Síntese, caracterização e avaliação do potencial farmacológico de híbridos de derivados 4-aminoquinolínicos e anti-inflamatórios não esteroidais

Abstract

Inflammation is a self-limiting homeostatic defense process (acute inflammation), which can also be continuous, resulting in the development of chronic inflammatory diseases (CIDs). An example of CID is rheumatoid arthritis, which is treated with disease-modifying antirheumatic drugs, such as chloroquine (4-aminoquinoline derivative), commonly associated with nonsteroidal anti-inflammatory drugs, such as propionic acid derivatives (ibuprofen, naproxen, ketoprofen, among others). According to this therapy, one of the possible approaches in the rational design of new drug candidates is molecular hybridization. Thus, the present study aimed to design and synthesize hybrid molecules containing 4-aminoquinoline fragments and ibuprofen, naproxen, and ketoprofen fragments, in addition to investigating their anti-inflammatory potential in vitro.The following hybrids were produced: ICEQ (C24H28ClN3O, 409,96 g/mol); NCEQ (C25H24ClN3O2 433,94 g/mol); KCEQ (C27H24ClN3O2, 457,96 g/mol); IDAPQ (C25H30ClN3O, 423,99 g/mol); NDAPQ (C26H26ClN3O2, 447,96 g/mol); e KDAPQ (C28H26ClN3O2, 471,99 g/mol). After obtaining and isolating the compounds, they were characterized by different spectroscopic techniques, in which the results confirmed the planned molecular structures. In the spectra obtained by Nuclear Magnetic Resonance (NMR), it was possible to unequivocally identify the hydrogen and carbon signals of the two hybridized fragments. In the spectra obtained by Fouriertransform infrared spectroscopy (FTIR), the hybridization was confirmed by the disappearance (NH2 and OH), displacement (C=O) and formation (N-CO) of bands involved in the coupling reaction of the two precursors containing the pharmacophoric groups. In addition, in the analysis of the spectra obtained by mass spectrometry (MS), the signals associated with the molecular peaks of all the synthesized hybrid drugs were observed.In silico analyses performed using the OSIRIS Property Explorer and SwissADME tools showed that the synthesized hybrids do not violate Lipinski's rule of 5, demonstrating drug-like structures, while being predicted to have high gastrointestinal absorption; moderate to low water solubility; ability to penetrate the blood-brain barrier (BBB); inhibition of cytochrome P450 enzymes; and potential mutagenic risk. In in vitro biological assays using the J774 macrophage cell line, it was observed that ICEQ and NCEQ hybrids were cell viable at concentrations ≤ 200 µM and 50 µM, respectively; while IDAPQ and NDAPQ hybrids were cell viable at concentrations ≤ 100 µM and 50 µM, respectively. In the evaluation of the in vitro antiinflammatory potential, based on the effect on the reduction of nitric oxide (NO) production, it was observed that ICEQ and NCEQ hybrids presented a lower antiinflammatory potential than the standard drugs tested, while IDAPQ and NDAPQ hybrids presented a better anti-inflammatory performance. NDAPQ stood out as the most promising hybrid due to its greater efficacy in reducing NO production, showing activity even at lower concentrations. Thus, the results demonstrate the potential of quinolinic derivatives in the form of molecular hybrids as promising candidates for the development of new anti-inflammatory agents.