Structure-Based Drug Design of Novel Heterocyclic Scaffolds as TgCDPK1 Inhibitors

IF 3.4 4区 医学 Q2 CHEMISTRY, MEDICINAL
ChemMedChem Pub Date : 2025-08-08 DOI:10.1002/cmdc.202500440
Anoopjit Singh Kooner, Mariah Norman, Igi Vilza, Michael P. Mannino, Mary Savari Dhason, Jon Helander, Shrushti Patil, L. David Sibley, James W. Janetka
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Abstract

Toxoplasmosis is caused by the protozoan parasite Toxoplasma gondii and poses grave health concern for immunocompromised patients. T. gondii has a family of calcium dependent protein kinases (CDPKs) that control a variety of critical processes. Among these, TgCDPK1 is required for parasite motility, cell invasion, and egress and hence is essential both for in vitro growth of T. gondii and to cause infections in animals. Using existing X-ray cocrystal structures of pyrazolopyrimidine (PP) inhibitors bound to TgCDPK1, six new chemical series of inhibitors are rationally designed. The synthesis of analogs based on the most promising novel series is pursued, which resulted in potent TgCDPK1 inhibitors that effectively block parasite growth in cells. The resulting lead compounds 44 and 45 belonging to the imidazopyrazine chemical series demonstrate the promising potential of this new class of inhibitors for the treatment and possible cure of the Toxoplasmosis.

Abstract Image

基于结构的新型杂环支架TgCDPK1抑制剂药物设计。
弓形虫病是由原生动物寄生虫刚地弓形虫引起的,对免疫功能低下的患者造成严重的健康问题。弓形虫有一个钙依赖性蛋白激酶(CDPKs)家族,控制着多种关键过程。其中,TgCDPK1是寄生虫运动、细胞入侵和出口所必需的,因此对弓形虫的体外生长和引起动物感染都是必不可少的。利用现有的结合TgCDPK1的pyrazolopy嘧啶(PP)抑制剂的x射线共晶结构,合理设计了6个新的化学系列抑制剂。基于最有希望的新系列的类似物的合成,产生了有效阻断寄生虫在细胞中的生长的有效的TgCDPK1抑制剂。由此得到的咪唑吡嗪化学系列先导化合物44和45显示了这类新型抑制剂治疗和可能治愈弓形虫病的潜力。
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来源期刊
ChemMedChem
ChemMedChem 医学-药学
CiteScore
6.70
自引率
2.90%
发文量
280
审稿时长
1 months
期刊介绍: Quality research. Outstanding publications. With an impact factor of 3.124 (2019), ChemMedChem is a top journal for research at the interface of chemistry, biology and medicine. It is published on behalf of Chemistry Europe, an association of 16 European chemical societies. ChemMedChem publishes primary as well as critical secondary and tertiary information from authors across and for the world. Its mission is to integrate the wide and flourishing field of medicinal and pharmaceutical sciences, ranging from drug design and discovery to drug development and delivery, from molecular modeling to combinatorial chemistry, from target validation to lead generation and ADMET studies. ChemMedChem typically covers topics on small molecules, therapeutic macromolecules, peptides, peptidomimetics, and aptamers, protein-drug conjugates, nucleic acid therapies, and beginning 2017, nanomedicine, particularly 1) targeted nanodelivery, 2) theranostic nanoparticles, and 3) nanodrugs. Contents ChemMedChem publishes an attractive mixture of: Full Papers and Communications Reviews and Minireviews Patent Reviews Highlights and Concepts Book and Multimedia Reviews.
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