Planejamento, síntese, caracterização e avaliação biológica preliminar de derivados quinolínicos-sulfonilacetoidrazida como potenciais fármacos anti-inflamatórios

Abstract

Inflammation is a process of the body's defense against pathogens and/or other factors of a physical, chemical or biological nature, which can lead to an acute or chronic process, whose signs and symptoms are characterized as pain, redness, heat, edema and can worsen to loss of tissue function. Existing pharmacological therapy consists mainly of steroidal and non-steroidal anti-inflammatory drugs, however, both classes have a significant number of adverse effects. Therefore, the objective of this work was to plan, based on a natural compound, quinolinic-N-acylhydrazonic derivatives with potential anti-inflammatory activity. To this end, the synthesis and characterization of hybrid derivatives was carried out, with synthetic routes already described and consolidated in the laboratory, based on compounds present in the literature that already show anti-inflammatory activity. Furthermore, in vitro studies were carried out, in which macrophages of the J774 lineage were cultivated and used in the compounds cytotoxicity experiments and the anti-inflammatory activity was measured by the ability to inhibit the production of nitric oxide (NO). Additionally, the possible mechanism of action of the compounds was evaluated through molecular docking on different inflammation targets, including COX-2 complexed with mefenamic acid (PDB ID: 5IKR), iNOS complexed with AR-C95791 inhibitor (PDB ID: 3E7G) and NLRP3 complexed with NP3-146 (PDB ID: 7ALV), in the GOLD 2022.3.0 program; as well as molecular dynamics simulations for the best complexes. Next, the in silico pharmacokinetic profile was predicted using the SwissADME, pkCSM and Xenosite programs. As a result, 5 final compounds were designed (KMR-01 to KMR-05), of which two were synthesized (KMR-01 and KMR-04). Regarding in vitro studies, the compounds tested (intermediate KM-02, KMR-01 and KMR-04) did not show cytotoxicity up to a concentration of 125 µM, which is the highest concentration used in evaluating NO production. KMR-04, the only one tested, showed inhibition of NO production at all concentrations tested (0.9-125 µM), allowing us to glimpse its potential through this route. Regarding molecular docking, KMR-05 demonstrated better anti-inflammatory potential. Thus, the complexes of KMR-04 and KMR-05 with iNOS were used in molecular dynamics simulations, in which both compounds demonstrated promising results. Further studies are needed to robustly evaluate a future anti-inflammatory lead compound.