Planejamento, síntese, avaliação in silico e in vitro de potenciais fármacos anti-inflamatórios e antiasmáticos a partir de scaffolds híbridos isatínicos hidrazônicos

Abstract

The persistence of the inflammatory process can trigger chronic diseases, such as asthma, which in 2019 affected 262 million and caused 455,000 deaths. In addition, there are gastric adverse effects and cardiovascular risks associated with non-selective and selective NSAIDs for COX-2, respectively, which are used for inflammatory diseases. And for asthma, the main classes used may cause tremors, tachycardia, loss of bone density, hyperglycemia etc. Evidencing the need to research for new scaffolds, Therefore, the objective is to develop new hybrid hydrazonic isatinic derivatives with potential anti-inflammatory and antiasthmatic activity. With initial evaluation by molecular docking in the Gold 5.8.1 program, using the crystallographic structures of COX-2 (5KIR), mPGES-1 (5TL9), Inos (3E7G), NLRP3 (7ALV), 5-LOX (6NCF), LTA4H (1HS6) and CisLT1 (6RZ5) obtained thorugh Protein Data Bank (PDB), the results indicated that the compounds YV-03 and YV-02 possess better anti-inflammatory and antiasthmatic profiles, respectively. Following the synthesis of the derivatives YV-01, YV-02, YV-03 and YV-04 by a linear synthetic route, the final molecules showed yields between 69.67 and 92.90%. After the synthesis, the molecules were characterized by IR and NMR techniques, it was noted the presence of suggestive bands of secondary amine in 3396 cm-1, amide carbonyl in 1680 cm-1, and pattern of monossubstituted and parassubstituted compounds. Added to the identification of a mixture of Z-E stereoisomers and conformers, by two simplets suggestive of CH2 at 4.97 and 4.55 ppm, followed by signals at 9.70 and 10.48 ppm (CH=N) and at 11.73 ppm (NH) of secondary amide. All compounds presented adequate ADME pharmacokinetic profile and met the druglikeness criteria. In in vitro studies, it was observed low cytotoxicity in macrophages stimulated with LPS+INF-γ and among them it is possible that YV-03 has anti-inflammatory potential, by reducing nitrite levels in all concentrations tested. Additionally, molecular dynamics simulations indicated that the possible mechanism of YV-03 is linked to iNOS inhibition and YV-02 related to LTA4H inhibition. In conclusion, the hydrazonic isatinic derivatives showed anti-inflammatory and antiasthmatic potential and it is expected to analyze their inhibitory activity against cytokines such as TNF-α and IL-1β, as well as to continue in vivo models for inflammation and asthma.