Exploration of thiophene-thiazole and bi-thiophene compounds: Synthesis and molecular modelling as anticancer agents

The current study focused on designing and synthesis of new thiophene-thiazole and bi-thiophene derivatives and evaluate their potential as anticancer agents and carbonic anhydrase inhibitors through experimental and computational investigations. The structure of manufactured thiophene-thiazole and bi-thiophene compounds have been elucidated from the NMR, FTIR, and mass spectral data. The DFT/B3LYP optimized structures of the chloroacetamides 3a-b were planar, whereas the oxothiazolidinylidene analogs 4a-b as well as thiophene carboxamides 7-13 showed a comparable strongly twisted structures. The frontier molecular orbitals (FMOs) of the planar conjugates 3a-b were spread over the full skeleton, while the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) of twisted hybrids have been confined to the planar π-aromatic system (substituted phenyldiazenyl thiophene moiety) and the various acceptor functionals, respectively. Furthermore, the cytotoxicity efficiency of the constructed analogues has investigated versus three human cancer cell lines and a normal fibroblast line, where the analogues 7 , 9a , 11 , 13a , and 13b showed higher cytotoxic efficacy than the reference doxorubicin, demonstrating the potential these scaffolds as lead structures for the development of antitumor drugs. Also, the carbonic anhydrase inhibition studies revealed potent activity against the tumor-associated isoforms CA IX and CA XII, with hybrids 9a , 9b , 11 , and 13b showing the strongest dual inhibition (IC ₅₀ = 0.049±0.006 - 0.350±0.036 μM for CA IX and 0.103±0.029 - 0.822±0.003 μM for CA XII). Meanwhile, molecular docking against the CA active site (PDB: 1ZXM) supported the experimental findings, with compounds 9a , 11 , and 13a displaying higher binding affinities than the reference Aza (-5.78 to -7.54 kcal/mol). In addition, SwissADME analysis further indicated favorable pharmacokinetic properties for several derivatives, particularly 9a , 9b , 13a , and 13b . Collectively, the results highlight bi-thiophene-based derivatives as promising leads for the development of carbonic anhydrase-targeted anticancer agents.