Development of new pyrazole–thiophene hybrids: synthesis, anticancer assessment, and molecular docking insights

Abstract

A novel series of pyrazole–thiophene hybrid derivatives (3a–c, 5a–c, 7a–c, and 9a,b) was synthesized through a one-step reaction pathway and structurally confirmed by various spectroscopic analyses. Hybridization of the pyrazole nucleus with the thiophene ring was designed to enhance the biological potential of both moieties, as each is known to exhibit diverse pharmacological properties. The MTT assay was used to assess the in vitro anticancer potential of the synthesized scaffolds against two human cancer cell lines: hepatocellular carcinoma (HepG2) and breast adenocarcinoma (MCF7). The results indicated that pyrazole–thiophene hybrids 3a and 5b demonstrated the highest cytotoxicity against HepG-2 and MCF-7 cells with inhibition values of 24 µM and 10.36 µM and 38.8 µM and 26.9 µM, respectively, compared with the reference drug vinblastine sulfate (8.22 µM for HepG2 and 4.63 µM for MCF-7). Structure–activity relationship (SAR) analysis revealed that the presence of electron-donating substituents on the aromatic ring and thiophene linkage contributed to enhanced cytotoxicity. Molecular docking was conducted to investigate the binding of the compounds to the target protein PDB: 2W3L. The binding free energies for the 2W3L protein ranged between −6.0251 and −7.3575 kcal mol⁻¹, indicating stronger binding compared to vinblastine, which has a binding energy of −5.9584 kcal mol⁻¹. In addition, in silico assessment of the pharmacokinetic profile using the SwissADME program showed that compounds 9a and 9b appeared as the most promising nominees within the series, demonstrating proper solubility, lower lipophilicity, and, for compound 9a, high GI absorption. This study presents noteworthy ADME challenges for the series, particularly regarding their solubility and permeability, leading to the need for more synthetic efforts towards more metabolically stable and bioavailable analogues. These findings suggest that pyrazole–thiophene hybrids represent promising scaffolds for the further development of potent anticancer agents.