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 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 ΔGbinding MM-PBSA of -9.6 kcal mol-1.

Novel asymmetrical azines appending 1,3,4-thiadiazole sulfonamide: synthesis, molecular structure analyses, in silico ADME, and cytotoxic effect.

Toward finding potential and novel anticancer agents, we designed and prepared novel differently substituted unsymmetrical azine-modified thiadiazole sulfonamide derivatives using the "combi-targeting approach". An efficient procedure for synthesizing the designed compounds starts with 5-acetyl-3-N-(4-sulfamoylphenyl)-2-imino-1,3,4-thiadi-azoline 4. The E/Z configuration for compound 5 was investigated based on spectral analysis combined with quantum mechanical calculation applying the DFT-B3LYP method and 6-31G(d) basis set. The computational results found that the E isomer was energetically more favorable than the Z isomer by 2.21 kcal mol-1. Moreover, 1H and 13C chemical shifts for the E and Z isomers in DMSO were predicted using the GIAO-B3LYP/6-31G(d) computations and IEF-PCM solvation model. The computed chemical shifts for both isomers are consistent with those observed experimentally, indicating that they exist in the solution phase. Moreover, the E/Z configuration for the synthesized azines 7a-c, 9, 11, 13, 15a and 15b was also studied theoretically using the DFT-B3LYP/6-31G(d) calculations. In silico prediction for the biological activities was reported regarding the HOMO-LUMO energy gaps and molecular reactivity descriptors besides the ADMT/drug-likeness properties. The cytotoxic effect of the synthesized compounds has been assayed via the determination of their IC50.