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（1-苄基-4-三唑基）-吲哚-2-甲酰胺类化合物抗弓形虫和微小隐孢子虫的活性。

Activity of (1-benzyl-4-triazolyl)-indole-2-carboxamides against Toxoplasma gondii and Cryptosporidium parvum.

机构信息

Department of Pathobiology, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, 2001 S. Lincoln Avenue, Urbana, IL, 61802, USA.

Chicago State University, College of Pharmacy, Department of Pharmaceutical Sciences, 9501 S. King Drive, Chicago, IL, 60628, USA.

出版信息

Int J Parasitol Drugs Drug Resist. 2022 Aug;19:6-20. doi: 10.1016/j.ijpddr.2022.04.001. Epub 2022 Apr 16.

DOI:10.1016/j.ijpddr.2022.04.001
PMID:35462232
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9046076/
Abstract

Parasitic diseases such as toxoplasmosis and cryptosporidiosis remain serious global health challenges, not only to humans but also to domestic animals and wildlife. With only limited treatment options available, Toxoplasma gondii and Cryptosporidium parvum (the causative agents of toxoplasmosis and cryptosporidiosis, respectively) constitute a substantial health threat especially to young children and immunocompromised individuals. Herein, we report the synthesis and biological evaluation of a series of novel (1-benzyl-4-triazolyl)-indole-2-carboxamides and related compounds that show efficacy against T. gondii and C. parvum. Closely related analogs 7c (JS-2-30) and 7e (JS-2-44) showed low micromolar activity with IC indices ranging between 2.95 μM and 7.63 μM against both T. gondii and C. parvum, whereas the compound representing (1-adamantyl)-4-phenyl-triazole, 11b (JS-2-41), showed very good activity with an IC of 1.94 μM, and good selectivity against T. gondii in vitro. Importantly, compounds JS-2-41 and JS-2-44 showed appreciable in vivo efficacy in decreasing the number of T. gondii cysts in the brains of Brown Norway rats. Together, these results indicate that (1-benzyl-4-triazolyl)-indole-2-carboxamides and (1-adamantyl)-4-phenyl-triazoles are potential hits for medicinal chemistry explorations in search for novel antiparasitic agents for effective treatment of cryptosporidiosis and toxoplasmosis.

摘要

寄生虫病，如弓形虫病和隐孢子虫病，仍然是严重的全球健康挑战，不仅对人类，而且对家畜和野生动物也是如此。由于现有的治疗选择有限，刚地弓形虫和微小隐孢子虫（分别为弓形虫病和隐孢子虫病的病原体）对幼儿和免疫功能低下的个体构成了重大健康威胁。在此，我们报告了一系列新型（1-苄基-4-三唑基）-吲哚-2-甲酰胺及其相关化合物的合成和生物学评价，这些化合物对刚地弓形虫和微小隐孢子虫具有疗效。密切相关的类似物 7c（JS-2-30）和 7e（JS-2-44）对刚地弓形虫和微小隐孢子虫均显示出低微摩尔活性，IC 指数在 2.95 μM 和 7.63 μM 之间，而代表（1-金刚烷基）-4-苯基-三唑的化合物 11b（JS-2-41）对刚地弓形虫表现出非常好的活性，IC 为 1.94 μM，体外对刚地弓形虫具有良好的选择性。重要的是，化合物 JS-2-41 和 JS-2-44 在降低布朗-挪威大鼠脑中刚地弓形虫包囊数量方面表现出良好的体内疗效。总之，这些结果表明，（1-苄基-4-三唑基）-吲哚-2-甲酰胺和（1-金刚烷基）-4-苯基-三唑是寻找新型抗寄生虫药物治疗隐孢子虫病和弓形虫病的有潜力的候选药物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4fe5/9046076/f29b0f55fcaf/gr8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4fe5/9046076/e74bf2c1d671/ga1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4fe5/9046076/b961518b91b1/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4fe5/9046076/54fd4b8dda53/sc1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4fe5/9046076/0160750f4634/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4fe5/9046076/a1d84f293e33/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4fe5/9046076/7376ac0877dd/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4fe5/9046076/9c0a30693c50/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4fe5/9046076/2c2466d67948/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4fe5/9046076/55d56c548dd2/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4fe5/9046076/f29b0f55fcaf/gr8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4fe5/9046076/e74bf2c1d671/ga1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4fe5/9046076/b961518b91b1/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4fe5/9046076/54fd4b8dda53/sc1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4fe5/9046076/0160750f4634/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4fe5/9046076/a1d84f293e33/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4fe5/9046076/7376ac0877dd/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4fe5/9046076/9c0a30693c50/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4fe5/9046076/2c2466d67948/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4fe5/9046076/55d56c548dd2/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4fe5/9046076/f29b0f55fcaf/gr8.jpg

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