Rational design of nitrofuran derivatives: Synthesis and valuation as inhibitors of Trypanosoma cruzi trypanothione reductase (original) (raw)
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Bioorganic & Medicinal Chemistry, 2013
The anti-Trypanosoma cruzi activity of 5-nitro-2-furfuriliden derivatives as well as the cytotoxicity of these compounds on J774 macrophages cell line and FN1 human fibroblast cells were investigated in this study. The most active compounds of series I and II were 4-butyl-[N 0-(5-nitrofuran-2-yl) methylene] benzidrazide (3g; IC 50 = 1.05 lM ± 0.07) and 3-acetyl-5-(4-butylphenyl)-2-(5-nitrofuran-2-yl)-2,3-dihydro,1,3,4-oxadiazole (4g; IC 50 = 8.27 lM ± 0.42), respectively. Also, compound 3g was more active than the standard drugs, benznidazole (IC 50 = 22.69 lM ± 1.96) and nifurtimox (IC 50 = 3.78 lM ± 0.10). Regarding the cytotoxicity assay, the 3g compound presented IC 50 value of 28.05 lM (SI = 26.71) against J774 cells. For the FN1 fibroblast assay, 3g showed IC 50 value of 98 lM (SI = 93.33). On the other hand, compound 4g presented a cytotoxicity value on J774 cells higher than 400 lM (SI >48), and for the FN1 cells its IC 50 value was 186 lM (SI = 22.49). Moreover, an exploratory data analysis, which comprises hierarchical cluster (HCA) and principal component analysis (PCA), was carried out and the findings were complementary. The molecular properties that most influenced the compounds' grouping were C log P and total dipole moment, pointing out the need of a lipophilic/hydrophilic balance in the designing of novel potential anti-T. cruzi molecules.
European Journal of Medicinal Chemistry, 2006
Growth inhibitory activity in vitro of sixteen new 5-nitrofuryl derivatives against the protozoan parasite Trypanosoma cruzi, the causative agent of American trypanosomiasis, was studied. The designed compounds combine in the same molecule the recognized 5-nitrofuryl group, an oxidative stress promoter, and lateral chains that could interact with biomolecules such as trypanothione reductase. Some of the derivatives were found to be very active against the epimastigote form of the parasite, being near to 3.0-fold more active than the reference compound, nifurtimox. Moreover, three-dimensional requirements for activity were clearly observed using a 3D-QSAR study based on a comparative molecular field analysis (CoMFA). The best CoMFA model, r 2 = 0.970 and q 2 = 0.725, points to the importance of a specific hydrogen-bonding pattern around the carbonyl or thiocarbonyl moieties, as well as the requirement for hydrophobic lateral chains. Theoretical pharmacokinetics (Lipinski's rule, PSA) supports further in vivo studies.
Chemija, 2020
Trypanothione reductase (TR) and trypanothione synthase (TS) are critical for the maintenance of thiol-redox homeostasis and antioxidant protection in trypanosomal parasites, which cause African sleeping sickness and Chagas disease. Both enzymes are absent in mammals. Thus, the design of efficient and specific TR and TS inhibitors represents one of the pathways for a development of new antitrypanosomal drugs. 5-Vinylquinoline-substituted nitrofurans (n = 7), studied in this work, acted as un- or noncompetitive to trypanothione inhibitors of Trypanosoma congolense TR. Their inhibition constants (Ki) varied from 2.3 µM to 150 µM. We for the first time observed a parallelism between their antitrypanosomal in vitro activity and their efficacy as TR inhibitors. The inhibition of TS appears not to be a significant factor of trypanocidal activity of examined compounds.
Chagas disease is caused by the parasite Trypanosoma cruzi. One of the two first-line drugs for treatment is nifurtimox, a nitrofuran that exhibits high toxicity. Therefore, the need arises to investigate new therapeutic options, and, in this sense, our objective was to study compounds that maintain the trypanocidal activity associated with the furan nucleus and by structural modification of substituents reduce their toxicity. In the following research work, a chemical library was formed using the databases PubChem, ChEMBL and ChemSpider, later a virtual screening was carried out with the chemoinformatic tools Way2Drug, molinspiration, DataWarrior and admetSAR obtaining the prediction of biological activity, physicochemical parameters, data of toxicity and pharmacokinetic properties, respectively. The last stage consisted of the molecular docking of the molecules at the active site of the trypanothione reductase protein of Trypanosoma cruzi, determining its binding energy and interm...
