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Abstract <p>A series of <i>N-</i>hydroxy-2-[4-(2-R<sup>1</sup>,3-R<sup>2</sup>,6-R<sup>3</sup>-quinolin-4-yl)phenyl]acetamides <b>4a</b>–<b>4n</b> (R<sup>1</sup>–R<sup>3</sup> = Me, Et, Cl, Ph) was synthesized, screened for HDAC8 inhibition and antiproliferative activity, and analyzed via in silico molecular docking. The synthesis of the hydroxamic acid-functionalized quinoline scaffolds involved the Friedlander reaction followed by Friedel–Craft alkylation and ester hydrolysis. The in vitro HDAC8 inhibition potential and antiproliferative activity of the synthesized compounds were assessed by the MTT assays. Molecular docking was performed of the products to the HDAC8 target protein (PDB ID: 5FCW) was performed to determine the binding energies and sites, as well as nature of interactions In the in vitro HDAC8 inhibition activity, <b>4g</b> showed a slightly higher (IC<sub>50</sub> = 9.53 µM), while <b>4a</b> exhibited a slightly lower activity (IC<sub>50</sub> = 21.24 µM) than the other compounds. Scaffold <b>4g</b> exhibited good in vitro anticancer activity (IC<sub>50</sub> = 3.69 µM) against the COLO 205 cell line, and scaffold <b>4h</b> was found to be active against two cancer cell lines: HCT 116 (IC<sub>50</sub> = 6.91 µM) and COLO320 DM (IC<sub>50</sub> = 8.91 µM). Molecular docking predicted high binding affinities of compounds <b>4g</b> and <b>4n</b> (–8.1 and –7.9 kcal/mol) to the HDAC8 target protein. The results highlight the HDAC8 inhibitory and anticancer potential of the new hydroxamic acid–appended quinoline derivatives, identifying compound <b>4g</b> as a particularly promising candidate for further development.</p>

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Synthesis, Antiproliferative Activity Evaluation, and Molecular Docking Analysis of N-Hydroxy-2-[4-(2-R1,3-R2,6-R3-quinolin-4-yl)phenyl]acetamides as Promising HDAC8 Inhibitors

  • 期刊论文

  • 发表日期：

    2025年11月1日

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  • S. S. Gagare,
  • V. P. Choudhari,
  • A. S. Jain,
  • S. N. Mali,
  • S. S. Gurav

摘要

Abstract

A series of N-hydroxy-2-[4-(2-R1,3-R2,6-R3-quinolin-4-yl)phenyl]acetamides 4a–4n (R1–R3 = Me, Et, Cl, Ph) was synthesized, screened for HDAC8 inhibition and antiproliferative activity, and analyzed via in silico molecular docking. The synthesis of the hydroxamic acid-functionalized quinoline scaffolds involved the Friedlander reaction followed by Friedel–Craft alkylation and ester hydrolysis. The in vitro HDAC8 inhibition potential and antiproliferative activity of the synthesized compounds were assessed by the MTT assays. Molecular docking was performed of the products to the HDAC8 target protein (PDB ID: 5FCW) was performed to determine the binding energies and sites, as well as nature of interactions In the in vitro HDAC8 inhibition activity, 4g showed a slightly higher (IC50 = 9.53 µM), while 4a exhibited a slightly lower activity (IC50 = 21.24 µM) than the other compounds. Scaffold 4g exhibited good in vitro anticancer activity (IC50 = 3.69 µM) against the COLO 205 cell line, and scaffold 4h was found to be active against two cancer cell lines: HCT 116 (IC50 = 6.91 µM) and COLO320 DM (IC50 = 8.91 µM). Molecular docking predicted high binding affinities of compounds 4g and 4n (–8.1 and –7.9 kcal/mol) to the HDAC8 target protein. The results highlight the HDAC8 inhibitory and anticancer potential of the new hydroxamic acid–appended quinoline derivatives, identifying compound 4g as a particularly promising candidate for further development.