In vitro antileishmanial activity of thioridazine on amphotericin B unresponsive/ sensitive Leishmania donovani promastigotes and intracellular amastigotes

IF 16.4 1区化学 Q1 CHEMISTRY, MULTIDISCIPLINARY Accounts of Chemical Research Pub Date : 2023-12-22 DOI:10.1016/j.exppara.2023.108688

Vikash Kumar , Shobha Kumari , Ravi Ranjan , Ashish Kumar , Dayakar Alti

{"title":"In vitro antileishmanial activity of thioridazine on amphotericin B unresponsive/ sensitive Leishmania donovani promastigotes and intracellular amastigotes","authors":"Vikash Kumar , Shobha Kumari , Ravi Ranjan , Ashish Kumar , Dayakar Alti","doi":"10.1016/j.exppara.2023.108688","DOIUrl":null,"url":null,"abstract":"<div>The recent increase in the drug (liposomal amphotericin-B) unresponsive cases becomes hostile for the visceral leishmaniasis (VL) elimination target. The quest for new antileishmanial drugs is on the way and may demand more time. Meanwhile, drug repurposing is a quite promising option to explore further. We made such an attempt with thioridazine (TRZ), a first-line antipsychotic drug, which was reported for antimicrobial activity. In this study, we evaluated the drug activity of TRZ against amphotericin-B (Amp-B) sensitive and unresponsive Leishmania donovani promastigotes, as well as intracellular amastigotes (drug sensitive). We observed a potent antileishmanial activity of TRZ with significantly low half maximal inhibitory concentrations (IC50) on both the variants of promastigotes (0.61 ± 0.15 μM). These concentrations are comparable to the previously reported IC50 concentration of the current antileishmanial drug (Amp-B) against L. donovani. Light microscopy reveals the perturbations in promastigote morphology upon TRZ treatment. The in vitro studies on human macrophage cell lines determine the 50% cytotoxicity concentration (CC50) of TRZ on host cells as 20.046 μM and a half maximal effective concentration (EC50) as 0.91 μM during L. donovani infection, in turn selectivity index (SI) was calculated as 22.03 μM. Altogether, the results demonstrate that TRZ has the potential for drug repurposing and further studies on animal models could provide better insights for VL treatment.</div>","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":null,"pages":null},"PeriodicalIF":16.4000,"publicationDate":"2023-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Accounts of Chemical Research","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0014489423002291","RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}

引用次数: 0

Abstract

The recent increase in the drug (liposomal amphotericin-B) unresponsive cases becomes hostile for the visceral leishmaniasis (VL) elimination target. The quest for new antileishmanial drugs is on the way and may demand more time. Meanwhile, drug repurposing is a quite promising option to explore further. We made such an attempt with thioridazine (TRZ), a first-line antipsychotic drug, which was reported for antimicrobial activity. In this study, we evaluated the drug activity of TRZ against amphotericin-B (Amp-B) sensitive and unresponsive Leishmania donovani promastigotes, as well as intracellular amastigotes (drug sensitive). We observed a potent antileishmanial activity of TRZ with significantly low half maximal inhibitory concentrations (IC₅₀) on both the variants of promastigotes (0.61 ± 0.15 μM). These concentrations are comparable to the previously reported IC₅₀ concentration of the current antileishmanial drug (Amp-B) against L. donovani. Light microscopy reveals the perturbations in promastigote morphology upon TRZ treatment. The in vitro studies on human macrophage cell lines determine the 50% cytotoxicity concentration (CC₅₀) of TRZ on host cells as 20.046 μM and a half maximal effective concentration (EC₅₀) as 0.91 μM during L. donovani infection, in turn selectivity index (SI) was calculated as 22.03 μM. Altogether, the results demonstrate that TRZ has the potential for drug repurposing and further studies on animal models could provide better insights for VL treatment.

Abstract Image

查看原文

微信好友朋友圈 QQ好友复制链接

本刊更多论文

硫利达嗪对两性霉素 B 无反应/敏感的唐氏利什曼原虫和细胞内变形体的体外抗利什曼活性

最近，对药物（脂质体两性霉素-B）无反应的病例有所增加，这对消除内脏利什曼病（VL）的目标不利。寻找新的抗利什曼病药物的工作正在进行中，可能需要更多时间。与此同时，药物再利用也是一个颇有前景的选择。我们对一线抗精神病药物硫利达嗪（TRZ）进行了这样的尝试，据报道该药物具有抗菌活性。在这项研究中，我们评估了硫利达嗪对两性霉素-B（Amp-B）敏感和无反应的唐氏利什曼原虫以及细胞内原虫（药物敏感）的药物活性。我们观察到了 TRZ 的强效抗利什曼病活性，其对两种变体原生体的半数最大抑制浓度（IC50）都很低（0.61 ± 0.15 μM）。这些浓度与之前报道的当前抗唐诺沃尼氏菌药物（Amp-B）的 IC50 浓度相当。光学显微镜显示了 TRZ 处理后原生动物形态的变化。在人巨噬细胞系上进行的体外研究确定，TRZ对宿主细胞的50%细胞毒性浓度（CC50）为20.046 μM，在唐诺瓦伊蚊感染期间的半数最大有效浓度（EC50）为0.91 μM，而选择性指数（SI）则计算为22.03 μM。总之，研究结果表明 TRZ 具有药物再利用的潜力，进一步的动物模型研究可为 VL 治疗提供更好的见解。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文去求助

来源期刊

Accounts of Chemical Research 化学-化学综合

CiteScore

31.40

自引率

1.10%

发文量

312

审稿时长

2 months

期刊介绍： Accounts of Chemical Research presents short, concise and critical articles offering easy-to-read overviews of basic research and applications in all areas of chemistry and biochemistry. These short reviews focus on research from the author’s own laboratory and are designed to teach the reader about a research project. In addition, Accounts of Chemical Research publishes commentaries that give an informed opinion on a current research problem. Special Issues online are devoted to a single topic of unusual activity and significance. Accounts of Chemical Research replaces the traditional article abstract with an article "Conspectus." These entries synopsize the research affording the reader a closer look at the content and significance of an article. Through this provision of a more detailed description of the article contents, the Conspectus enhances the article's discoverability by search engines and the exposure for the research.