Planejamento in silico e síntese de derivados de a e b amirinascom atividade antileishmania

Abstract

Leishmaniasis is a group of neglected tropical diseases caused by different parasites of the Leishmania genus. This diseases is endemic in 98 countries and affect 12 to 15 million people worldwide annually. Current treatments show many side effects, prolonged use time and often therapeutic failure. Due to this scenario, there is a need to seek substances with antileishmania potential. A modern approach to drug discovery consists of using computational methods such as molecular docking, which allows the selection of molecules most likely to obtain positive experimental results. Pentacyclic triterpenes have been reported as potential antileishmania molecules. Despite this, the α and β amyrin triterpenes have been poorly investigated. In this study, rational planning and design of derivatives were carried out using base skeleton the triterpenes α and β amyrins. All the modifications were around the C-3 which is functionalized with an alcohol. The first series of derivatives consist of n-alkyl chain sulfonamides and ortho- and para-substituted aryl sulfonamides. The second series of derivatives consist of 5-membered heterocycles, fused to the main skeleton. The designed structures were converted into a 3D format and optimized. The CYP51 Leishmania infantum enzyme (PDB: 3L4D) and the GOLD program were used to perform molecular docking. Six derivatives from the series of alkyl sulfonamides (3/4, 5/6 and 9/10), eight derivatives from the series of aryl sulfonamides (21/22, 29/30, 41/42 and 45/46) and eight derivatives were selected of the series of heterocycles (55/56, 59/60, 61/62 and 63/64), which presented a better profile of chemical interactions and free energy binding. The derivatives presented in pairs correspond to the isomers α and β. For the synthesis of derivatives, the triterpenes α and β amirins were extracted and purified from the resin of Protium sp. For the synthesis of the aryl sulfonamide series, the intermediate 3-amino α and β amirine was used, which was treated with different sulfonyl chlorides to obtain derivatives 29/30 (4 / acetamidobenzene sulfonamide from α and β amirine), 41/42 (α and β amirine 4-nitrobenzene sulfonamide), 45/46 (α and β amirine 4-chlorobenzene sulfonamide) with yields that varied from 45 to 71%. All sulfonamide derivatives obtained are unprecedented in the literature. For the series of heterocycles, the intermediate 2-bromo-3-oxo α and β amirine was used, which was condensed with different nucleophiles. The derivative 63/64 (aminothiazole derivative α and β amirine) was obtained, with 99% yield, an example of molecular modification already reported in other triterpenes, however it is the first time inserted in α and β amirines. The present study contributed to the application of computational methodologies combined with methods of rational design, aiming at the semisynthesis of molecules with biological activity antileishmania. The molecules synthesized in this work will be sent for biological evaluation to confirm their potential as drugs.