Investigating the Anti-Leishmanial Potential of Phytoconstituents Derived from Anchusa arvensis: In-vitro and Network Pharmacology Study

Background: Leishmaniasis is a neglected tropical disease with limited treatment options, characterized by high toxicity, rising resistance, and poor affordability of currently available drugs. Plant-derived bioactive compounds represent a promising alternative, offering potential for safer, more cost-effective therapeutics. Anchusa arvensis (Boraginaceae) has long been used in traditional medicine and is reported to possess diverse pharmacological properties, yet its anti-leishmanial potential remains underexplored. Objective: This study aimed to evaluate the anti-leishmanial efficacy, drug-likeness, and safety profiles of two key phytoconstituents from A. arvensis—p-methoxy catechol and uvaol—using an integrated approach combining in silico network pharmacology, molecular docking, ADMET prediction, and in vitro assays. Methods: Computational tools including PASS Online, SwissADME, pkCSM, FAME3, GLORY, Pred-hERG, and Endocrine Disruptome were used to predict pharmacokinetics, toxicity, and drug-likeness. Molecular docking was performed against the Leishmania tropica leishmanolysin (gp63; PDB ID: 1LML), followed by molecular dynamics simulation to assess complex stability. In vitro anti-leishmanial activity was tested against L. tropica promastigotes using MTT assays, with glucantime as a reference drug. Results: p-Methoxy catechol exhibited favorable drug-likeness (Lipinski compliant), low predicted toxicity, and strong activity as an inhibitor of aspulvinone dimethylallyltransferase and chlordecone reductase. Uvaol demonstrated additional hepatoprotective and anti-inflammatory potentials but showed moderate risks of hepatotoxicity and skin sensitization. Molecular docking revealed binding energies of −5.74 kcal/mol (p-methoxy catechol) and −9.0 kcal/mol (uvaol), with stable hydrogen bonding at key gp63 residues. In vitro assays confirmed significant anti-leishmanial activity with IC₅₀ values of 5.60 µg/mL (p-methoxy catechol) and 16.17 µg/mL (uvaol), compared to 0.78 µg/mL for glucantime. Conclusion: The findings establish p-methoxy catechol as a potent, safe, and druggable candidate, while uvaol offers complementary therapeutic value through multi-target pharmacology. Both compounds represent promising leads for the development of affordable plant-based anti-leishmanial therapies, aligning with global health goals to combat neglected tropical diseases.