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<p>A novel series of fifteen indole-benzimidazole conjugated <i>β</i>-lactams (<b>6a–o</b>) was synthesized via a bimetallic Pd(PPh<sub>3</sub>)<sub>4</sub>/CuI catalyzed alkynylation of 3-chloroazetidine-2-one (<i>β</i>-lactam derivative) with structurally diverse terminal alkynes through tandem C–C bond activation/Sonogashira-type coupling. The synthetic strategy encompasses Schiff base formation between indole-3-carbaldehyde and 2-aminobenzimidazole, followed by cyclization to the <i>β</i>-lactam framework, and sequential C(sp<sup>3</sup>)–X/C(sp)–H functionalization, enabling efficient formation of C(sp<sup>3</sup>)–C(sp) bonds, affording yields up to 87%. The mechanistic interplay highlights the synergistic role of Pd and Cu, especially during the transmetallation step, affording broad substrate scope and high functional group tolerance. The synthesized analogs were further screened for antiproliferative activity against A549 and MCF-7 cancer cell lines. Among them, compounds <b>6b</b>, <b>e–g</b>, exhibited pronounced growth inhibition against A549 cells (GI<sub>50</sub> =  &lt; 10&#xa0;µg/mL), while <b>6e–g</b>, <b>6i</b> and <b>6j</b> showed potent activity against MCF-7 cells (GI<sub>50</sub> =  &lt; 10–12&#xa0;µg/mL). Notably, three compounds <b>6e–g</b> bearing electron-withdrawing substituents (Cl, Br, and NO<sub>2</sub>, respectively) on the aromatic ring demonstrate strong antiproliferative activity against both cell lines, identifying them as the most active analogs. The structural activity relationship analysis also confirms the critical role of electron-withdrawing substituents in enhancing antiproliferative activity. Overall, these results highlight the indole-benzimidazole conjugated <i>β</i>-lactum hybrids as promising lead scaffolds for future development of anticancer drugs.</p> Graphical abstract <p></p>

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Unveiling the Pd(PPh3)4/CuI-catalyzed efficient synthesis of indole-benzimidazole conjugated β-lactams with antiproliferative profiling

  • 期刊论文

  • 发表日期：

    2026年3月5日

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  • Rachana Upadhyay,
  • Amit B. Patel

摘要

A novel series of fifteen indole-benzimidazole conjugated β-lactams (6a–o) was synthesized via a bimetallic Pd(PPh3)4/CuI catalyzed alkynylation of 3-chloroazetidine-2-one (β-lactam derivative) with structurally diverse terminal alkynes through tandem C–C bond activation/Sonogashira-type coupling. The synthetic strategy encompasses Schiff base formation between indole-3-carbaldehyde and 2-aminobenzimidazole, followed by cyclization to the β-lactam framework, and sequential C(sp3)–X/C(sp)–H functionalization, enabling efficient formation of C(sp3)–C(sp) bonds, affording yields up to 87%. The mechanistic interplay highlights the synergistic role of Pd and Cu, especially during the transmetallation step, affording broad substrate scope and high functional group tolerance. The synthesized analogs were further screened for antiproliferative activity against A549 and MCF-7 cancer cell lines. Among them, compounds 6b, e–g, exhibited pronounced growth inhibition against A549 cells (GI50 =  < 10 µg/mL), while 6e–g, 6i and 6j showed potent activity against MCF-7 cells (GI50 =  < 10–12 µg/mL). Notably, three compounds 6e–g bearing electron-withdrawing substituents (Cl, Br, and NO2, respectively) on the aromatic ring demonstrate strong antiproliferative activity against both cell lines, identifying them as the most active analogs. The structural activity relationship analysis also confirms the critical role of electron-withdrawing substituents in enhancing antiproliferative activity. Overall, these results highlight the indole-benzimidazole conjugated β-lactum hybrids as promising lead scaffolds for future development of anticancer drugs.

Graphical abstract