Pharmacophore Identification and Structure–Activity Relationship Analysis of a Series of Substituted Azaindoles as Inhibitors of Trypanosoma brucei
Year: 2024
Type: article
Abstract: High Resolution Image Download MS PowerPoint Slide 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.
Source: Journal of Medicinal Chemistry
Authors: Lori Ferrins, Rosario Diaz, Carlos Cordon-Obras, Domingo Rojas-Barros, Antonio Quotadamo, Daniel P. Oehme, Gloria Ceballos-Pérez, Uma Swaminathan, Guiomar Pérez-Moreno, Cristina Bosch-Navarrete, Raquel García-Hernández, Claudia Gomez-Liñan, Andreu Saura, Luis Miguel Ruiz-Perez, Francisco Gamarro, Maria Santos Martinez-Martinez, Pilar Manzano, Dolores González-Pacanowska, Miguel Navarro, Michael P. Pollastri
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,500
OpenAlex ID: W4401542229