Síntese e avaliação da atividade anti-inflamatória e antibacteriana de derivados e análogos da clindamicina.

Abstract

The pain is considered an unpleasant experience and involves several sensory and emotional aspects of the individual. The pharmacological one mainly includes NSAIDs such as paracetamol, naproxen, e morphine derivatives, such as codeine and fentanyl. It is well known that both NSAID classes and opioid derivatives have several adverse effects. The NSAID are associated with gastrointestinal bleeding and ulcers and the morphine derivatives are susceptible to sedation, respiratory depression and dependence. New alternatives for pain management are necessary. Drug repositioning studies allowed the identification of the antibiotic clindamycin as a potential anti-inflammatory drug. Molecular modifications in the structure of clindamycin, as well as the synthesis of analogues with a simpler chemical structure, were proposed with the aim of establishing a structure relationship between antimicrobial and anti-inflammatory activity. In this context, in the present work, derivatives and analogues of clindamycin were synthesized using easily accessible starting materials (L-proline, methyl α-D-glucopyranoside, N-methyl-2-pyrrolecarboxaldehyde and clindamycin) and classic reactions in organic synthesis, such as alkylation, acetylation, reduction, oxidation, reductive amination, amidation, nucleophilic substitution reaction and 1,3-dipolar cycloaddition A total of 30 compounds were synthesized, five of which were new (1a, 2, 10 and 11). The synthesized compounds were subjected to in vitro tests to evaluate their antibacterial activity. After optimizing the reactions, the products were generally obtained in good yields. The anti-inflammatory activity of the peracetylated clindamycin derivative (2) was evaluated in a murine model with results comparable to those obtained for clindamycin. The main advantage of this derivative is that it did not show antimicrobial activity in vitro. None of the synthesized substances showed antimicrobial activity, which indicates a potential selectivity in relation to anti-inflammatory activity. To confirm this premise, the anti-inflammatory activity of the synthesized substances will be further evaluated. The results obtained in this work were promising, opening new perspectives for the synthesis of other analogues with the possibility of optimizing the biological activity.