Prakash
authors: P
authors: Vachaspati
authors: Balachandra
authors: B
authors: Bandodkar
authors: Manoranjan
authors: M
authors: Panda
authors: Monalisa
authors: M
authors: Chatterji
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D024881:Drug Resistance, Bacterial; D057166:High-Throughput Screening Assays; D006801:Humans; D051379:Mice; D008826:Microbial Sensitivity Tests; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D020641:Polymorphism, Single Nucleotide; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D054852:Small Molecule Libraries; D013844:Thiazoles; D011494:Protein Kinases