Abstract
The compound (E)-2-cyano-3-(1H-indol-3-yl)-N-phenylacrylamide (ICMD-01) was designed and developed based on the structures of clinically relevant drugs indomethacin and paracetamol through the molecular hybridization strategy. This derivative was obtained by an amidation reaction between substituted anilines and ethyl 2-cyanoacetate followed by a Knoevenagel-type condensation reaction with indole aldehyde that resulted in both a viable synthesis and satisfactory yield. In order to assess the immunomodulatory and anti-inflammatory activity, in vitro assays were performed in J774 macrophages, and significant inhibitions (p < 0.05) of the production of nitrite and the production of cytokines (IL-1β and TNFα) in noncytotoxic concentrations were observed. The anti-inflammatory effect was also studied via CFA-induced paw edema in vivo tests and zymosan-induced peritonitis. In the paw edema assay, ICMD01 (50 mg kg−1) showed satisfactory activity, as did the group treated with dexamethasone, reducing edema in 2–6 h. In addition, there was no significant inhibition of PGE2, IL-1β or TNFα in vivo. Moreover, in the peritonitis assay that assesses leukocyte migration, ICMD-01 exhibited promising results. Therefore, these preliminary studies demonstrate this compound to be a strong candidate for an anti-inflammatory drug together with an improved gastrointestinal safety profile when compared to the conventional anti-inflammatory drugs.
Highlights
According to the World Health Organization (WHO), diseases of inflammatory etiology constitute the greatest hazard to human life
Pharmacological therapies used for the clinical treatment of inflammatory diseases include non-steroidal (NSAIDs) and steroidal (SAIDs) drugs
In the first stage of the procedure, indomethacin was redocked at the active site of COX-2, presenting a free binding energy of −11.26 kcal mol−1, while the proposed compound ICMD-01 bonded
Summary
According to the World Health Organization (WHO), diseases of inflammatory etiology constitute the greatest hazard to human life. They are the main causes of death in the world, and are estimated to become more prominent causes of death over the 30 years in the United States. Steroidal drugs, represented by glucocorticoids, are considered the gold standard acting on immune modulation and inflammatory processes. They have serious side effects associated with metabolic and endocrine disorders when used for prolonged periods [4]
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