Article
Evaluation of 7-arylaminopyrazolo[1,5-a]pyrimidines as anti-Plasmodium falciparum, antimalarial, and Pf-dihydroorotate dehydrogenase inhibitors
Registro en:
AZEREDO, Luís Felipe S. P. et al. Evaluation of 7-arylaminopyrazolo[1,5-a]pyrimidines as anti-Plasmodium falciparum, antimalarial, and Pf-dihydroorotate dehydrogenase inhibitors. European Journal of Medicinal Chemistry, v. 126, p. 72-83, 2017.
0223-5234
10.1016/j.ejmech.2016.09.073
Autor
Azeredo, Luís Felipe S. P.
Coutinho, Julia Penna
Jabor, Valquíria Aparecida Polisel
Feliciano, Patricia Rosa
Costa, Maria Cristina Nonato
Kaiser, Carlos Roland
Menezes, Carla Maria S.
Hammes, Amanda S. O.
Caffarena, Ernesto Raul
Hoelz, Lucas Villas Bôas
Souza, Nicolli Bellotti de
Pereira, Glaecia Aparecida do Nascimento
Cerávolo, Isabela Penna
Krettli, Antoniana Ursine
Andrade, Nubia Boechat
Resumen
Malaria remains one of the most serious global infectious diseases. An important target for antimalarial chemotherapy is the enzyme dihydroorotate dehydrogenase from Plasmodium falciparum (PfDHODH), which is responsible for the conversion of dihydroorotate to orotate in the de novo pyrimidine biosynthetic pathway. In this study, we have designed and synthesized fifteen 7-arylpyrazolo[1,5-a]pyrimidine derivatives using ring bioisosteric replacement and molecular hybridization of functional groups based on the highly active 5-methyl-N-(naphthalen-2-yl)-2-(trifluoromethyl)- [1,2,4]triazolo[1,5-a]pyrimidin-7-amine. The compounds were tested against Plasmodium falciparum, as antimalarials in mice with P. berghei, and as inhibitors of PfDHODH. Thirteen compounds were found to be active against P. falciparum, with IC50 values ranging from 1.2 ± 0.3 to 92 ± 26 mM in the anti-HRP2 and hypoxanthine assays. Four compounds showed the highest selective index (SI), which is a ratio between cytotoxicity and activity in vitro. The inhibition of PfDHODH showed that compound 30 (R2 ¼ CH3; R5 ¼ CF3; Ar ¼ 7-b-naphthyl) displayed higher and selective inhibitory activity, with IC50 ¼ 0.16 ± 0.01 mM, followed by 25 (R2 ¼ CH3; R5 ¼ CH3; Ar ¼ 7-b-Naphthyl) and 19 (R2 ¼ CF3; R5 ¼ CF3; Ar ¼ 7-b-naphthyl), with IC50 ¼ 4 ± 1 mM and 6 ± 1 mM, respectively. The trifluoromethyl group at the 2- or 5-positions of the pyrazolo[1,5-a]pyrimidine ring led to increased drug activity. The docking results agreed with the values obtained from enzymatic assays. 2023-01-01