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

被引：8
作者：
Visbal, Gonzalo [1 ]
Justo, Rodrigo M. S. [2 ]
Miranda, Gabrielle dos Santos da Silva e [3 ]
Silva, Sara Teixeira de Macedo [4 ]
de Souza, Wanderley [5 ,6 ]
Rodrigues, Juliany Cola Fernandes [3 ]
Navarro, Maribel [2 ]
机构：
[1] Inst Nacl Metrol Qualidade & Tecnol, Lab Acidos Nucl Laban, Coordenacao Geral Biol Cobio, Diretoria Metrol Cient & Ind,DIMCI, BR-25250020 Rio De Janeiro, Brazil
[2] Univ Fed Juiz Fora Juiz Fora, Dept Quim, Lab Quim Bioinorgan & Catalise LaQB, Inst Ciencias Exatas, BR-36036900 Juiz De Fora, Brazil
[3] Univ Fed Rio de Janeiro, Nucleo Multidisciplinar Pesquisa Biol NUMPEX Bio, GdSSeM, Campus UFRJ Duque Caxias Prof Geraldo Cidade, BR-21941901 Rio De Janeiro, Brazil
[4] Univ Fed Rio Janeiro, Ctr Nacl Biol Estrutural & Bioimagem, CENABIO, BR-21941901 Rio De Janeiro, Brazil
[5] Univ Fed Rio de Janeiro, Lab Ultraestrutura Celular Hertha Meyer, Inst Biofis Carlos Chagas Filho, BR-21941901 Rio De Janeiro, Brazil
[6] Univ Estado Amazonas, Ctr Multiusuario Anal Fenomenos Biol, Escola Super Saude, BR-69850000 Manaus, Brazil
来源：
PHARMACEUTICS | 2023年 / 15卷 / 04期
关键词：
zinc; sterol hydrazone; Leishmania; sterol methyltransferase; parasites; metal-drug; IN-VITRO; BIOSYNTHESIS INHIBITORS; TRYPANOSOMA-CRUZI; ERGOSTEROL; METAL; ANTICANCER; GROWTH;
D O I：
10.3390/pharmaceutics15041113
中图分类号：
R9 [药学];
学科分类号：
1007 ;
摘要：
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-3 beta-ol, a well-known bioactive molecule functioning as a sterol Delta(24)-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 mu M and 2.5 mu M 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 mu M, SI = 156) is more selective than H3 (CC50 = 10 mu M, 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-3 beta-ol and cholesta-7,24-dien-3 beta-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).
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页数：18
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