Development of Benzothiophene-Bearing Bis-oxadiazole Derivatives for Potential Anticancer Targets: Evaluation of DFT, ADME-Tox, and In Silico Docking.

Authors

Nagaraju Madala, Vishal Sharma, Srilalitha Vinnakota

Published in

Chemistry & biodiversity. Volume 23. Issue 10. Pages e71782.

Abstract

Combining two pharmacophores into one molecule with multiple applications presents interest in the field of medicinal chemistry. Benzo[b]thiophenes are among privileged scaffolds due to their wide biological activities, whereas oxadiazoles are versatile linkers with pharmacological potential. Thus, this article focused on the synthesis of novel benzo[b]thiophene-linked bis-oxadiazoles and the exploration of their anticancer potential. The structural elucidation of the prepared oxadiazole compounds was established by ¹H NMR, ¹³C NMR, and HRMS spectroscopic analysis. The in vitro anticancer activity effect on the human colorectal (HT-29, HCT-116 and Caco-2) and breast (MDA-MB-231) cancer cell lines was assessed for each synthesized compound. It was revealed that compounds 7b and 7g showed well-established anticancer affinities on HT-29 and Caco-2 cell lines with inhibitory concentrations of 6.2 ± 0.67 and 8.1 ± 0.89 µg/mL in comparison to the reference drug etoposide (IC₅₀ = 7.5 ± 1.04 and 9.5 ± 1.01 µg/mL). Notably, compound 7i displayed the highest antiproliferative activity among the tested compounds, with selectivity towards the MDA-MB-231, IC₅₀ 9.5 ± 0.38 µg/mL, with respect to Etoposide (IC₅₀ = 8.4 ± 0.91 µg/mL). Ligand 7i showed the best docking score (-9.92 kcal*mol^-1), followed by ligand 7 g (-10.68 kcal*mol^-1), with favorable H-bonding residues GlnA:64, AsnA:103, GlnA:112 and SerA:111 within the colorectal active site (PDB code: 2HQ6). DFT analyses elucidated electronic properties, including geometry optimization, frontier molecular orbitals, and E_HOMO-E_LUMO (0.12766-0.15523 eV), correlating with observed bioactivity. The theoretical predictions by DFT and in silico docking and ADMET-physicochemical properties were well supported by the experimental studies and revealed strong anticancer activity. Collectively, these findings highlight the benzo[b]thiophene scaffold as a highly promising candidate for the development of new anticancer inhibitors, warranting further investigation.

PMID:
42855935
Bibliographic data and abstract were imported from PubMed on 10 Oct 2026.

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