Simple dialkyl pyrazole-3,5-dicarboxylates show in vitro and in vivo activity against disease-causing trypanosomatids

Abstract

The synthesis and antiprotozoal activity of some simple dialkyl pyrazole-3,5-dicarboxylates (compounds 2-6) and their sodium salts (pyrazolates) (compounds 7-9) against Trypanosoma cruzi, Leishmania infantum and Leishmania braziliensis are reported. In most cases the studied compounds showed, especially against the clinically significant amastigote forms, in vitro activities higher than those of the reference drugs (benznidazole for T. cruzi and glucantime for Leishmania spp.); furthermore, the low non-specific cytotoxicities against Vero cells and macrophages shown by these compounds led to good selectivity indexes, which are 8-72 times higher for T. cruzi amastigotes and 15-113 times higher for Leishmania spp. amastigotes than those of the respective reference drugs. The high efficiency of diethyl ester 3 and its sodium salt 8 against the mentioned protozoa was confirmed by further in vitro assays on infection rates and by an additional in vivo study in a murine model of acute and chronic Chagas disease. The inhibitory capacity of compounds 3 and 8 on the essential iron superoxide dismutase of the aforementioned parasites may be related to the observed anti-trypanosomatid activity. The low acute toxicity of compounds 3 and 8 in mice is also reported in this article.

Synthesis and Pharmacological Activities of Pyrazole Derivatives: A Review

“…Reviriego et al reported the synthesis and antiprotozoal activity of some simple dialkyl pyrazole-3,5-dicarboxylates against Trypanosoma cruzi , Leishmania infantum and Leishmania braziliensis . The diethyl ester 476 showed high efficiency against the mentioned protozoa [ 373 ].…”

Synthesis of Novel Pyrazole Derivatives and Their Tumor Cell Growth Inhibitory Activity

“…In combination with their favorable drug-like properties, privileged structures or scaffolds are widely used in rational drug design to find new lead compounds or drug candidates [1,2,3]. Pyrazole derivatives represent one of the most active classes of compounds that possess a wide spectrum of biological activities, including antibacterial and antifungal [4,5], antitumor [6,7], anti-inflammatory and analgesic [8,9], antitubercular [10], antiviral [11,12], anti-Alzheimer’s [13,14], α-glucosidase inhibitory [15], anti-diabetic [16], antileishmanial [17,18], anti-malarial [19], radioimaging [20], acaricidal and insecticidal [21,22] activities. As a privileged scaffold, pyrazole has been recently widely used in the design of anticancer agents for a multiple of tumor targets [23].…”

Structural Optimization and Biological Activity of Pyrazole Derivatives: Virtual Computational Analysis, Recovery Assay and 3D Culture Model as Potential Predictive Tools of Effectiveness against Trypanosoma cruzi

“…The enzymatic activity data demonstrated that 3g, 3j, and 3m are weak inhibitors of cysteine protease and, therefore, the improvement of trypanocidal activity against intracellular parasites involves other mechanisms of action not yet elucidated. Evidence has shown that, in addition to cruzipain, the iron-dependent superoxide dismutase (Fe-SOD) [46,47] and CYP51 [48] are molecular targets implicated in the trypanocidal activity of the pyrazole derivatives. Thus, it is possible that the trypanocidal activity of promising pyrazole derivatives is associated with mitochondrial dysfunction, as predicted by the pyrazole derivatives distribution in the ADMET analysis, which will be a target of further analysis.…”