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

Samir Bondock; Tallah Albarqi; Mohamed Abboud; Tamer Nasr; Nada M Mohamed; Moaz M Abdou

doi:10.1039/d3ra02528d

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

RSC Adv. 2023 Aug 10;13(34):24003-24022. doi: 10.1039/d3ra02528d. eCollection 2023 Aug 4.

Authors

Samir Bondock¹, Tallah Albarqi¹, Mohamed Abboud¹, Tamer Nasr^{2

3}, Nada M Mohamed³, Moaz M Abdou⁴

Affiliations

¹ Chemistry Department, Faculty of Science, King Khalid University 9004 Abha Saudi Arabia bondock@mans.edu.eg.
² Pharmaceutical Chemistry Department, Faculty of Pharmacy, Helwan University 11795 Helwan Cairo Egypt.
³ Pharmaceutical Chemistry Department, Faculty of Pharmacy, Modern University for Technology and Information, MTI 12055 Cairo Egypt.
⁴ Egyptian Petroleum Research Institute Nasr City 11727 Cairo Egypt.

Abstract

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 α-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 ΔG_binding MM-PBSA of -9.6 kcal mol^-1.