Synthesis and antitrypanosomal evaluation of E-isomers of 5-nitro-2-furaldehyde and 5-nitrothiophene-2-carboxaldehyde semicarbazone derivatives. Structure-activity relationships

Bioenergetics Center, Universidad de Buenos Aires, Paraguay 2120, Buenos Aires, Argentina
European Journal of Medicinal Chemistry (Impact Factor: 3.45). 04/2000; 35(3):343-350. DOI: 10.1016/S0223-5234(00)00131-8


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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    • "Thiosemicarbazide analogues possess a wide range of biological activities including anti convulsant (Tripathi et al., 2012), anti microbial (Zhong et al., 2011), anti viral (Garcial et al., 2003), anti trypanosomal (Moreira et al., 2014), and mushroom tyrosinase inhibitors (Yi, W et al., 2011). On the other hand, Semicarbazide analogues exhibits anti convalsant (Rajak et al., 2013), anti tubercular (Sriram et al., 2004), anti trypanosomal (Cerecetto et al., 2000), anti inflammatory (Vieira et al., 2012), anti amnesic, cognition enhancing and anti cholinesterase (Sinha and Shrivastava., 2013) and anti cancer activity (Qi et al., 2013). "
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    Arabian Journal of Chemistry 02/2015; 18. DOI:10.1016/j.arabjc.2015.02.006 · 3.73 Impact Factor
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    • "Guanylhydrazones have been previously shown to display strong activity against T. cruzi [99]. It is also well known that some functionalised hydrazone-related derivatives [100-102] presented trypanocidal activity, which could be correlated with an action on essential enzymes of T. cruzi, such as cruzipain and trypanothione reductase, potential targets of new drugs for CD [27]. Such a strategy led us to identify a new potent trypanocide prototype S1 (Brazilizone A) (Fig. 6), which was two times more potent than megazol against the infective bloodstream form of the parasite and was selected for subsequent in vitro and in vivo studies. "
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    ABSTRACT: Chagas disease (CD), caused by the intracellular protozoan Trypanosoma cruzi, is a parasitic illness endemic in Latin America. In the centennial after CD discovery by Carlos Chagas (1909), although it still represents an important public health problem in these affected areas, the existing chemotherapy, based on benznidazole and nifurtimox (both introduced more than four decades ago), is far from being considered ideal due to substantial toxicity, variable effect on different parasite stocks and well-known poor activity on the chronic phase. CD is considered one of the major "neglected" diseases of the world, as commercial incentives are very limited to guarantee investments for developing and discovering novel drugs. In this context, our group has been pursuing, over the last years, the efficacy, selectivity, toxicity, cellular targets and mechanisms of action of new potential anti-T. cruzi candidates screened from an in-house compound library of different research groups in the area of medicinal chemistry. A brief review regarding these studies will be discussed, mainly related to the effect on T. cruzi of (i) diamidines and related compounds, (ii) natural naphthoquinone derivatives, and (iii) megazol derivatives.
    The Open Medicinal Chemistry Journal 03/2011; 5:21-30. DOI:10.2174/1874104501105010021
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    • "The general data set used in this study consists of 440 compounds of great structural variation, 143 of which are actives and 297 are inactive against trypanosome. The antitrypanosomals considered in this study are representative of families with diverse structural patterns and were collected from previous publications (Gillmor et al., 1997; Urbina et al., 1998; Bonse et al., 1999; Cerecetto et al., 2000; Hiyoshi et al., 2000; Werbovetz, 2000; Buckner et al., 2001; Salmon-Chemin et al., 2001; Zuccotto et al., 2001; Daunes and D'Silva, 2002; Du et al., 2002; Elhalem et al., 2002; Gilbert, 2002; Bal et al., 2003; Buckner et al., 2003; Hamilton et al., 2003; Huang et al., 2003; Urbina et al., 2004) . "
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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.
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