Synthesis and antitrypanosomal evaluation of E-isomers of 5-nitro-2-furaldehyde and 5-nitrothiophene-2-carboxaldehyde semicarbazone derivatives. Structure–activity relationships.
ABSTRACT Several novel semicarbazone derivatives were prepared from 5-nitro-2-furaldehyde or 5-nitrothiophene-2-carboxaldehyde and semicarbazides bearing a spermidine-mimetic moiety. All derivatives presented the E-configuration, as determined by NMR-NOE experiments. These compounds were tested in vitro as potential antitrypanosomal agents, and some of them, together with the parent compounds, 5-nitro-2-furaldehyde and 5-nitrothiophene-2-carboxaldehyde semicarbazone derivatives, were also evaluated in vivo using infected mice. Structure–activity relationship studies were carried out using voltammetric response and lipophilic–hydrophilic balance as parameters. Two of the compounds (1 and 3) displayed the highest in vivo activity. A correlation was found between lipophilic–hydrophilic properties and trypanocidal activity, high RM values being associated with low in vivo effects.
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ABSTRACT: A series of novel N-1 and C-3 substituted indole derivatives (5a-f) were designed, synthesized and evaluated for their cytotoxic properties, viz brine shrimp lethality bioassay (BSLB) besides 5-lipoxygenase (5-LOX) inhibitory activities through in vitro assays. Structure Activity Relation (SAR) studies showed that compound 5d with an LC50 of 6.49 μM and 5c with an IC50 of 33.69 μM were found to be interesting for cytotoxicity and 5-LOX inhibitory activity respectively.Arabian Journal of Chemistry 02/2015; 18. DOI:10.1016/j.arabjc.2015.02.006 · 2.68 Impact Factor
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ABSTRACT: Herein we present results of a quantitative structure-activity relationship (QSAR) studies to classify and design, in a rational way, new antitrypanosomal compounds by using non-stochastic and stochastic bond-based quadratic indices. A data set of 440 organic chemicals, 143 with antitrypanosomal activity and 297 having other clinical uses, is used to develop QSAR models based on linear discriminant analysis (LDA). Non-stochastic model correctly classifies more than 93% and 95% of chemicals in both training and external prediction groups, respectively. On the other hand, the stochastic model shows an accuracy of about the 87% for both series. As an experiment of virtual lead generation, the present approach is finally satisfactorily applied to the virtual evaluation of 9 already synthesized in house compounds. The in vitro antitrypanosomal activity of this series against epimastigote forms of Trypanosoma cruzi is assayed. The model is able to predict correctly the behaviour for the majority of these compounds. Four compounds (FER16, FER32, FER33 and FER 132) showed more than 70% of epimastigote inhibition at a concentration of 100 microg/mL (86.74%, 78.12%, 88.85% and 72.10%, respectively) and two of these chemicals, FER16 (78.22% of AE) and FER33 (81.31% of AE), also showed good activity at a concentration of 10 microg/mL. At the same concentration, compound FER16 showed lower value of cytotoxicity (15.44%), and compound FER33 showed very low value of 1.37%. Taking into account all these results, we can say that these three compounds can be optimized in forthcoming works, but we consider that compound FER33 is the best candidate. Even though none of them resulted more active than Nifurtimox, the current results constitute a step forward in the search for efficient ways to discover new lead antitrypanosomals.European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences 10/2009; 39(1-3):30-6. DOI:10.1016/j.ejps.2009.10.007 · 3.01 Impact Factor
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ABSTRACT: In this "Critical Review" we made a historical introduction of drugs assayed against Chagas disease beginning in 1912 with the works of Mayer and Rocha Lima up to the experimental use of nitrofurazone. In the beginning of the 70s, nifurtimox and benznidazole were introduced for clinical treatment, but results showed a great variability and there is still a controversy about their use for chronic cases. After the introduction of these nitroheterocycles only a few compounds were assayed in chagasic patients. The great advances in vector control in the South Cone countries, and the demonstration of parasite in chronic patients indicated the urgency to discuss the etiologic treatment during this phase, reinforcing the need to find drugs with more efficacy and less toxicity. We also review potential targets in the parasite and present a survey about new classes of synthetic and natural compounds studied after 1992/1993, with which we intend to give to the reader a general view about experimental studies in the area of the chemotherapy of Chagas disease, complementing the previous papers of Brener (1979) and De Castro (1993).Memórias do Instituto Oswaldo Cruz 02/2002; 97(1):3-24. DOI:10.1590/S0074-02762002000100001 · 1.57 Impact Factor