Susceptibility of Leishmania to novel pentavalent organometallics: Investigating impact on DNA and membrane integrity in antimony(III)-sensitive and -resistant strains

IF 3.5 4区医学 Q2 CHEMISTRY, MEDICINAL

Drug Development Research Pub Date : 2024-05-05 DOI:10.1002/ddr.22194

Arshad Islam, Bruno Rodrigues do Prado, Dalton Dittz, Bernardo Lages Rodrigues, Sydnei Magno da Silva, Rubens L. do Monte-Neto, Muhammad Shabeer, Frédéric Frézard, Cynthia Demicheli

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Abstract

The aim the present study was to investigate the impact of novel pentavalent organobismuth and organoantimony complexes on membrane integrity and their interaction with DNA, activity against Sb(III)-sensitive and -resistant Leishmania strains and toxicity in mammalian peritoneal macrophages. Ph₃M(L)₂ type complexes were synthesized, where M = Sb(V) or Bi(V) and L = deprotonated 3-(dimethylamino)benzoic acid or 2-acetylbenzoic acid. Both organobismuth(V) and organoantimony(V) complexes exhibited efficacy at micromolar concentrations against Leishmania amazonensis and L. infantum but only the later ones demonstrated biocompatibility. Ph₃Sb(L1)₂ and Ph₃Bi(L1)₂ demonstrated distinct susceptibility profiles compared to inorganic Sb(III)-resistant strains of MRPA-overexpressing L. amazonensis and AQP1-mutated L. guyanensis. These complexes were able to permeate the cell membrane and interact with the Leishmania DNA, suggesting that this effect may contribute to the parasite growth inhibition via apoptosis. Taken altogether, our data substantiate the notion of a distinct mechanism of uptake pathway and action in Leishmania for these organometallic complexes, distinguishing them from the conventional inorganic antimonial drugs.

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利什曼原虫对新型五价有机金属的敏感性：调查对锑(III)敏感和抗性菌株的 DNA 和膜完整性的影响

本研究旨在探讨新型五价有机铋和有机锑配合物对膜完整性的影响、它们与 DNA 的相互作用、对 Sb（III）敏感和抗性利什曼病菌株的活性以及在哺乳动物腹腔巨噬细胞中的毒性。合成了 Ph3M(L)2 型复合物，其中 M = Sb(V) 或 Bi(V)，L = 去质子化的 3-（二甲基氨基）苯甲酸或 2-乙酰苯甲酸。有机铋（V）和有机锑（V）复合物在微摩尔浓度下对亚马逊利什曼原虫和婴儿利什曼原虫都有疗效，但只有后一种复合物具有生物相容性。Ph3Sb(L1)2 和 Ph3Bi(L1)2 与抗无机 Sb(III) 的亚马逊利什曼原虫和 AQP1 基因突变的圭亚那利什曼原虫相比，表现出不同的敏感性。这些复合物能够渗透细胞膜并与利什曼病 DNA 相互作用，表明这种作用可能有助于通过细胞凋亡抑制寄生虫的生长。总之，我们的数据证实了这些有机金属复合物在利什曼原虫体内的吸收途径和作用机制与传统的无机抗锑药物不同。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Drug Development Research 医学-药学

CiteScore

6.40

自引率

2.60%

发文量

104

审稿时长

6-12 weeks

期刊介绍： Drug Development Research focuses on research topics related to the discovery and development of new therapeutic entities. The journal publishes original research articles on medicinal chemistry, pharmacology, biotechnology and biopharmaceuticals, toxicology, and drug delivery, formulation, and pharmacokinetics. The journal welcomes manuscripts on new compounds and technologies in all areas focused on human therapeutics, as well as global management, health care policy, and regulatory issues involving the drug discovery and development process. In addition to full-length articles, Drug Development Research publishes Brief Reports on important and timely new research findings, as well as in-depth review articles. The journal also features periodic special thematic issues devoted to specific compound classes, new technologies, and broad aspects of drug discovery and development.