Design and synthesis of triazolopyrimidine acylsulfonamides as novel anti-mycobacterial leads acting through inhibition of acetohydroxyacid synthase.
Novel triazolopyrimidine acylsulfonamides class of antimycobacterial agents, which are mycobacterial acetohydroxyacid synthase (AHAS) inhibitors were designed by hybridization of known AHAS inhibitors such as sulfonyl urea and triazolopyrimidine sulfonamides. This Letter describes the synthesis and SAR studies of this class of molecules by variation of two parts of the molecule, the phenyl and triazolopyrimidine rings. SAR study describes optimisation of enzyme potency, whole cell potency and evidence of mechanism of action.
AstraZeneca India Pvt. Ltd, Avishkar, Kirloskar Business Park, Bellary Road, Hebbal, Bangalore 560 024, Karnataka, India.
Vikas
V
Patil
AstraZeneca India Pvt. Ltd, Avishkar, Kirloskar Business Park, Bellary Road, Hebbal, Bangalore 560 024, Karnataka, India.
Manoj
M
Kale
AstraZeneca India Pvt. Ltd, Avishkar, Kirloskar Business Park, Bellary Road, Hebbal, Bangalore 560 024, Karnataka, India.
Anandkumar
A
Raichurkar
EDC Creative Technology Solutions Private Limited, EDC Conclave, Jeevith Gardens [Off. ITPL Road], Bangalore 560 037, India.
Brahatheeswaran
B
Bhaskar
AstraZeneca India Pvt. Ltd, Avishkar, Kirloskar Business Park, Bellary Road, Hebbal, Bangalore 560 024, Karnataka, India.
Dwarakanath
D
Prahlad
AstraZeneca India Pvt. Ltd, Avishkar, Kirloskar Business Park, Bellary Road, Hebbal, Bangalore 560 024, Karnataka, India.
Meenakshi
M
Balganesh
Ambernath Organics, 307/314, Creative Industries Premises, Road No. 2, Sunder Nagar, Kalina, Mumbai 400 098, India.
Santosh
S
Nandan
AstraZeneca India Pvt. Ltd, Avishkar, Kirloskar Business Park, Bellary Road, Hebbal, Bangalore 560 024, Karnataka, India. Electronic address: shahul.mehar@astrazeneca.com.
P
P
Shahul Hameed
D000095:Acetolactate Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D014376:Tuberculosis / Q000188:drug therapy / Q000201:enzymology / Q000382:microbiology
D000900:Anti-Bacterial Agents; D011743:Pyrimidines; D013449:Sulfonamides; D000095:Acetolactate Synthase
Acetohydroxyacid synthase; Antimycobacterial; Triazolopyrimidine acylsulfonamides