title: Design, synthesis and biological evaluation of quinazoline derivatives as anti-trypanosomatid and anti-plasmodial agents.
abstract: In this paper, the design, synthesis and biological evaluation of a set of quinazoline-2,4,6-triamine derivatives (1-9) as trypanocidal, antileishmanial and antiplasmodial agents are explained. The compounds were rationalized basing on docking studies of the dihydrofolate reductase (DHFR from Trypanosoma cruzi, Leishmania major and Plasmodium vivax) and pteridin reductase (PTR from T. cruzi and L. major) structures. All compounds were in vitro screened against both bloodstream trypomastigotes of T. cruzi (NINOA and INC-5 strains) and promatigotes of Leishmania mexicana (MHOM/BZ/61/M379 strain), and also for cytotoxicity using Vero cell line. Against T. cruzi, three compounds (5, 6 and 8) were the most effective showing a better activity profile than nifurtimox and benznidazole (reference drugs). Against L. mexicana, four compounds (5, 6, 8, and 9) exhibited the highest activity, even than glucantime (reference drug). In the cytotoxicity assay, protozoa were more susceptible than Vero cells. In vivo Plasmodium berghei assay (ANKA strain), the compounds 1, 5, 6 and 8 showed a more comparable activity than chloroquine and pyrimethamine (reference drugs) when they were administrated by the oral route. The antiprotozoal activity of these substances, endowed with redox properties, represented a good starting point for a medicinal chemistry program aiming for chemotherapy of Chagas' disease, leishmaniosis and malaria.
authors.affiliation: Programa de Maestría y Doctorado en Ciencias Químicas, UNAM, México, DF 04510, Mexico; Facultad de Química, Departamento de Farmacia, UNAM, México, DF 04510, Mexico.
authors.forename: César
authors.initials: C
authors.lastname: Mendoza-Martínez
authors.affiliation: Escuela Superior de Medicina, Laboratorio de Modelado Molecular y Bioinformática de la SEPI, IPN, México, DF 11340, Mexico.
authors.forename: José
authors.initials: J
authors.lastname: Correa-Basurto
authors.affiliation: Escuela Nacional de Ciencias Biológicas, Departamento de Parasitología, IPN, México, DF 11340, Mexico.
authors.forename: Rocío
authors.initials: R
authors.lastname: Nieto-Meneses
authors.affiliation: Escuela Nacional de Ciencias Biológicas, Departamento de Parasitología, IPN, México, DF 11340, Mexico.
authors.forename: Adrián
authors.initials: A
authors.lastname: Márquez-Navarro
authors.affiliation: Escuela Nacional de Ciencias Biológicas, Departamento de Parasitología, IPN, México, DF 11340, Mexico.
authors.forename: Rocío
authors.initials: R
authors.lastname: Aguilar-Suárez
authors.affiliation: Escuela Nacional de Ciencias Biológicas, Departamento de Parasitología, IPN, México, DF 11340, Mexico.
authors.forename: Miriam Dinora
authors.initials: MD
authors.lastname: Montero-Cortes
authors.affiliation: Escuela Nacional de Ciencias Biológicas, Departamento de Parasitología, IPN, México, DF 11340, Mexico.
authors.forename: Benjamín
authors.initials: B
authors.lastname: Nogueda-Torres
authors.affiliation: Escuela Nacional de Ciencias Biológicas, Departamento de Parasitología, IPN, México, DF 11340, Mexico.
authors.forename: Erick
authors.initials: E
authors.lastname: Suárez-Contreras
authors.affiliation: Departamento de Infectología, Instituto Nacional de Perinatología, México, DF 11000, Mexico.
authors.forename: Norma
authors.initials: N
authors.lastname: Galindo-Sevilla
authors.affiliation: Tecsiquim S.A. de C.V., Toluca Estado de México 50233, Mexico.
authors.forename: Ángela
authors.initials: Á
authors.lastname: Rojas-Rojas
authors.affiliation: Tecsiquim S.A. de C.V., Toluca Estado de México 50233, Mexico.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Rodriguez-Lezama
authors.affiliation: Programa de Maestría y Doctorado en Ciencias Químicas, UNAM, México, DF 04510, Mexico; Facultad de Química, Departamento de Farmacia, UNAM, México, DF 04510, Mexico. Electronic address: franher@unam.mx.
authors.forename: Francisco
authors.initials: F
authors.lastname: Hernández-Luis
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology; D000981:Antiprotozoal Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005260:Female; D018320:Leishmania major / Q000187:drug effects*; D008288:Malaria / Q000188:drug therapy; D051379:Mice; D008815:Mice, Inbred Strains; D008958:Models, Molecular; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010966:Plasmodium vivax / Q000187:drug effects*; D011799:Quinazolines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014349:Trypanosoma cruzi / Q000187:drug effects*; D014709:Vero Cells
chemical_list: D000962:Antimalarials; D000981:Antiprotozoal Agents; D011799:Quinazolines
keywords: Dihydrofolate reductase; Leishmania mexicana; Plasmodium berghei; Pteridin reductase; Quinazoline; Trypanosoma cruzi