Desenvolvimento de candidatos à fármacos leishmanicidas: estudos computacionais por modelagem molecular e síntese química de novos derivados do safrol

Abstract

Leishmaniasis, in different clinical forms, consists of a neglected tropical disease, caused by several species of the protozoan of the genus Leishmania. With a high worldwide incidence, it affects mainly developing countries and is considered a public health problem in Minas Gerais and throughout Brazil, as it has a high degree of morbidity and mortality in addition to a scarce therapeutic arsenal. There are enzymes essential for cell growth and viability of Leishmania that are investigated as targets for new drugs. In this sense, the following study sought to analyze a series of bioactive molecules that have an affinity profile in molecular targets related to Leishmaniasis, using Molecular Modeling and Bioinformatics tools, as well as the planning and synthesis of novel substances that are candidates for leishmanicidal drugs. The oxime ethers, class of substances studied, was chosen based on the fact that oximic derivatives have several known biological activities (including protozoicide), as well as the starting material (safrol), which has antifungal action, to be easily acquired commercially. With the aid of Molecular Modeling studies, it was possible to evaluate the affinity profiles between the proposed substances with selected biological targets, among them CRK3 and rCPB2.8 from Leishmania, which have been widely discussed as essential for the parasite's cell viability. The enzymes were predicted by the homology modeling technique using one model and multiple models, respectively, due to the absence of a crystallographic structure of this protein in the database. In order to obtain these new chemical substances, the planning of a simple and reproducible synthetic route was considered. A series of oxime ethers

derived from safrol was obtained, bearing different substituents at the para- disubstituted ring moiety were investigated, varying the substituents with electron

donating groups as well as electron withdrawing groups of different electronegativity. The new substances were structurally elucidated using spectroscopic tools. The study allowed to verify that the proposed molecules had an affinity profile for the study enzyme. Three oxy-chemical derivatives (MS-05i, MS-05a and MS-05f) showed high affinity for the CRK3 enzyme, higher than the drug Pentamidine used currently to treat the disease. In the case of the rCPB2.8 enzyme, the ligands that carried very electronegative atoms (MS-05b and MS-05g) showed high affinity between the catalytic site amino acids, in addition to the atomic distances between the ligand and residues of the enzyme active site possible covalent bond, which would be essential for enzyme inhibitory activity.