TY - JOUR
T1 - Design, synthesis and biological evaluation of quinazoline derivatives as anti-trypanosomatid and anti-plasmodial agents
AU - Mendoza-Martínez, César
AU - Correa-Basurto, José
AU - Nieto-Meneses, Rocío
AU - Márquez-Navarro, Adrián
AU - Aguilar-Suárez, Rocío
AU - Montero-Cortes, Miriam Dinora
AU - Nogueda-Torres, Benjamín
AU - Suárez-Contreras, Erick
AU - Galindo-Sevilla, Norma
AU - Rojas-Rojas, Ángela
AU - Rodriguez-Lezama, Alejandro
AU - Hernández-Luis, Francisco
N1 - Publisher Copyright:
© 2015 Elsevier Masson SAS. All rights reserved.
PY - 2015/5/26
Y1 - 2015/5/26
N2 - 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.
AB - 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.
KW - Dihydrofolate reductase
KW - Leishmania mexicana
KW - Plasmodium berghei
KW - Pteridin reductase
KW - Quinazoline
KW - Trypanosoma cruzi
UR - http://www.scopus.com/inward/record.url?scp=84927938537&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2015.04.028
DO - 10.1016/j.ejmech.2015.04.028
M3 - Artículo
C2 - 25899334
SN - 0223-5234
VL - 96
SP - 296
EP - 307
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
ER -