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

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.