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Abstract <p>The design, synthesis, in silico analysis, and in vitro evaluation of eleven novel indole–1,3,4-oxa­diazole hybrids as inhibitors of the EGFR enzyme are described. Among the novel indole–oxadiazole derivatives, those containing 4-chloro-2-fluorobenzyl, 4-(dimethylamino)benzyl, and 2,6-difluorobenzyl groups were found to be more effective EGFR inhibitors (IC<sub>50</sub> = 0.83±0.18, 0.96±0.06, and 1.33±0.09 μM, respec­tively). 4-Methoxy- and 4-(dimethylamino)benzylsulfanyl oxadiazoles possessed the strongest cytotoxicity on the A549 cell line with IC<sub>50</sub> values of 10.34±0.27 and 9.02±0.09 μM, respectively. These compounds were examined for their binding ability against lung cancer-derived EGFR mutants (PBD IDs: 2ITW and 2ITZ) and were found to interact with the amino acid residues Asp160(A), Thr95(A), Lys50(A), Ala48(A), Leu23(A), Asp160(A), Met98(A), Val31(A), and Ile94(A). Further evidence for the in vitro cytotoxicity of these derivatives was obtained from in silico predictions, including ADMETlab 3.0 and pkCSM simulations. Computational studies such as molecular docking and drug-likeness assessments confirmed the stability, favorable pharmaco­kinetics, and drug-like properties of these compounds. These findings highlight the promise of these compounds as candidates for further optimization and development as anticancer agents.</p>

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Development of Novel Indole–1,3,4-Oxadiazole Hybrids Targeting EGFR in Lung Cancer: Synthesis, Anticancer Evaluation, and Computational Study

  • 期刊论文

  • 发表日期：

    2025年12月1日

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  • N. V. N. K. Ganesh Babu,
  • M. Sudha,
  • S. Subramanyam,
  • T. R. Allaka

摘要

Abstract

The design, synthesis, in silico analysis, and in vitro evaluation of eleven novel indole–1,3,4-oxa­diazole hybrids as inhibitors of the EGFR enzyme are described. Among the novel indole–oxadiazole derivatives, those containing 4-chloro-2-fluorobenzyl, 4-(dimethylamino)benzyl, and 2,6-difluorobenzyl groups were found to be more effective EGFR inhibitors (IC50 = 0.83±0.18, 0.96±0.06, and 1.33±0.09 μM, respec­tively). 4-Methoxy- and 4-(dimethylamino)benzylsulfanyl oxadiazoles possessed the strongest cytotoxicity on the A549 cell line with IC50 values of 10.34±0.27 and 9.02±0.09 μM, respectively. These compounds were examined for their binding ability against lung cancer-derived EGFR mutants (PBD IDs: 2ITW and 2ITZ) and were found to interact with the amino acid residues Asp160(A), Thr95(A), Lys50(A), Ala48(A), Leu23(A), Asp160(A), Met98(A), Val31(A), and Ile94(A). Further evidence for the in vitro cytotoxicity of these derivatives was obtained from in silico predictions, including ADMETlab 3.0 and pkCSM simulations. Computational studies such as molecular docking and drug-likeness assessments confirmed the stability, favorable pharmaco­kinetics, and drug-like properties of these compounds. These findings highlight the promise of these compounds as candidates for further optimization and development as anticancer agents.