New Amino Naphthoquinone Derivatives as Anti-Trypanosoma cruzi Agents Targeting Trypanothione Reductase
Por:
Espinosa-Bustos C., Pérez M.O., Gonzalez-Gonzalez A., Zarate A.M., Rivera G., Belmont-Díaz J.A., Saavedra E., Cuellar M.A., Vázquez K., Salas C.O.
Publicada:
1 ene 2022
Categoría:
Pharmaceutical science
Resumen:
To develop novel chemotherapeutic alternatives for the treatment of Chagas disease, in this study, a set of new amino naphthoquinone derivatives were synthesised and evaluated in vitro on the epimastigote and trypomastigote forms of Trypanosoma cruzi strains (NINOA and INC-5) and on J774 murine macrophages. The design of the new naphthoquinone derivatives considered the incorporation of nitrogenous fragments with different substitution patterns present in compounds with activity on T. cruzi, and, thus, 19 compounds were synthesised in a simple manner. Compounds 2e and 7j showed the lowest IC50 values (0.43 µM against both strains for 2e and 0.19 µM and 0.92 µM for 7j). Likewise, 7j was more potent than the reference drug, benznidazole, and was more selective on epimastigotes. To postulate a possible mechanism of action, molecular docking studies were performed on T. cruzi trypanothione reductase (TcTR), specifically at a site in the dimer interface, which is a binding site for this type of naphthoquinone. Interestingly, 7j was one of the compounds that showed the best interaction profile on the enzyme; therefore, 7j was evaluated on TR, which behaved as a non-competitive inhibitor. Finally, 7j was predicted to have a good pharmacokinetic profile for oral administration. Thus, the naphthoquinone nucleus should be considered in the search for new trypanocidal agents based on our hit 7j. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.
Filiaciones:
Espinosa-Bustos C.:
Departamento de Farmacia, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, Vicuña Mackenna 4860, Santiago, 7820436, Chile
Pérez M.O.:
Departamento de Parasitología, Facultad de Medicina Veterinaria y Zootecnia, Universidad Autónoma de Nuevo León, Francisco Villa 20, General Escobedo, 66054, Mexico
Gonzalez-Gonzalez A.:
Laboratorio de Biotecnología Farmacéutica, Centro de Biotecnología Genómica, Instituto Politécnico Nacional, Boulevard del Maestro s/n, Reynosa, 88710, Mexico
Zarate A.M.:
Departamento de Química Orgánica, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, Vicuña Mackenna 4860, Macul, Santiago, 7820436, Chile
Rivera G.:
Laboratorio de Biotecnología Farmacéutica, Centro de Biotecnología Genómica, Instituto Politécnico Nacional, Boulevard del Maestro s/n, Reynosa, 88710, Mexico
Belmont-Díaz J.A.:
Departamento de Bioquímica, Instituto Nacional de Cardiología Ignacio Chávez, México City, 14080, Mexico
Saavedra E.:
Departamento de Bioquímica, Instituto Nacional de Cardiología Ignacio Chávez, México City, 14080, Mexico
Cuellar M.A.:
Centro de Investigación Farmacopea Chilena, Escuela de Química y Farmacia, Facultad de Farmacia, Universidad de Valparaíso, Av. Gran Bretaña 1093, Valparaíso, 2340000, Chile
Vázquez K.:
Departamento de Parasitología, Facultad de Medicina Veterinaria y Zootecnia, Universidad Autónoma de Nuevo León, Francisco Villa 20, General Escobedo, 66054, Mexico
Salas C.O.:
Departamento de Química Orgánica, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, Vicuña Mackenna 4860, Macul, Santiago, 7820436, Chile
Gold
|