Evaluation of 7-arylaminopyrazolo[1,5-a]pyrimidines as anti-Plasmodium falciparum, antimalarial, and Pf-dihydroorotate dehydrogenase inhibitors

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Azeredo, Luis Felipe S. P. ; Coutinho, Julia P. ; Jabor, Valquiria A. P. ; Feliciano, Patricia R. ; Nonato, Maria Cristina ; Kaiser, Carlos R. ; Menezes, Carla Maria S. ; Hammes, Amanda S. O. ; Caffarena, Ernesto Raul ; Hoelz, Lucas V. B. ; de Souza, Nicolli B. ; Pereira, Glaecia A. N. ; Ceravolo, Isabela P. ; Krettli, Antoniana U. ; Boechat, Nubia

• Document type: Journal article
• Source: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY; v. 126, p. 72-83, JAN 27 2017.
• Web of Science Citations: 18

Abstract

Malaria remains one of the most serious global infectious diseases. An important target for antimalarial chemotherapy is the enzyme dihydroorotate dehydrogenase from Plasmodium falciparum (PJDHODH), 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-alpha]pyrimidine derivatives using ring bioisosteric replacement and molecular hybridization of functional groups based on the highly active 5-methyl-N-(naphthalen-2-y1)-2-(trifluoromethyl)-{[}1,2,4]triazolo{[}1,5 -a]pyrimidin7-amine. The compounds were tested against Plasmodium falciparum, as antimalarials in mice with P. berghei, and as inhibitors of PJDHODH. Thirteen compounds were found to be active against P. falciparum, with IC50 values ranging from 1.2 +/- 0.3 to 92 +/- 26 mu M 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 PJDHODH showed that compound 30 (R-2 = CH3; R-5 = CF3; Ar = 7-(beta-naphthyl) displayed higher and selective inhibitory activity, with IC50 = 0.16 +/- 0.01 mu M, followed by 25 (R-2 = CH3; R-5 = CH3; Ar = 7-beta-Naphthyl) and 19 (R-2 = CF3; R-5 = CF3; Ar = 7-beta-naphthyl), with 1050 = 4 +/- 1 mu M and 6 +/- 1 mu M, 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. (C) 2016 Elsevier Masson SAS. All rights reserved. (AU)

• FAPESP's process: 12/25075-0 - Development of leishmanicidal drugs based on the selective inhibition of the enzyme dihydroorotate dehydrogenase
• Grantee: Maria Cristina Nonato
• Support Opportunities: Regular Research Grants