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

• Published in: Journal of medicinal chemistry Vol. 67; no. 16; pp. 13985 - 14006
• Main Authors: Ferrins, Lori, Diaz, Rosario, Cordon-Obras, Carlos, Rojas-Barros, Domingo, Quotadamo, Antonio, Oehme, Daniel P., Ceballos-Pérez, Gloria, Swaminathan, Uma, Pérez-Moreno, Guiomar, Bosch-Navarrete, Cristina, García-Hernández, Raquel, Gomez-Liñan, Claudia, Saura, Andreu, Ruiz-Perez, Luis Miguel, Gamarro, Francisco, Martinez-Martinez, Maria Santos, Manzano, Pilar, González-Pacanowska, Dolores, Navarro, Miguel, Pollastri, Michael P.
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 22-08-2024
• Subjects: Animals; Aza Compounds - chemical synthesis; Aza Compounds - chemistry; Aza Compounds - pharmacology; Humans; Indoles - chemical synthesis; Indoles - chemistry; Indoles - pharmacology; Mice; Molecular Structure; Pharmacophore; Structure-Activity Relationship; Trypanocidal Agents - chemical synthesis; Trypanocidal Agents - chemistry; Trypanocidal Agents - pharmacology; Trypanosoma brucei brucei - drug effects; Trypanosomiasis, African - drug therapy
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.4c00785

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.