Newly synthesized pyranopyrazole nicotinamides derivatives as potent anti-inflammatory agents: In-silico, in-vitro, and in-vivo studies

Inflammation is a clinical condition prevalent in numerous pathologies, and it is a primary contributor to organ dysfunction. Non-steroidal anti-inflammatory medicines (NSAIDs) are a category of pharmaceuticals that have demonstrated anti-inflammatory efficacy but are associated with significant adverse effects. Therefore, to identify new potential non-steroidal anti-inflammatory agents with lower side effects, we herein report the synthesis of novel pyranopyrazole nicotinamide derivatives (4a-f). Using several spectral techniques (IR, ¹H NMR, ¹³C NMR, and MS), their chemical structures were elucidated. The capability of newly synthesized pyranopyrazole nicotinamide derivatives to suppress inflammatory response was evaluated via in-silico analyses targeting the NF-κβ signaling pathway. Moreover, the anti-inflammatory efficacy of the synthesized compounds 4a-f were tested in-vitro by measuring their anti-hemolytic and protein denaturation activities. Our results showed that compound 4d had the supreme binding energy of -9.4578 kcal/mol when employing molecular docking; hence, it was selected for in-vivo investigation and achieved optimal in-vitro anti-inflammatory outcomes. All inflammatory biomarkers (TNF-α, IL-6, INF-γ, NF-κβ, CRP, and ESR) resulting from the carrageenan-induced paw edema model in rats showed excellent regression to nearly normal ranges after treatment with the newly synthesized compound 4d. Furthermore, the toxic effect of 4d was examined on the liver and kidney and considered safe and did not show hepatorenal toxicity even in the high dose. Therefore, compound 4d can be regarded as a new, safe, and promising candidate for anti-inflammatory treatment.

Anti-inflammatory; Carrageenan; NF-κβ; Pyranopyrazole; Pyrazolone.