Reactivity, bioactivity, and antileishmanial activity of dihydrosyrindine and syringine: Modelling, cytotoxicity, molecular docking, molecular dynamics, and MM-GBSA analyses

Dihydrosyrindine (a) and Syringine (b) are phenylpropanoid derivatives with structural variations that may influence their biological activity, particularly against Leishmania major. This study investigates the impact of chirality on their bioactivity by assessing molecular, electronic, pharmacokinetic, and cytotoxic properties through computational methods to evaluate their potential as therapeutic agents.

Electronic analyses (HOMO–LUMO, MESP, NCI-RDG) revealed that dihydrosyrindine possesses greater electronic delocalization and a lower HOMO-LUMO gap than syringine, suggesting higher reactivity. Molecular docking against L. major methionyl-tRNA synthetase (PDB: 3KFL) showed stronger binding for dihydrosyrindine (−138.905 MolDock score) compared to syringine (−135.958), though both were weaker than the co-crystallized ligand ME8 (−196.543). Molecular dynamics confirmed the stability of the complexes, with dihydrosyrindine showing lower RMSD values (about 1.6 Å), indicating stronger binding retention of syringine. Syringine demonstrated strong and stable binding energies throughout the simulation (−66.81 to −76.04 kcal/mol), outperforming ME8 at later frames, whose binding energy decreased from −106.95 to −65.48 kcal/mol. In contrast, dihydrosyrindine showed weaker and unstable binding, with values fluctuating and dropping as low as −6.62 kcal/mol, indicating lower affinity and complex stability compared to both Syringine and ME8. Pharmacokinetic predictions revealed moderate intestinal absorption (about 40 %) and low CNS penetration. Both compounds lacked CYP or hERG liabilities; syringine showed better predicted clearance, while dihydrosyrindine exhibited higher environmental toxicity. Biological outcome predictions showed moderate cytotoxicity for both compounds against HL-60 (leukemia) and NCI-H838 (lung cancer) cell lines. However, both also exhibited non-selective effects on normal lung fibroblasts (WI-38 VA13), suggesting limited therapeutic windows.

Dihydrosyrindine demonstrates stronger reactivity and enzyme binding, indicating greater antiprotozoal potential, whereas syringine shows improved metabolic stability and consistent target engagement. The increased chirality in dihydrosyrindine enhances molecular recognition, leading to improved hydrogen bonding and hydrophobic interactions compared to syringine. However, ME8 remains the strongest binder due to its optimized interaction profile, supporting their potential as lead structures for anti-Leishmania drug development.