Computer-Aided drug design of new 2-amino-thiophene derivatives as anti-leishmanial agents.

The leishmaniasis is a neglected disease caused by a group of protozoan parasites from the genus Leishmania whose treatment is limited, obsolete, toxic, and ineffective in certain cases. These characteristics motivate researchers worldwide to plan new therapeutic alternatives for the treatment of leishmaniasis, where the use of cheminformatics tools applied to computer-assisted drug design has allowed research to make great advances in the search for new drugs candidates. In this study, a series of 2-amino-thiophene (2-AT) derivatives was screened virtually using QSAR tools, ADMET filters and prediction models, allowing direct the synthesis of compounds, which were evaluated in vitro against promastigotes and axenic amastigotes of Leishmania amazonensis. The combination of different descriptors and machine learning methods led to obtaining robust and predictive QSAR models, which was obtained from a dataset composed of 1862 compounds extracted from the ChEMBL database, with correct classification rates ranging from 0.53 (for amastigotes) to 0.91 (for promastigotes), allowing to select eleven 2-AT derivatives, which do not violate Lipinski's rules, exhibit good druglikeness, and with probability ≤70% of potential activity against the two evolutionary forms of the parasite. All compounds were properly synthesized and 8 of them were shown to be active at least against one of the evolutionary forms of the parasite with IC50 values lower than 10 µM, being more active than the reference drug meglumine antimoniate, and showing low or no citotoxicity against macrophage J774.A1 for the most part. Compounds 8CN and DCN-83, respectively, are the most active against promastigote and amastigote forms, with IC50 values of 1.20 and 0.71 µM, and selectivity indexes (SI) of 36.58 and 119.33. Structure Activity Relationship (SAR) study was carried out and allowed to identify some favorable and/or essential substitution patterns for the leishmanial activity of 2-AT derivatives. Taken together, these findings demonstrate that the use of ligand-based virtual screening proved to be quite effective and saved time, effort, and money in the selection of potential anti-leishmanial agents, and confirm, once again that 2-AT derivatives are promising hit compounds for the development of new anti-leishmanial agents.

Influence of Reduction with NaBH4 and HCl in Obtaining Amino Derivatives of Cashew Gum and Cytotoxic Profile.

Tree-exuded gums are natural polymers that represent an abundant raw material in the food and pharmaceutical industries. The cashew gum can be obtained by exudation of trees of the genus Anacardium, a native species of the Brazilian northeast; its polymer consists of monosaccharide units propitious to the action of chemical reactions that tend to improve their intrinsic characteristics among them, as the degree of hydro-solubility. The objective of this work was to modify the exudate gum of Anacardium occidentale (cashew gum (CG)) through an amine reaction. The modification was confirmed by Nuclear Magnetic Resonance (1H NMR), infrared spectroscopy (FTIR), gel permeation chromatography (GPC), zeta potential, and thermogravimetric analysis (TG). In addition, the chemical modification altered the molar mass and surface charge of the CG, and the amino group binding to the CG polymers was confirmed by FTIR spectra. In addition, cytotoxicity tests were performed where cell viability was estimated by an MTT assay on RAW 264.7 macrophages. Through these tests, it was found that the amine caused an increase in the thermal stability of the amino compounds and did not present cytotoxic potential at concentrations below 50.0 mg/L.