Synthesis and biological evaluation of coumarin‐thiazole hybrids as selective carbonic anhydrase IX and XII inhibitors

Abstract

A series of coumarin‐linked thiazoles (6a–p) was synthesized and the synthesized compounds were evaluated against human carbonic anhydrases (hCAs) IX and XII, which have been implicated in cancer. All the compounds exhibited selective inhibition of both isoforms. The designed compounds inhibited hCA IX in a moderate nanomolar to submicromolar range. The hCA XII was inhibited in a low to moderate nanomolar range. Compound 6o exhibited the best inhibition of hCA XII with a Ki value of 91.1 nM. The hydrolyzed form of compound 6o also exhibited favorable interactions as well as good docking scores with both the isoforms. Hence, this compound can be taken as a template for the design of selective and potent hCA XII inhibitors.

Coumaryl‐sulfonamide moiety: Unraveling their synthetic strategy and specificity toward hCA IX/XII, facilitating anticancer drug development

“…On the other hand, some substituted sulfonamides such as aryl sulfonamide, arylsulfonamide hydrazino bearing thiazole moiety, amino-pyrazonyl sulfone at the 6th position of coumarin had been reported to exhibit significant anticancer activity against different cancer cell lines. [83][84][85] Therefore, to deduce a broad SAR, Schemes The molecular docking studies have been preferred for a larger group of studies; [12,86] however, being specific to a particular type of compound and associated linker, here we have chosen only five compounds (35b, 58f, 93h, 107q, 112i) from above schemes along with their standard acetazolamide (AAZ) for comparison against the housekeeping gene hCAII and the overexpressed genes hCA IX and XII, which can produce a better picture for drug development research in the near future.…”

“…On the other hand, some substituted sulfonamides such as aryl sulfonamide, arylsulfonamide hydrazino bearing thiazole moiety, amino‐pyrazonyl sulfone at the 6th position of coumarin had been reported to exhibit significant anticancer activity against different cancer cell lines. [ 83–85 ] Therefore, to deduce a broad SAR, Schemes 3, 6, 8, 12, 15, 18, 19, and 22 have been chosen which specifically focus on the h CA I, II, IX, and XII inhibition and the potent compounds reported for the enzyme activity either inhibited in a very submicromolar concentration or at nanomolar concentration and for further clear understanding molecular docking studies have been performed by taking five best potent compounds; two groups have been made keeping two different types of linkers in between coumarin and sulfonamide. Compounds 35b and 58f were containing thiazole as a linker whereas compounds 93h and 112i had 1,2,3‐triazole as a linker; however, compound 93h is lacking coumarin which will differentiate the binding affinity of coumarin toward the hCA II, IX, and XII targets.…”