Synthesis of furan-based pyrazoline as an anticancer agent: An in vitro and in silico approach toward COX-2 inhibition

Abstract

Pyrazoline is a versatile heterocyclic compound known for its easy synthesis and structural modification, making it an excellent framework for enhancing biological activity. The incorporation of additional heterocyclic systems, such as furan, has significantly improved its anticancer potential, offering a promising avenue for developing new therapeutic agents. In this study, furan-based pyrazoline derivatives were synthesized via reflux using chalcone intermediates. Their structures were confirmed by gas chromatography–mass spectrometry (GC–MS), Fourier transform infrared (FTIR), proton and carbon nuclear magnetic resonance (¹H- and ¹³C-NMR) spectroscopy. The anticancer activities of eight pyrazoline derivatives (4a–4h) were investigated using the MTT assay against HeLa, WiDr, MCF-7, and T47D cancer cell lines, with normal Vero cells as a control to evaluate their selectivity. Among these compounds, 3-(furan-2-yl)-5-(4-methoxyphenyl)-1-phenyl-4,5-dihydro-1H-pyrazole (4d) demonstrated the best anticancer activity, with half-maximal inhibitory concentration values of 1.07 and 2.25 µg/mL against HeLa and WiDr cells, respectively, and a selectivity index > 100. Molecular docking analysis of 4d with cyclooxygenase-2 revealed a binding affinity of −9.7 kcal/mol. Thus, further molecular dynamics simulations confirmed stable interactions with the formation of persistent hydrogen bonds with the Ser530 residue. Pharmacokinetic predictions indicated good absorption and distribution profiles, although 4d is probably metabolized by the CYP3A4 enzyme in the liver. These findings suggest that compound 4d is a promising lead compound for further development as a selective anticancer agent.