Synthesis and anti-antileishmanial profile of novel thiazolidine-4-one derivatives and molecular docking and molecular dynamics simulations studies

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Abstract
Leishmaniasis is a severely neglected intracellular protozoan disease caused by infection with parasites of the Leishmania genus, affecting over 98 countries globally. Presently, the infection threatens the health of more than 350 million people globally, resulting in an estimated 60,000 deaths yearly from both visceral and cutaneous forms of the parasite. In present research, a novel series of thiazolidine-4-one analogues (7a-g) was synthesized and evaluated against Leishmania major. In vitro assays demonstrated using Leishmania major promastigotes and amastigotes, while cytotoxicity was assessed on the J774.A1 macrophage cell line. All tested compounds exhibited inhibitory effects against promastigotes, with compounds 7a (IC50 = 34.97 μM), 7c (IC50 = 40.79 μM), and 7b (IC50 = 62.59 μM) showing the highest potency. Against the amastigote form, analogues 7a, 7b, and 7d demonstrated notable efficacy, with IC50 values of 354.53 μM, 665.72 μM, and 746.59 μM, respectively. Flow cytometry analysis revealed that these compounds induce multiple stages of apoptosis, including both early and late apoptosis, as well as necrosis, in promastigotes. Furthermore, some derivatives exhibited moderate cytotoxic effects on macrophages. Compounds 7a and 7b demonstrated the highest selectivity indices (SI) of 6.23 and 3.22, respectively. Overall, the tested compounds showed stronger anti-promastigote activity compared to their anti-amastigote effects. In silico analyses indicated that the thiazolidine-4-one derivatives possess satisfactory drug-likeness characteristics and identified probable metabolic sites via major cytochrome P450 enzymes. Finally, molecular docking and molecular dynamics simulations were performed at the active site of Leishmania major pteridine reductase 1 (LmPTR1). They revealed that the most active compounds, 7a and 7c, adopt favorable binding orientations and maintain stable interactions with key residues of LmPTR1, correlating with their enhanced in vitro activity. Additionally, RMSD, RMSF, hydrogen bonds, Rg, SASA, PCA, and energy analysis during molecular dynamics simulations indicated stable binding of two compounds with LmPTR1. Furthermore, the results from docking and molecular dynamics simulations demonstrated that hydrophobic interactions were critical in the binding of these compounds to LmPTR1.

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