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<p>Leishmaniasis, a neglected tropical disease caused by Leishmania parasites, lacks safe and effective treatments due to drug resistance and toxicity. This study introduces novel tetrahydropyridine (THP) derivatives as potential inhibitors of trypanothione reductase (TR), a unique redox enzyme essential for parasite survival. Eight THP analogs were synthesized and screened for antileishmanial activity against <i>Leishmania major</i> promastigotes (strain MRHO/IR/75/ER) using the MTT assay, revealing compound <b>A5</b> as the most potent (IC<sub>50</sub> = 89.2 ± 4.5 nM) with favorable selectivity over J774 macrophages. Structure-activity relationship analysis highlighted the role of electron-withdrawing substituents (e.g., Cl at R<sub>1</sub>) in enhancing potency, while bulky or highly polar groups (e.g., NO<sub>2</sub> at R<sub>2</sub> in <b>A7</b>) diminished efficacy. Molecular docking against <i>L. infantum</i> TR (PDB: 6T95) demonstrated strong binding affinities for active compounds, with <b>A5</b> forming key π-π stacking interactions (Trp21, Tyr110) and π-sulfur interactions (Met113). Stability was confirmed via 100-ns molecular dynamics simulations, showing low RMSD and RMSF values and persistent interactions. Density functional theory (DFT) calculations at the B3LYP/6–31 + G(d, p) level correlated electronic descriptors (e.g., wider HOMO-LUMO gap and higher hardness in <b>A5</b>) with superior biological activity, docking scores, and ADME (Absorption, Distribution, Metabolism, and Excretion) profiles. In silico pharmacokinetic predictions indicated good oral absorption and low blood-brain barrier penetration, supporting drug-likeness. Overall, this integrated phenotypic and computational approach identifies THP scaffolds, particularly <b>A5</b>, as promising leads for developing orally bioavailable antileishmanial agents targeting TR, paving the way for further optimization and in vivo validation.</p>

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In Vitro antileishmanial evaluation, molecular docking, dynamics simulations, and DFT Studies of tetrahydropyridine derivatives as potential trypanothione reductase inhibitors

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月4日

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  • Elaheh Ataollahi,
  • Razieh Sabet,
  • Gholamreza Hatam,
  • Alireza poustforoosh,
  • Nazi Dastkhosh,
  • Atefe Omidi,
  • Aida Solhjoo,
  • Leila Zamani,
  • Leila Emami,
  • Soghra Khabnadideh

摘要

Leishmaniasis, a neglected tropical disease caused by Leishmania parasites, lacks safe and effective treatments due to drug resistance and toxicity. This study introduces novel tetrahydropyridine (THP) derivatives as potential inhibitors of trypanothione reductase (TR), a unique redox enzyme essential for parasite survival. Eight THP analogs were synthesized and screened for antileishmanial activity against Leishmania major promastigotes (strain MRHO/IR/75/ER) using the MTT assay, revealing compound A5 as the most potent (IC50 = 89.2 ± 4.5 nM) with favorable selectivity over J774 macrophages. Structure-activity relationship analysis highlighted the role of electron-withdrawing substituents (e.g., Cl at R1) in enhancing potency, while bulky or highly polar groups (e.g., NO2 at R2 in A7) diminished efficacy. Molecular docking against L. infantum TR (PDB: 6T95) demonstrated strong binding affinities for active compounds, with A5 forming key π-π stacking interactions (Trp21, Tyr110) and π-sulfur interactions (Met113). Stability was confirmed via 100-ns molecular dynamics simulations, showing low RMSD and RMSF values and persistent interactions. Density functional theory (DFT) calculations at the B3LYP/6–31 + G(d, p) level correlated electronic descriptors (e.g., wider HOMO-LUMO gap and higher hardness in A5) with superior biological activity, docking scores, and ADME (Absorption, Distribution, Metabolism, and Excretion) profiles. In silico pharmacokinetic predictions indicated good oral absorption and low blood-brain barrier penetration, supporting drug-likeness. Overall, this integrated phenotypic and computational approach identifies THP scaffolds, particularly A5, as promising leads for developing orally bioavailable antileishmanial agents targeting TR, paving the way for further optimization and in vivo validation.