Zinc(II)-Sterol Hydrazone Complex as a Potent Anti-Leishmania Agent: Synthesis, Characterization, and Insight into Its Mechanism of Antiparasitic Action

Abstract

Searching for new alternatives for treating leishmaniasis, we present the synthesis, characterization, and biological evaluation against Leishmania amazonensis of the new ZnCl2(H3)2 complex. H3 is 22-hydrazone-imidazoline-2-yl-chol-5-ene-3β-ol, a well-known bioactive molecule functioning as a sterol Δ24-sterol methyl transferase (24-SMT) inhibitor. The ZnCl2(H3)2 complex was characterized by infrared, UV-vis, molar conductance measurements, elemental analysis, mass spectrometry, and NMR experiments. The biological results showed that the free ligand H3 and ZnCl2(H3)2 significantly inhibited the growth of promastigotes and intracellular amastigotes. The IC50 values found for H3 and ZnCl2(H3)2 were 5.2 µM and 2.5 µM for promastigotes, and 543 nM and 32 nM for intracellular amastigotes, respectively. Thus, the ZnCl2(H3)2 complex proved to be seventeen times more potent than the free ligand H3 against the intracellular amastigote, the clinically relevant stage. Furthermore, cytotoxicity assays and determination of selectivity index (SI) revealed that ZnCl2(H3)2 (CC50 = 5 μΜ, SI = 156) is more selective than H3 (CC50 = 10 μΜ, SI = 20). Furthermore, as H3 is a specific inhibitor of the 24-SMT, free sterol analysis was performed. The results showed that H3 was not only able to induce depletion of endogenous parasite sterols (episterol and 5-dehydroepisterol) and their replacement by 24-desalkyl sterols (cholesta-5,7,24-trien-3β-ol and cholesta-7,24-dien-3β-ol) but also its zinc derivative resulting in a loss of cell viability. Using electron microscopy, studies on the fine ultrastructure of the parasites showed significant differences between the control cells and parasites treated with H3 and ZnCl2(H3)2. The inhibitors induced membrane wrinkle, mitochondrial injury, and abnormal chromatin condensation changes that are more intense in the cells treated with ZnCl2(H3)2.

4‐Quinolinylhydrazone analogues kill Leishmania (Leishmania) amazonensis by inducing apoptosis and mitochondria‐dependent pathway cell death

“…In addition, the molecules used in this work, have a hydrazone bond joining the quinolinic nucleus to the substituent nucleus. Hydrazone bonds are widely used in the design of molecules for activity studies in various microorganisms, such as fungi (Hassan et al, 2022;Kim et al, 2023), bacteria (Hassan et al, 2022;Irfan et al, 2022;Verma et al, 2023), and Leishmania spp (Coimbra et al, 2019;Visbal et al, 2023). Hydrazone is a pH sensitive functional group.…”

“…In our work, the pharmacophoric group of the compounds is conjugate to the substituent (Kucharski et al, 2022) group through a hydrazone bond. Hydrazones are widely explored compounds that have diverse activities, such as antifungal (Hassan et al, 2022;Kim et al, 2023), antibacterial (Hassan et al, 2022;Irfan et al, 2022;Verma et al, 2023), antitumoral (Faisalabad et al, 2021Kim et al, 2023), and antileishmanial activity (Coimbra et al, 2019;Visbal et al, 2023). Therefore, in continuation with our research, we aimed to evaluate the antileishmanial activity, the mode of action on the parasite and the potency of the most promising compound in the murine model of cutaneous leishmaniasis.…”