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<p>In this work, we explored the role of Lewis acid catalysts such as Scandium triflate (Sc(OTf)<sub>3</sub>) and Copper triflate (Cu(OTf)₂) in accelerating [4+2] cycloaddition reactions of 3-alkyl-2-vinylindoles and β,γ-unsaturated α-ketoesters using DFT calculations with the B3LYP functional and SDD and 6-311G(d,p) basis sets. This includes studies that are focused on understanding how catalytic parameters like reaction pathways, regioselectivity, or efficiency contribute to these transformations. Using molecular electron density theory (MEDT) and computational studies to analyze these catalytic effects, the catalysts were found to enhance the electrophilicity of β,γ-unsaturated α-ketoesters to a great degree, favoring a polar pathway and regioselectivity. Among the wide range of catalysts being screened, Sc(OTf)<sub>3</sub> was confirmed as the best one with the catalytic ability of activating bond cleavage and stabilizing intermediates, especially favoring the fastest exo pathway leading to the main product P-1. Furthermore, molecular docking and&#xa0;absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis suggested that synthesized indole-harboring pyrans have promising potency against HIV-1 and SARS-CoV-2. Notably, P4 and P3 showed relatively high binding affinities against HIV-1 whereas P1 showed a trespass degree of binding toward SARS-CoV-2 proteins that is more than existing benchmark drugs in certain aspects. These compounds have been reported to possess favorable ADME profiles, high gastrointestinal absorption, and blood–brain barrier permeability that highlighted their potential to be leads for antiviral drug development.</p>

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The role of Lewis acid catalysts in [4+2] cycloaddition of 3-alkyl-2-vinylindoles with β,γ-unsaturated α-ketoesters: absorption, distribution, metabolism, excretion, and toxicity study and molecular docking against SARS-CoV-2 and HIV-1

  • 期刊论文

  • 发表日期：

    2025年6月28日

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  • Khadija El Idrissi,
  • Abdellah Zeroual,
  • Abdallah M. Elgorban,
  • Ali H. Bahkali,
  • Shifa Wang,
  • Hocine Garmes

摘要

In this work, we explored the role of Lewis acid catalysts such as Scandium triflate (Sc(OTf)3) and Copper triflate (Cu(OTf)₂) in accelerating [4+2] cycloaddition reactions of 3-alkyl-2-vinylindoles and β,γ-unsaturated α-ketoesters using DFT calculations with the B3LYP functional and SDD and 6-311G(d,p) basis sets. This includes studies that are focused on understanding how catalytic parameters like reaction pathways, regioselectivity, or efficiency contribute to these transformations. Using molecular electron density theory (MEDT) and computational studies to analyze these catalytic effects, the catalysts were found to enhance the electrophilicity of β,γ-unsaturated α-ketoesters to a great degree, favoring a polar pathway and regioselectivity. Among the wide range of catalysts being screened, Sc(OTf)3 was confirmed as the best one with the catalytic ability of activating bond cleavage and stabilizing intermediates, especially favoring the fastest exo pathway leading to the main product P-1. Furthermore, molecular docking and absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis suggested that synthesized indole-harboring pyrans have promising potency against HIV-1 and SARS-CoV-2. Notably, P4 and P3 showed relatively high binding affinities against HIV-1 whereas P1 showed a trespass degree of binding toward SARS-CoV-2 proteins that is more than existing benchmark drugs in certain aspects. These compounds have been reported to possess favorable ADME profiles, high gastrointestinal absorption, and blood–brain barrier permeability that highlighted their potential to be leads for antiviral drug development.