Identification of Substituted 4-Aminocinnolines as Broad-Spectrum Antiparasitic Agents.

IF 4 2区医学 Q2 CHEMISTRY, MEDICINAL

ACS Infectious Diseases Pub Date : 2025-03-14 Epub Date: 2025-02-12 DOI:10.1021/acsinfecdis.4c00666

Andrew Spaulding, Amrita Sharma, Miriam A Giardini, Benjamin Hoffman, Jean A Bernatchez, Laura-Isobel McCall, Claudia M Calvet, Jasmin Ackermann, Julia M Souza, Diane Thomas, Caroline C Millard, William G Devine, Baljinder Singh, Everton M Silva, Susan E Leed, Norma E Roncal, Erica C Penn, Jessey Erath, Gaurav Kumar, Yadira Sepulveda, Arnold Garcia, Ana Rodriguez, Nelly El-Sakkary, Richard J Sciotti, Robert F Campbell, Jeremiah D Momper, James H McKerrow, Conor R Caffrey, Jair L Siqueira-Neto, Michael P Pollastri, Kojo Mensa-Wilmot, Lori Ferrins

{"title":"Identification of Substituted 4-Aminocinnolines as Broad-Spectrum Antiparasitic Agents.","authors":"Andrew Spaulding, Amrita Sharma, Miriam A Giardini, Benjamin Hoffman, Jean A Bernatchez, Laura-Isobel McCall, Claudia M Calvet, Jasmin Ackermann, Julia M Souza, Diane Thomas, Caroline C Millard, William G Devine, Baljinder Singh, Everton M Silva, Susan E Leed, Norma E Roncal, Erica C Penn, Jessey Erath, Gaurav Kumar, Yadira Sepulveda, Arnold Garcia, Ana Rodriguez, Nelly El-Sakkary, Richard J Sciotti, Robert F Campbell, Jeremiah D Momper, James H McKerrow, Conor R Caffrey, Jair L Siqueira-Neto, Michael P Pollastri, Kojo Mensa-Wilmot, Lori Ferrins","doi":"10.1021/acsinfecdis.4c00666","DOIUrl":null,"url":null,"abstract":"Neglected tropical diseases such as Chagas disease, human African trypanosomiasis, leishmaniasis, and schistosomiasis have a significant global health impact in predominantly developing countries, although these diseases are spreading due to increased international travel and population migration. Drug repurposing with a focus on increasing antiparasitic potency and drug-like properties is a cost-effective and efficient route to the development of new therapies. Here we identify compounds that have potent activity against Trypanosoma cruzi and Leishmania donovani, and the latter were progressed into the murine model of infection. Despite the potent in vitro activity, there was no effect on parasitemia, necessitating further work to improve the pharmacokinetic properties of this series. Nonetheless, valuable insights have been obtained into the structure-activity and structure-property relationships of this compound series.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":"584-599"},"PeriodicalIF":4.0000,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11915375/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Infectious Diseases","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1021/acsinfecdis.4c00666","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/2/12 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}

引用次数: 0

Abstract

Neglected tropical diseases such as Chagas disease, human African trypanosomiasis, leishmaniasis, and schistosomiasis have a significant global health impact in predominantly developing countries, although these diseases are spreading due to increased international travel and population migration. Drug repurposing with a focus on increasing antiparasitic potency and drug-like properties is a cost-effective and efficient route to the development of new therapies. Here we identify compounds that have potent activity against Trypanosoma cruzi and Leishmania donovani, and the latter were progressed into the murine model of infection. Despite the potent in vitro activity, there was no effect on parasitemia, necessitating further work to improve the pharmacokinetic properties of this series. Nonetheless, valuable insights have been obtained into the structure-activity and structure-property relationships of this compound series.

查看原文本刊更多论文

取代4-氨基皂苷类广谱抗寄生虫剂的鉴定。

被忽视的热带病，如恰加斯病、非洲人类锥虫病、利什曼病和血吸虫病，主要在发展中国家对全球健康产生重大影响，尽管由于国际旅行和人口移徙的增加，这些疾病正在蔓延。以提高抗寄生虫效力和药物样特性为重点的药物再利用是开发新疗法的一种经济有效的途径。在这里，我们发现了对克氏锥虫和多诺瓦利什曼原虫具有有效活性的化合物，并将后者进展到小鼠感染模型中。尽管具有强大的体外活性，但对寄生虫病没有影响，需要进一步的工作来改善该系列的药代动力学特性。尽管如此，对该化合物系列的结构-活性和结构-性质关系获得了有价值的见解。

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分钟内获得全文求助全文

来源期刊

ACS Infectious Diseases CHEMISTRY, MEDICINALINFECTIOUS DISEASES&nb-INFECTIOUS DISEASES

CiteScore

9.70

自引率

3.80%

发文量

213

期刊介绍： ACS Infectious Diseases will be the first journal to highlight chemistry and its role in this multidisciplinary and collaborative research area. The journal will cover a diverse array of topics including, but not limited to: * Discovery and development of new antimicrobial agents — identified through target- or phenotypic-based approaches as well as compounds that induce synergy with antimicrobials. * Characterization and validation of drug target or pathways — use of single target and genome-wide knockdown and knockouts, biochemical studies, structural biology, new technologies to facilitate characterization and prioritization of potential drug targets. * Mechanism of drug resistance — fundamental research that advances our understanding of resistance; strategies to prevent resistance. * Mechanisms of action — use of genetic, metabolomic, and activity- and affinity-based protein profiling to elucidate the mechanism of action of clinical and experimental antimicrobial agents. * Host-pathogen interactions — tools for studying host-pathogen interactions, cellular biochemistry of hosts and pathogens, and molecular interactions of pathogens with host microbiota. * Small molecule vaccine adjuvants for infectious disease. * Viral and bacterial biochemistry and molecular biology.