Pharmacophore Identification and Structure–Activity Relationship Analysis of a Series of Substituted Azaindoles as Inhibitors of <i>Trypanosoma brucei</i>
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 <b>1</b>. Structure-activity and structure-property relationship analysis, informed by cheminformatics, identified <b>4s</b> as a potent inhibitor of <i>Trypanosoma brucei</i> growth. While <b>4s</b> appeared to be fast acting and cidal in the <i>in vitro</i> 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.
Authors
- Antonio Quotadamo (ORCID: https://orcid.org/0000-0002-0357-3504)
- Uma Swaminathan (ORCID: https://orcid.org/0009-0002-3930-3204)
- Andreu Saura (ORCID: https://orcid.org/0009-0002-6187-0969)
- Gloria Ceballos-Pérez (ORCID: https://orcid.org/0000-0002-6012-9995)
- Guiomar Pérez‐Moreno (ORCID: https://orcid.org/0000-0002-6892-6083)
- Dolores González‐Pacanowska (ORCID: https://orcid.org/0000-0002-4303-5209)
- Miguel Navarro (ORCID: https://orcid.org/0000-0003-2301-2699)
- Lori Ferrins (ORCID: https://orcid.org/0000-0001-8992-0919)
- Claudia Gómez-Liñán (ORCID: https://orcid.org/0000-0003-4499-2219)
- Michael P. Pollastri (ORCID: https://orcid.org/0000-0001-9943-7197)
- Maria Santos Martínez (ORCID: https://orcid.org/0000-0001-7894-2135)
- Cristina Bosch‐Navarrete (ORCID: https://orcid.org/0000-0002-6064-0064)
- Raquel García‐Hernández (ORCID: https://orcid.org/0000-0001-9997-6051)
- Daniel P. Oehme (ORCID: https://orcid.org/0000-0002-0291-4856)
- Francisco Gamarro (ORCID: https://orcid.org/0000-0003-1347-3440)
- Domingo I. Rojas-Barros (ORCID: https://orcid.org/0000-0001-8625-2564)
- Rosario Díaz-González (ORCID: https://orcid.org/0000-0002-3187-2704)
- Carlos Cordón-Obras
- Luis M. Ruiz‐Pérez (ORCID: https://orcid.org/0000-0001-7681-4471)
- Pilar Manzano
Institutions
- University of Modena and Reggio Emilia (IT)
- Northeastern University (US)
- Consejo Superior de Investigaciones Científicas (ES)
- Instituto de Parasitología y Biomedicina "López - Neyra" (ES)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-08-13
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c00785
- Citations
- 1
- Primary Topic
- Trypanosoma species research and implications
- Type
- article
- Field-Weighted Citation Impact
- 0.39
Funders
- Ministerio de Ciencia, Innovación y Universidades
- Red de Investigación Cooperativa en Enfermedades Tropicales
- Instituto de Salud Carlos III
- European Regional Development Fund
- National Institute of Allergy and Infectious Diseases