Estudos de relação estrutura-atividade para derivados naftoimidazólicos com atividade tripanocida: cálculos de descritores físico-químicos, aplicação quimiométrica multivariada e estudos de ancoramento molecular

Abstract

This study aimed to calculate physicochemical descriptors for a class of 22 naphtoimidazolic derived compounds that possess microbicidal, bactericidal, fungicidal, trypanocidal activity and so on. The descriptors were also calculated for benznidazole, a drug used in the treatment of Chagas disease and the ravuconazole, which shows itself effective in all strains of the parasite. After calculation of the descriptors found at which of these would be responsible for the separation of compounds into active and inactive. To do so, the structures were pre-optimized through chemical calculations of molecular mechanics and optimized by semi empirical calculations, based on Austin Model 1. After the molecular optimization, multivariate chemometric calculations to make the separation of active and inactive compounds were performed and verify which of descriptors were calculated for separating the relevant class of compounds. Were made 4 chemometric analysis of principal component analysis and hierarchical cluster analysis, where information was available and the similarities of groups formed for the compounds and the descriptors. In the last chemometric analysis it was found that the most active compounds were FSE-1, FSE-2, FSE-13 and FSE-14 and the descriptor responsible for the observed activity would be ELUMO while that would be responsible for the inactivity was AE. Through calculations of the LUMO frontier orbitals, we found that the benzene ring and the imidazole ring are regions in structures that favor the formation of molecular interaction. For benzene of naphthalene, it was observed that the para and ortho positions are also regions of probable formation of molecular interaction. The electrostatic potential maps calculated showed that clusters with concentration of negative charges do not encourage biological activity of naphttimidazolic derivatives. To calculate the molecular anchoring it was used the cruzain enzyme from T. cruzi due its importance in all stages of the parasite life cycle. Realized molecular anchoring it was found that the most relevant interactions are stacking interactions and interactions with the imidazole ring in the ortho and para positions of the naphthalene ring of FSE derivatives.