(E)-2-Cyano-3-(1H-Indol-3-yl)-N-Phenylacrylamide, a Hybrid Compound Derived from Indomethacin and Paracetamol: Design, Synthesis and Evaluation of the Anti-Inflammatory Potential

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.

Small molecule compounds with good anti-inflammatory activity reported in the literature from 01/2009 to 05/2021: a review

“…Moreover, in the peritonitis assay that assesses leukocyte migration, the compound 29 also exhibited promising results. Therefore, these preliminary studies demonstrated that compound 29 is a strong candidate for development of an anti-inflammatory drug with an improved gastrointestinal safety profile as compared to the conventional anti-inflammatory drugs 44 . Zhang et al synthesised a series of novel tetrahydroisoquinoline derivatives based on the crystal structure of phosphodiesterase 4 (PDE4).…”

Potential of Tryptamine Derivatives as Multi-Target Directed Ligands for Alzheimer’s Disease: AChE, MAO-B, and COX-2 as Molecular Targets

“…Indomethacin shares the indole nucleus of synthesized tryptamine derivatives. Additionally, the choice of this protein is substantiated by its frequent appearance in recent publications, signifying its relevance and significance in ongoing research efforts [ 57 , 58 ].…”

Virtual Screening of Different Subclasses of Lignans with Anticancer Potential and Based on Genetic Profile

“…In view of this, the results obtained suggest that lignans (L3, L4 and L7) have a high volume of distribution with values (logL/kg > 0.45); however, all compounds have a low permeation potential in the brain with regard to bioavailability in the CNS (logBB < −1 and logPS < −3). Therefore, these results demonstrate that lignans have low pharmacological potential against neurological disorders and little influence on neurotoxic processes [ 28 ]. The in silico tool also made it possible to identify whether the structures are substrates or inhibitors of the mitochondrial enzymatic metabolism system—CYP450.…”