RESUMO
Aim: To study a new series of [1,2,3]triazolo[1,5-α]pyridine derivatives as trypanocidal agents because current antichagasic pharmacologic therapy is only partially effective. Materials & methods: The effect of the series upon Trypanosoma cruzi epimastigotes and murine macrophages viability, cell cycle, cell death and on the metabolites of the sterol biosynthesis pathway was measured; also, docking in 14α-demethylase was analyzed. Results: Compound 16 inhibits 14α-demethylase producing an imbalance in the cholesterol/ergosterol synthesis pathway, as suggested by a metabolic control and theoretical docking analysis. Consequently, it prevented cell proliferation, stopping the cellular cycle at the G2/M phase, inducing cell death. Conclusion: Although the exact cell death mechanism remained elusive, this series can be used for the further rational design of novel antiparasitic molecules.
Assuntos
Piridinas/farmacologia , Esteróis/metabolismo , Triazóis/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Vias Biossintéticas/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Doença de Chagas/tratamento farmacológico , Humanos , Camundongos , Piridinas/química , Células RAW 264.7 , Triazóis/química , Tripanossomicidas/química , Trypanosoma cruzi/metabolismoRESUMO
For years, Chagas disease treatment has been limited to only two drugs of highly questionable and controversial use (Nifurtimox(®) and Benznidazole(®)). In the search of effective drugs, many efforts have been made, but only a few structures have emerged as actual candidates. Heading into this, the multitarget-directed approach appears as the best choice. In this framework, indazoles were shown to be potent Trypanosoma cruzi growth inhibitors, being able to lead both the formation of reactive oxygen species and the inhibition of trypanothione reductase. Herein, we discuss the main structural factors that rule the anti-T. cruzi properties of indazoles, and how they would be involved in the biological properties as well as in the action mechanisms, attempting to make parallels between the old paradigms and current evidences in order to outline what could be the next steps to follow in regard to the future drug design for Chagas disease treatment.
Assuntos
Indazóis/química , Tripanossomicidas/química , Trypanosoma cruzi/metabolismo , Doença de Chagas/tratamento farmacológico , Doença de Chagas/parasitologia , Desenho de Fármacos , Humanos , Indazóis/farmacologia , Indazóis/uso terapêutico , NADH NADPH Oxirredutases/antagonistas & inibidores , NADH NADPH Oxirredutases/metabolismo , Nifurtimox/química , Nifurtimox/farmacologia , Nifurtimox/uso terapêutico , Nitroimidazóis/química , Nitroimidazóis/farmacologia , Nitroimidazóis/uso terapêutico , Proteínas de Protozoários/antagonistas & inibidores , Proteínas de Protozoários/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Tripanossomicidas/farmacologia , Tripanossomicidas/uso terapêutico , Trypanosoma cruzi/efeitos dos fármacos , Trypanosoma cruzi/enzimologiaRESUMO
A new nitrooxoisoaporphine derivative was synthetized and characterized by cyclic voltammetry and electron spin resonance. Its aqueous solubility was improved by complexes formation with ß-cyclodextrin, heptakis(2,6-di-O-methyl)-ß-cyclodextrin and (2-hydroxypropyl)-ß-cyclodextrin. In order to assess the inclusion degree reached by nitrooxoisoaporphine in cyclodextris cavity, the stability constants of formation of the complexes were determined by phase-solubility measurements obtaining in all cases a type-A(L) diagram. Moreover, electrochemical studies were carried out, where the observed change in the EPC value indicated a lower feasibility of the nitro group reduction. Additionally, a detailed spatial configuration is proposed for inclusion of derivate within the cyclodextrins cavity by 2D NMR techniques. Finally, these results are further interpreted by means of molecular modeling studies. Thus, theoretical results are in complete agreement with the experimental data.
Assuntos
Aporfinas/química , beta-Ciclodextrinas/química , 2-Hidroxipropil-beta-Ciclodextrina , Aporfinas/síntese química , Técnicas Eletroquímicas , Espectroscopia de Ressonância de Spin Eletrônica , Espectroscopia de Ressonância Magnética , Menispermaceae/química , Modelos Moleculares , Solubilidade , beta-Ciclodextrinas/síntese químicaRESUMO
A series of fused tri- and tetracyclic indazoles and analogues compounds (NID) with potential antiparasitic effects were studied using voltamperometric and spectroscopic techniques. Nitroanion radicals generated by cyclic voltammetry were characterized by electron spin resonance spectroscopy (ESR) and their spectral lines were explained and analyzed using simulated spectra. In addition, we examined the interaction between radical species generated from nitroindazole derivatives and glutathione (GSH). Biological assays such as activity against Trypanosoma cruzi and cytotoxicity against macrophages were carried out. Finally, spin trapping and molecular modeling studies were also done in order to elucidate the potentials action mechanisms involved in the trypanocidal activity.
Assuntos
Antiparasitários/química , Antiparasitários/farmacologia , Indazóis/química , Indazóis/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Ânions , Antiparasitários/toxicidade , Bioensaio , Morte Celular/efeitos dos fármacos , Linhagem Celular , Simulação por Computador , Dimetil Sulfóxido/química , Técnicas Eletroquímicas , Eletrodos , Espectroscopia de Ressonância de Spin Eletrônica , Indazóis/toxicidade , Macrófagos/efeitos dos fármacos , Camundongos , Modelos Moleculares , NADH NADPH Oxirredutases/química , Marcadores de SpinRESUMO
Electrochemical and ESR studies were carried out in this work with the aim of characterizing the reduction mechanisms of 4-substituted and 1,4-disubstituted 7-nitroquinoxalin-2-ones by means of cyclic voltammetry in DMSO as aprotic solvent. Two reduction mechanisms were found for these compounds: the first, for compounds bearing a labile hydrogen by following a self-protonation mechanism (ECE steps), and the second, for compounds without labile hydrogen, based on a purely electrochemical reduction mechanism (typical of nitroheterocycles). The electrochemical results were corroborated using ESR spectroscopy allowing us to propose the hyperfine splitting pattern of the nitro-radical, which was later corroborated by the ESR simulation spectra. All these compounds were assayed as growth inhibitors against Trypanosoma cruzi: first, on the non-proliferative (and infective) form of the parasite (trypomastigote stage), and then, the ones that displayed activity, were assayed on the non-infective form (epimastigote stage). Thus, we found four new compounds highly active against T. cruzi. Finally, molecular modeling studies suggest the inhibition of the trypanothione reductase like one of the possible mechanisms involved in the trypanocidal action.