Síntese e perfil admet de novos derivados 2-aminotiofênicos piperidínicos como candidatos a fármacos para tratamento das leishmanioses

Abstract

Given the limited therapeutic context of leishmaniasis, characterized by old, obsolete treatment options with known toxicity, and administered via routes that do not promote treatment adherence, searching for new anti-leishmanial compounds is necessary. In this regard, the chemical class of 2-aminothiophene (2-AT) derivatives has emerged as a potential therapeutic alternative, with several prototypes demonstrating promise as anti-leishmanial drug candidates. In this context, the present research aimed to contribute to the optimization and development of new therapeutic alternatives for leishmaniasis by evaluating the effect on pharmacomodulation of modifying the position of the N-tert-butyloxycarbonyl (N-Boc) group from C-6 to C-7 on the piperidinyl ring of 2-AT derivatives. The synthesis of the compounds was carried out in two steps, starting with the production of the Gewald adult, which was then condensed with five indole aldehydes and two benzaldehydes, resulting in 8 final compounds obtained in yields ranging from 35% to 69%. The chemical structures were confirmed by Infrared and Nuclear Magnetic Resonance spectroscopy. Pharmacokinetic parameters (ADMET) were determined using Osiris Property Explorer and SwissADME software, revealing that 6 of the 8 derivatives did not violate any of Lipinski's and Veber's rules, thus presenting desirable profiles for the development of molecules with oral bioavailability. In vitro bioactivity assays were performed against Leishmania amazonensis, L. donovani, L. infantum, and L. braziliensis promastigote forms; however, no compound showed activity up to the highest concentration evaluated (IC50 > 10 μM). By comparing the activity values from the previous study, we conclude that modifying the N-Boc group's position from C-6 to C-7 is unfavorable for anti-leishmanial activity, resulting in a reduction/lost of its activity. Therefore, future studies will focus on obtaining and evaluating the anti-leishmanial activity of 5-N-Boc substituted derivatives to determine the most favorable position of the N-Boc group in 2-AT derivatives.