Tail-approach based design, synthesis, and cytotoxic evaluation of novel disubstituted and trisubstituted 1,3-thiazole benzenesulfonamide derivatives with suggested carbonic anhydrase IX inhibition mechanism

A novel series of 2,4,5- and 2,3,4-trisubstituted thiazole hybrids with 1,3,4-thiadiazolylbenzenesulfonamide was designed following the tail approach as possible hCAIX inhibitors. The key intermediate 1 was condensed with thiosemicarbazide 2a to give 1,3,4-thiadiazolylthiosemicarbazone 3, which upon hetero-cyclization with substituted a-haloketones and esters afforded 2,4,5-trisubstituted thiazole-1,3,4-thiadiazole conjugates 4-8. Furthermore, the trisubstituted thiazole-1,3,4-thiadiazole hybrids 12a-d were synthesized via the regioselective cyclization of 4-substituted-1,3,4-thiadiazolylthiosemicarbazones with phenacyl bromide. The cyclized 2,4-disubstituted thiazole 4 enhanced cytotoxicity by nine, four and two times against HepG-2, Caco2, and MCF-7, respectively. Moreover, the simple methyl substitution on the thiosemicarbazone terminus 9a improved the parent derivative 3 cytotoxicity by nine, fourteen, and six times against HepG-2, Caco2, and MCF-7, respectively. This astonishing cytotoxicity was elaborated with hCAIX molecular docking simulation of 4, 9a, and 12d demonstrating binding to zinc and its catalytic His94. Furthermore, molecular dynamic simulation 9a revealed stable hydrogen bonding with hCAIX with interaction energy of -61.07 kcal mol(-1) and & UDelta;G(binding) MM-PBSA of -9.6 kcal mol(-1).

Automated summary

A novel series of thiazole hybrids targeting hCAIX were synthesized and evaluated for their cytotoxicity. The compounds showed enhanced cytotoxicity against different cancer cell lines, with some derivatives exhibiting significant improvements. Molecular docking and dynamic simulation studies provided insights into the binding of the compounds with the target enzyme and their potential mechanism of action.