Comparative study between the anti-P. falciparum activity of triazolopyrimidine, pyrazolopyrimidine and quinoline derivatives and the identification of new PfDHODH inhibitors

Author(s):Show less -

Silveira, Flavia F. ^{[1, 2]} ; de Souza, Juliana O. ^[3] ; Hoelz, Lucas V. B. ^[2] ; Campos, Vinicius R. ^[4] ; Jabor, Valquiria A. P. ^[5] ; Aguiar, Anna C. C. ^[3] ; Nonato, M. Cristina ^[5] ; Albuquerque, Magaly G. ^[1] ; Guido, Rafael V. C. ^[3] ; Boechat, Nubia ^{[1, 2]} ; Pinheiro, Luiz C. S. ^[2]

Affiliation

^[1] Univ Fed Rio de Janeiro, PGQu Inst Quim, Programa Posgrad Quim, Rio De Janeiro, RJ - Brazil

^[2] Fiocruz MS, Fundacao Oswaldo Cruz, Inst Tecnol Farmacos Farmanguinhos, Lab Sintese Farmacos, Rua Sizenando Nabuco 100, BR-21041250 Rio De Janeiro, RJ - Brazil

^[3] Univ Sao Paulo, Inst Fis Sao Carlos, Av Joao Dagnone 1-100, Sao Carlos, SP - Brazil

^[4] Univ Fed Fluminense, Inst Quim, Dept Quim Organ, Programa Posgrad Quim, Niteroi, RJ - Brazil

^[5] Univ Sao Paulo, Fac Ciencias Farmaceut Ribeirao Preto, Dept Ciencias BioMol, Lab Cristalog Prot, Ave Cafe S-N Monte Alegre, BR-14040903 Ribeirao Preto, SP - Brazil

• Document type: Journal article
• Source: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY; v. 209, JAN 1 2021.
• Web of Science Citations: 0

Abstract

In this work, we designed and synthesized 35 new triazolopyrimidine, pyrazolopyrimidine and quinoline derivatives as P. falciparum inhibitors (3D7 strain). Thirty compounds exhibited anti-P. falciparum activity, with IC50 values ranging from 0.030 to 9.1 mu M. The {[}1,2,4] triazolo{[}1,5-a]pyrimidine derivatives were more potent than the pyrazolo{[}1,5-a]pyrimidine and quinoline analogues. Compounds 20, 21, 23 and 24 were the most potent inhibitors, with IC50 values in the range of 0.030-0.086 mu M and were equipotent to chloroquine. In addition, the compounds were selective, showing no cytotoxic activity against the human hepatoma cell line HepG2. All {[}1,2,4]triazolo{[}1,5-a]pyrimidine derivatives inhibited PfDHODH activity in the low micromolar to low nanomolar range (IC50 values of 0.08-1.3 mu M) and did not show significant inhibition against the HsDHODH homologue (0-30% at 50 mu M). Molecular docking studies indicated the binding mode of {[}1,2,4]triazolo{[}1,5-a]pyrimidine derivatives to PfDHODH, and the highest interaction affinities for the PfDHODH enzyme were in agreement with the in vitro experimental evaluation. Thus, the most active compounds against P. falciparum parasites 20 (R = CF3, R-1 = F; IC50 = 0.086 mu M), 21 (R = CF3; R-1 = CH3; IC50 = 0.032 mu M), 23, (R = CF3, R-1 = CF3; IC50 = 0.030 mu M) and 24 (R = CF3, 2-naphthyl; IC50 = 0.050 mu M) and the most active inhibitor against PfDHODH 19 (R = CF3, R-1 = Cl; IC50 = 0.08 mu M - PfDHODH) stood out as new lead compounds for antimalarial drug discovery. Their potent in vitro activity against P. falciparum and the selective inhibition of the PfDHODH enzyme strongly suggest that this is the mechanism of action underlying this series of new {[}1,2,4]triazolo{[}1,5-a]pyrimidine derivatives. (c) 2020 Elsevier Masson SAS. All rights reserved. (AU)

• FAPESP's process: 17/26679-0 - 4-Quinolone derivatives as antimalarial drug candidates: Antiplasmodial activity characterization in vitro, in vivo and of the mode of action
• Grantee: Juliana Oliveira de Souza
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 13/07600-3 - CIBFar - Center for Innovation in Biodiversity and Drug Discovery
• Grantee: Glaucius Oliva
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC