0000000000206842
AUTHOR
Maria Celeste Vega
Synthesis, biological evaluation and chemometric analysis of indazole derivatives. 1,2-Disubstituted 5-nitroindazolinones, new prototypes of antichagasic drug
Chagas disease chemotherapy, currently based on only two drugs, nifurtimox and benznidazole, is far from satisfactory and therefore the development of new antichagasic compounds remains an important goal. On the basis of antichagasic properties previously described for some 1,2-disubstituted 5-nitroindazolin-3- ones (21, 33) and in order to initiate the optimization of activity of this kind of compounds, we have prepared a series of related analogs (22-32, 34-38, 58 and 59) and tested in vitro these products against epimastigote forms of Trypanosoma cruzi. 2-Benzyl-1-propyl (22), 2-benzyl-1-isopropyl (23) and 2-benzyl-1-butyl (24) derivatives have shown high trypanocidal activity and low un…
New ligand-based approach for the discovery of antitrypanosomal compounds.
The antitrypanosomal activity of 10 already synthesized compounds was in silico predicted as well as in vitro and in vivo explored against Trypanosoma cruzi. For the computational study, an approach based on non-stochastic linear fingerprints to the identification of potential antichagasic compounds is introduced. Molecular structures of 66 organic compounds, 28 with antitrypanosomal activity and 38 having other clinical uses, were parameterized by means of the TOMOCOMD-CARDD software. A linear classification function was derived allowing the discrimination between active and inactive compounds with a confidence of 95%. As predicted, seven compounds showed antitrypanosomal activity (%AE > 7…
Ligand-based discovery of novel trypanosomicidal drug-like compounds: In silico identification and experimental support
Abstract Two-dimensional bond-based linear indices and linear discriminant analysis are used in this report to perform a quantitative structure–activity relationship study to identify new trypanosomicidal compounds. A database with 143 anti-trypanosomal and 297 compounds having other clinical uses, are utilized to develop the theoretical models. The best discriminant models computed using bond-based linear indices provides accuracies greater than 90 for both training and test sets. Our models identify as anti-trypanosomals five out of nine compounds of a set of already-synthesized substances. The in vitro anti-trypanosomal activity of this set against epimastigote forms of Trypanosoma cruzi…
Antiprotozoan lead discovery by aligning dry and wet screening: Prediction, synthesis, and biological assay of novel quinoxalinones
Protozoan parasites have been one of the most significant public health problems for centuries and several human infections caused by them have massive global impact. Most of the current drugs used to treat these illnesses have been used for decades and have many limitations such as the emergence of drug resistance, severe side-effects, low-to-medium drug efficacy, administration routes, cost, etc. These drugs have been largely neglected as models for drug development because they are majorly used in countries with limited resources and as a consequence with scarce marketing possibilities. Nowadays, there is a pressing need to identify and develop new drug-based antiprotozoan therapies. In …
Computational discovery of novel trypanosomicidal drug-like chemicals by using bond-based non-stochastic and stochastic quadratic maps and linear discriminant analysis.
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 …
Bond-based bilinear indices for computational discovery of novel trypanosomicidal drug-like compounds through virtual screening
Two-dimensional bond-based bilinear indices and linear discriminant analysis are used in this report to perform a quantitative structure-activity relationship study to identify new trypanosomicidal compounds. A data set of 440 organic chemicals, 143 with antitrypanosomal activity and 297 having other clinical uses, is used to develop the theoretical models. Two discriminant models, computed using bond-based bilinear indices, are developed and both show accuracies higher than 86% for training and test sets. The stochastic model correctly indentifies nine out of eleven compounds of a set of organic chemicals obtained from our synthetic collaborators. The in vitro antitrypanosomal activity of …
Identification In Silico and In Vitro of Novel Trypanosomicidal Drug-Like Compounds
Atom-based bilinear indices and linear discriminant analysis are used to discover novel trypanosomicidal compounds. The obtained linear discriminant analysis-based quantitative structure–activity relationship models, using non-stochastic and stochastic indices, provide accuracies of 89.02% (85.11%) and 89.60% (88.30%) of the chemicals in the training (test) sets, respectively. Later, both models were applied to the virtual screening of 18 in-house synthesized compounds to find new pro-lead antitrypanosomal agents. The in vitro antitrypanosomal activity of this set against epimastigote forms of Trypanosoma cruzi is assayed. Predictions agree with experimental results to a great extent (16/18…
Identification <i>In Silico</i> and <i>In Vitro</i> of Novel Trypanosomicidal Drug-like Compounds
Atom-based bilinear indices and linear discriminant analysis are used to discover novel trypanosomicidal compounds. The obtained linear discriminant analysis-based quantitative structure–activity relationship models, using non-stochastic and stochastic indices, provide accuracies of 89.02% (85.11%) and 89.60% (88.30%) of the chemicals in the training (test) sets, respectively. Later, both models were applied to the virtual screening of 18 in-house synthesized compounds to find new pro-lead antitrypanosomal agents. The in vitro antitrypanosomal activity of this set against epimastigote forms of Trypanosoma cruzi is assayed. Predictions agree with experimental results to a great extent (16/18…