Convergent synthesis of carbonic anhydrase inhibiting bi‐heterocyclic benzamides: Structure–activity relationship and mechanistic explorations through enzyme inhibition, kinetics, and computational studies

• Published in: Journal of heterocyclic chemistry Vol. 58; no. 5; pp. 1089 - 1103
• Main Authors: Khan, Farhan M., Abbasi, Muhammad A., Aziz‐ur‐Rehman, Siddiqui, Sabahat Z., Sadiq Butt, Abdul R., Raza, Hussain, Zafar, Ayesha, Ali Shah, Syed A., Shahid, Muhammad, Seo, Sung‐Yum
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Inc 01-05-2021; Wiley Subscription Services, Inc
• Subjects: Carbonic anhydrase; Convergence; Enzymes; Kinetics
• ISSN: 0022-152X; 1943-5193
• DOI: 10.1002/jhet.4240

By using a convergent methodology, a novel series of N‐arylated 4‐yl‐benzamides containing a bi‐heterocyclic thiazole–triazole core was synthesized, and the structures of these hybrid molecules, 9a–k, were corroborated through spectral analyses. The in vitro studies of these multifunctional molecules demonstrated their potent carbonic anhydrase inhibition relative to the standard used. The kinetics mechanism was exposed by Lineweaver–Burk plots, which revealed that 9j inhibited carbonic anhydrase non‐competitively by forming an enzyme‐inhibitor complex. The inhibition constants Ki calculated from Dixon plots for this compound was 1.2 μM. The computational study was also persuasive with the experimental results, and these molecules disclosed good results of all scoring functions and interactions, which suggested a good binding to carbonic anhydrase. So, it was predicted from the inferred results that these molecules might be considered as promising medicinal scaffolds for various diseases related to the uncontrolled production of this enzyme.