89852-99-3Relevant academic research and scientific papers
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.
6-Nitrotriazolo[1,5-a]pyrimidines as promising structures for pharmacotherapy of septic conditions
Savateev,Ulomsky,Fedotov,Rusinov,Sivak,Lyubishin,Kuzmich,Aleksandrov
, p. 421 - 428 (2017/08/08)
Promising 6-nitro-1,2,4-triazolo[1,5-a]pyrimidine analogues, structural analogues of synthetic inhibitors of adenosine receptors, were sorted out on the basis of quantum-chemical calculations. The compounds were synthesized by nitration and chlorodeoxygenation reactions. The in vivo activity of 6-nitroheterocycles was studied and the affinity to adenosine receptor A2A was demonstrated in regard to septic conditions.
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.
scheme or table, 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.
Formation, structure and heterocyclization of aminoguanidine and ethyl acetoacetate condensation products
Erkin,Krutikov
experimental part, p. 1204 - 1209 (2011/05/03)
Condensation of aminoguanidine hydrochloride and ethyl acetoacetate results in 2,3-diamino-6-methylpyrimidin-4(3H)-one, 5-hydroxy-1-carboxamidino-3- methylpyrazole or ethyl N-[(5-hydroxy-3-methylpyrazol-1-yl)imidoyl] aminocrotonoate depending on the type of the base. Formation of pyrazole derivatives occurs in the case of dequaternized substrate imine-group protonating by the acids formed as a result of ion exchange reaction. Chelate fragment of amidinohydroxypyrazole structure provides stabilization of this compound and stipulates its inertness towared the heterocycle closure.
SYNTHESIS AND REARRANGEMENTS OF IMIDAZOLO- AND TRIAZOLO-DIAZINES
Khadem, H. S. El,Kawai, J.,Swartz, D. L.
, p. 239 - 248 (2007/10/02)
3-Methylimidazolopyridine and 3-methyl-1,2,4-triazolopyrazine were prepared by coupling ethyl dithioacetate with 2-(aminomethyl)pyridine and 2-hydrazinopyrazine, respectively.Both compounds are stable in dilute acids and bases, unlike 3-methyl-1,2,4-triazolopyrimidine obtained by coupling the same dithioacetate with 2-hydrazinopyrimidine, which quickly undergoes a Dimroth type rearrangement.Coupling ethyl dithioacetate with 2-hydrazino-4-hydroxy-6-methylpyrimidine yielded a mixture of 3,5-dimethyl-1,2,4-triazolo-7(8H)-pyrimidone and 3,7-dimethyl-1,2,4-triazolo-5(8H)-pyrimidone, which were identified by 2D nmr.The last compound underwent a Dimroth rearrangement with acids to yield 2,5-dimethyl-1,2,4-triazolo-7(4H)-pyrimidone, whereas the first did not.Finally, coupling ethyl dithioacetate with 5-chloro-4-hydrazinopyrimidine afforded 8-chloro-3-methyl-1,2,4-triazolopyrimidine, which upon treatment with acids underwent a reversible ring opening to afford 2-chloro-1-formamido-2-(5-methyl-1,3,4-triazolo-2-yl)ethene.The latter on pyrolysis gave the starting base without undergoing rearrangement.