Bioorganic & Medicinal Chemistry, 2009
Chagas disease represents a serious public health problem in South America. The first line of treatment is Nifurtimox and Benznidazole which generate toxic effects in treated patients. We have recently shown that a number of 5-nitrofuranes possess activity against Trypanosoma cruzi through oxidative stress and inhibition of parasite ergosterol biosynthesis, specifically at the level of squalene epoxidase. Here, we identify new 5-nitrofuranes and the thia-analogues with excellent effects on the viability of T. cruzi and adequate parasite/mammal selectivity indexes. Analysis of the free sterols from parasite incubated, during 120 h, with the compounds showed that some of them accumulated squalene suggesting the squalene epoxidase activity inhibition of the parasite. Nifurtimox was able to accumulate squalene only at lower incubation times. Due to this fact some derivatives were also tested as antifungal agents. Quantitative structure-activity relationship studies were also performed showing relevant features for further new derivatives design. Taken together, the results obtained in the present work point to a more general effect of 5-nitrofuranes and 5-nitrothiophenes in trypanosomatids, opening potential therapeutic possibilities of them for these infectious diseases.
Synthesis and characterization of potent inhibitors of Trypanosoma cruzi dihydrofolate reductase
Bioorganic & Medicinal Chemistry, 2010
Dihydrofolate reductase (DHFR) of the parasite Trypanosoma cruzi (T. cruzi) is a potential target for developing drugs to treat Chagas’ disease. We have undertaken a detailed structure–activity study of this enzyme. We report here synthesis and characterization of six potent inhibitors of the parasitic enzyme. Inhibitory activity of each compound was determined against T. cruzi and human DHFR. One of these compounds, ethyl 4-(5-[(2,4-diamino-6-quinazolinyl)methyl]amino-2-methoxyphenoxy)butanoate (6b) was co-crystallized with the bifunctional dihydrofolate reductase-thymidylate synthase enzyme of T. cruzi and the crystal structure of the ternary enzyme:cofactor:inhibitor complex was determined. Molecular docking was used to analyze the potential interactions of all inhibitors with T. cruzi DHFR and human DHFR. Inhibitory activities of these compounds are discussed in the light of enzyme–ligand interactions. Binding affinities of each inhibitor for the respective enzymes were calculated based on the experimental or docked binding mode. An estimated 60–70% of the total binding energy is contributed by the 2,4-diaminoquinazoline scaffold.
Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy, 2011
Cyclic voltammetry and electron spin resonance techniques were used in the investigation of several potential antiprotozoal containing thiosemicarbazone and carbamate nitrofurans. In the electrochemical behaviour, a self-protonation process involving the nitro group was observed. The reactivity of the nitro anion radical for these derivatives with glutathione, a biological relevant thiol, was also studied in means of cyclic voltammetry. These studies demonstrated that glutathione could react with radical species from 5-nitrofuryl system. Furthermore, from the voltammetric results, some parameters of biological significance as E(7)(1) (indicative of the biological nitro anion radical formation), and [Formula: see text] (thermodynamic indicator the of oxygen redox cycling) have been calculated. We also evaluated the stability of the nitro anion radical in terms of the dimerization constant (k(d)). The nitrofuran-free radicals from cyclic voltammetry were characterized by electron spin...
International Journal of Molecular Sciences
American trypanosomiasis is a worldwide health problem that requires attention due to ineffective treatment options. We evaluated n-butyl and isobutyl quinoxaline-7-carboxylate 1,4-di-N-oxide derivatives against trypomastigotes of the Trypanosoma cruzi strains NINOA and INC-5. An in silico analysis of the interactions of 1,4-di-N-oxide on the active site of trypanothione reductase (TR) and an enzyme inhibition study was carried out. The n-butyl series compound identified as T-150 had the best trypanocidal activity against T. cruzi trypomastigotes, with a 13% TR inhibition at 44 μM. The derivative T-147 behaved as a mixed inhibitor with Ki and Ki’ inhibition constants of 11.4 and 60.8 µM, respectively. This finding is comparable to the TR inhibitor mepacrine (Ki = 19 µM).
Bioorganic & Medicinal Chemistry Letters, 1999
This paper describes the design and synthesis of potential inhibitors of Trypanosoma cruzi dihydrofolate reductase using a structure-based approach. A model of the structure of the T. cruzi enzyme was compared with the structure of the human enzyme. The differences were used to design modifications of methotrexate to produce compounds which should be selective for the parasite enzyme. The derivatives of methotrexate were synthesised and tested against the enzyme and intact parasites.