Pharmacophore Identification and Structure–Activity Relationship Analysis of a Series of Substituted Azaindoles as Inhibitors of Trypanosoma brucei,Journal of Medicinal Chemistry

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Pharmacophore Identification and Structure–Activity Relationship Analysis of a Series of Substituted Azaindoles as Inhibitors of Trypanosoma brucei
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-08-13 , DOI: 10.1021/acs.jmedchem.4c00785
Lori Ferrins ₁ , Rosario Diaz ₂ , Carlos Cordon-Obras ₂ , Domingo Rojas-Barros ₂ , Antonio Quotadamo _{1,

3} , Daniel P Oehme ₁ , Gloria Ceballos-Pérez ₂ , Uma Swaminathan ₁ , Guiomar Pérez-Moreno ₂ , Cristina Bosch-Navarrete ₂ , Raquel García-Hernández ₂ , Claudia Gomez-Liñan ₂ , Andreu Saura ₂ , Luis Miguel Ruiz-Perez ₂ , Francisco Gamarro ₂ , Maria Santos Martinez-Martinez ₄ , Pilar Manzano ₄ , Dolores González-Pacanowska ₂ , Miguel Navarro ₂ , Michael P Pollastri ₁

Affiliation

Human African trypanosomiasis is among the World Health Organization’s designated neglected tropical diseases. Repurposing strategies are often employed in academic drug discovery programs due to financial limitations, and in this instance, we used human kinase inhibitor chemotypes to identify substituted 4-aminoazaindoles, exemplified by 1. Structure–activity and structure–property relationship analysis, informed by cheminformatics, identified 4s as a potent inhibitor of Trypanosoma brucei growth. While 4s appeared to be fast acting and cidal in the in vitro assays, it failed to cure a murine model of infection. Preliminary efforts to identify the potential mechanism of action of the series pointed to arginine kinase, though, as we demonstrate, this does not appear to be the sole target of our compounds. This comprehensive approach to drug discovery, encompassing cheminformatics, structure–potency and structure–property analysis, and pharmacophore identification, highlights our multipronged efforts to identify novel lead compounds for this deadly disease.

中文翻译：

一系列取代氮杂吲哚类布氏锥虫抑制剂的药效团鉴定及构效关系分析

非洲人类锥虫病是世界卫生组织指定的被忽视的热带疾病之一。由于资金限制，学术药物发现项目中经常采用重新利用策略，在这种情况下，我们使用人激酶抑制剂化学型来识别取代的 4-氨基氮杂吲哚，例如1 。根据化学信息学的结构-活性和结构-性质关系分析，确定4s是布氏锥虫生长的有效抑制剂。虽然4s在体外试验中似乎具有快速作用和杀灭作用，但它未能治愈小鼠感染模型。确定该系列潜在作用机制的初步努力指向精氨酸激酶，但正如我们所证明的那样，这似乎并不是我们化合物的唯一目标。这种全面的药物发现方法，包括化学信息学、结构效力和结构性质分析以及药效团鉴定，突显了我们为识别这种致命疾病的新型先导化合物而付出的多方面努力。

更新日期：2024-08-13

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