Abstract
The compound (E)-2-cyano-N,3-diphenylacrylamide (JMPR-01) was structurally developed using bioisosteric modifications of a hybrid prototype as formed from fragments of indomethacin and paracetamol. Initially, in vitro assays were performed to determine cell viability (in macrophage cultures), and its ability to modulate the synthesis of nitrite and cytokines (IL-1β and TNFα) in non-cytotoxic concentrations. In vivo, anti-inflammatory activity was explored using the CFA-induced paw edema and zymosan-induced peritonitis models. To investigate possible molecular targets, molecular docking was performed with the following crystallographic structures: LT-A4-H, PDE4B, COX-2, 5-LOX, and iNOS. As results, we observed a significant reduction in the production of nitrite and IL-1β at all concentrations used, and also for TNFα with JMPR-01 at 50 and 25 μM. The anti-edematogenic activity of JMPR-01 (100 mg/kg) was significant, reducing edema at 2–6 h, similar to the dexamethasone control. In induced peritonitis, JMPR-01 reduced leukocyte migration by 61.8, 68.5, and 90.5% at respective doses of 5, 10, and 50 mg/kg. In silico, JMPR-01 presented satisfactory coupling; mainly with LT-A4-H, PDE4B, and iNOS. These preliminary results demonstrate the strong potential of JMPR-01 to become a drug for the treatment of inflammatory diseases.
Highlights
IntroductionInflammation is the body’s reaction to aggressive chemical, physical, or biological agents, promoting coordinated activation of signaling pathways with the aim of instituting repair processes
The final molecule was obtained through the Knoevenagel condensation reaction presented in Scheme 1
Β-unsaturated products obtained by this type of condensation have been widely used as intermediates in the synthesis of drugs, chemicals, cosmetics, foodstuffs, and agrochemicals [17,18,19]
Summary
Inflammation is the body’s reaction to aggressive chemical, physical, or biological agents, promoting coordinated activation of signaling pathways with the aim of instituting repair processes. The process is initiated by activation of standard cell surface receptors, which recognize stimuli, and activate intracellular signaling cascades, inducing the translocation of transcription factors and resulting in the expression of various inflammatory mediators [1,2]. At the tissue level, during the inflammatory response, typical acute symptoms such as edema, redness, heat, and pain, which may progress to loss of tissue function, are observed [3,4].
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