Hybrids of thiophene, pyrazole and oxadiazol: Synthesis, DFT calculations, molecular docking studies and biological evaluation for anticancer and antimicrobial activity
Dhavalkumar M. Bhatt, Gaurav B. Patel, Yogesh O. Bhola, Piyush V. Dholaria, Amitkumar M. Patel
Abstract
Nine novel pyrazole-thiophene-oxadiazole hybrid compounds (8a–i) were synthesized, characterized using spectroscopic techniques, and evaluated for anticancer and antimicrobial activities using molecular docking, DFT calculations, and ADMET profiling. Compound 8i exhibited the most potent anticancer activity against HepG2 (IC50 = 1.3 ± 1 μM) and MCF-7 (IC50 = 10.6 ± 1 μM) cell lines, comparable to that of doxorubicin. Antimicrobial screening revealed that compound 8b exhibited the highest antibacterial activity (40.6 ± 0.8 mm zone against S. aureus). In contrast, compound 8c demonstrated superior broad-spectrum activity against bacteria (32.2 mm against S. aureus and 30.1 mm against E. coli) and fungi (12.3 mm against C. albicans), surpassing that of the reference drugs. Molecular docking showed compound 8i with the highest binding affinity to Human Topoisomerase IIα (−7.6030 kcal/mol vs. −5.4560 kcal/mol for doxorubicin). In comparison, compound 8c exhibited optimal binding to the Candida albicans target 5AEZ (−6.055 kcal/mol), which correlated with the experimental results. DFT calculations (B3LYP/6–311++G(d,p)) revealed that compound 8i possessed the smallest HOMO-LUMO gap (3.9464 eV), highest reactivity, and optimal softness (0.4998). The RDG analysis confirmed the extensive noncovalent interactions that contribute to molecular stability. ADMET profiling indicated low gastrointestinal absorption and CYP3A4 inhibition for all compounds, with compound 8g exhibiting the most favorable metabolic profile. These findings establish pyrazole-thiophene-oxadiazole hybrids as promising dual anticancer and antimicrobial scaffolds for further development of novel therapeutic agents.