885461-50-7Relevant articles and documents
Comparative study between the anti-P. falciparum activity of triazolopyrimidine, pyrazolopyrimidine and quinoline derivatives and the identification of new PfDHODH inhibitors
Silveira, Flávia F.,de Souza, Juliana O.,Hoelz, Lucas V.B.,Campos, Vinícius R.,Jabor, Valquíria A.P.,Aguiar, Anna C.C.,Nonato, M. Cristina,Albuquerque, Magaly G.,Guido, Rafael V.C.,Boechat, Nubia,Pinheiro, Luiz C.S.
, (2020/11/10)
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 μM. 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 μM 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 μM) and did not show significant inhibition against the HsDHODH homologue (0–30% at 50 μM). 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, R1 = F; IC50 = 0.086 μM), 21 (R = CF3; R1 = CH3; IC50 = 0.032 μM), 23, (R = CF3, R1 = CF3; IC50 = 0.030 μM) and 24 (R = CF3, 2-naphthyl; IC50 = 0.050 μM) and the most active inhibitor against PfDHODH 19 (R = CF3, R1 = Cl; IC50 = 0.08 μM - 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.
NEW SUBSTITUTED TRIAZOLOPYRIMIDINES AS ANTI-MALARIAL AGENTS
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Paragraph 0098, (2016/10/06)
The present invention is related to a use of triazolopyrimidine derivatives in the manufacture of a medicament for preventing or treating malaria. Specifically, the present invention is related to triazolopyrimidine derivatives useful for the preparation of a pharmaceutical formulation for the inhibition of malaria parasite proliferation.
Novel Selective Inhibitor of Leishmania (Leishmania) amazonensis Arginase
Da Silva, Edson R.,Boechat, Nubia,Pinheiro, Luiz C. S.,Bastos, Monica M.,Costa, Carolina C. P.,Bartholomeu, Juliana C.,Da Costa, Talita H.
, p. 969 - 978 (2015/10/28)
Arginase is a glycosomal enzyme in Leishmania that is involved in polyamine and trypanothione biosynthesis. The central role of arginase in Leishmania (Leishmania) amazonensis was demonstrated by the generation of two mutants: one with an arginase lacking
New trifluoromethyl triazolopyrimidines as Anti-Plasmodium falciparum agents
Boechat, Nubia,Pinheiro, Luiz C.S.,Silva, Thiago S.,Aguiar, Anna C.C.,Carvalho, Alcione S.,Bastos, Monica M.,Costa, Carolina C.P.,Pinheiro, Sergio,Pinto, Angelo C.,Mendonca, Jorge S.,Dutra, Karen D.B.,Valverde, Alessandra L.,Santos-Filho, Osvaldo A.,Ceravolo, Isabela P.,Krettli, Antoniana U.
experimental part, p. 8285 - 8302 (2012/10/08)
According to the World Health Organization, half of the World's population, approximately 3.3 billion people, is at risk for developing malaria. Nearly 700,000 deaths each year are associated with the disease. Control of the disease in humans still relies on chemotherapy. Drug resistance is a limiting factor, and the search for new drugs is important. We have designed and synthesized new 2-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyrimidine derivatives based on bioisosteric replacement of functional groups on the anti-malarial compounds mefloquine and amodiaquine. This approach enabled us to investigate the impact of: (i) ring bioisosteric replacement; (ii) a CF3 group substituted at the 2-position of the [1,2,4]triazolo[1,5-a]pyrimidine scaffold and (iii) a range of amines as substituents at the 7-position of the of heterocyclic ring; on in vitro activity against Plasmodium falciparum. According to docking simulations, the synthesized compounds are able to interact with P. falciparum dihydroorotate dehydrogenase (PfDHODH) through strong hydrogen bonds. The presence of a trifluoromethyl group at the 2-position of the [1,2,4]triazolo [1,5-a]pyrimidine ring led to increased drug activity. Thirteen compounds were found to be active, with IC50 values ranging from 0.023 to 20 μM in the anti-HRP2 and hypoxanthine assays. The selectivity index (SI) of the most active derivatives 5, 8, 11 and 16 was found to vary from 1,003 to 18,478.
ANTIMALARIAL AGENTS THAT ARE INHIBITORS OF DIHYDROOROTATE DEHYDROGENASE
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Page/Page column 46-47, (2011/04/25)
Inhibitors of parasitic dihydroorotate dehydrogenase enzyme (DHOD) are candidate therapeutics for treating malaria. Illustrative of such therapeutic agents include the compound: and a triazolopyrimidine class of compounds that conform to Formula (IX): and their solvates, stereoisomers, tautomers and pharmaceutically acceptable salts.
Structure-guided lead optimization of triazolopyrimidine-ring substituents identifies potent plasmodium falciparum dihydroorotate dehydrogenase inhibitors with clinical candidate potential
Coteron, Jose M.,Marco, María,Esquivias, Jorge,Deng, Xiaoyi,White, Karen L.,White, John,Koltun, Maria,El Mazouni, Farah,Kokkonda, Sreekanth,Katneni, Kasiram,Bhamidipati, Ravi,Shackleford, David M.,Angulo-Barturen, I?igo,Ferrer, Santiago B.,Jiménez-Díaz, María Belén,Gamo, Francisco-Javier,Goldsmith, Elizabeth J.,Charman, William N.,Bathurst, Ian,Floyd, David,Matthews, David,Burrows, Jeremy N.,Rathod, Pradipsinh K.,Charman, Susan A.,Phillips, Margaret A.
experimental part, p. 5540 - 5561 (2011/10/03)
Drug therapy is the mainstay of antimalarial therapy, yet current drugs are threatened by the development of resistance. In an effort to identify new potential antimalarials, we have undertaken a lead optimization program around our previously identified triazolopyrimidine-based series of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors. The X-ray structure of PfDHODH was used to inform the medicinal chemistry program allowing the identification of a potent and selective inhibitor (DSM265) that acts through DHODH inhibition to kill both sensitive and drug resistant strains of the parasite. This compound has similar potency to chloroquine in the humanized SCID mouse P. falciparum model, can be synthesized by a simple route, and rodent pharmacokinetic studies demonstrated it has excellent oral bioavailability, a long half-life and low clearance. These studies have identified the first candidate in the triazolopyrimidine series to meet previously established progression criteria for efficacy and ADME properties, justifying further development of this compound toward clinical candidate status.
