Design, synthesis, anti-inflammatory evaluation, and molecular modelling of new coumarin-based analogs combined curcumin and other heterocycles as potential TNF-α production inhibitors via upregulating Nrf2/HO-1, downregulating AKT/mTOR signalling pathways and downregulating NF-κB in LPS induced macrophages

Abstract

Persistent inflammation contributes to various inflammatory conditions. Inflammation-related diseases may be treated by inhibiting pro-inflammatory mediators and cytokines. Curcumin and coumarin derivatives can target signalling pathways and cellular factors to address immune-related and inflammatory ailments. This study involved designing and synthesising three series of coumarin-based analogs that incorporated curcumin and other heterocycles. These analogs were evaluated for their potential as anti-inflammatory agents in LPS-induced macrophages. Among the fourteen synthesised coumarin derivatives, compound 14b , which contained 3,4-dimethoxybenzylidene hydrazinyl, demonstrated the highest anti-inflammatory activity with an EC 50 value of 5.32 μM. The anti-inflammatory effects of 14b were achieved by modulating signalling pathways like AKT/mTOR and Nrf2/HO-1, and downregulating NF-kβ, resulting in reduced production of pro-inflammatory cytokines such as IL-6, IL-1β, and TNF-α. The modelling studies revealed that 14b and dexamethasone bind to the same TNF-α pocket, suggesting that 14b has potential as a therapeutic agent superior to dexamethasone for TNF-α.

Design, synthesis and antiproliferative screening of newly synthesized coumarin-acrylamide hybrids as potential cytotoxic and apoptosis inducing agents

“…In light of these discoveries, our objective is to devise innovative antitubulin inhibitors, employing a hybrid structure-based approach as an effective strategy for creating novel drug candidates. 8,25 This initiative aims to address the escalating prevalence of resistance to current therapeutic remedies. In this endeavor, we have amalgamated 7-substituted coumarin, the acrylate framework, and the trimethoxybenzene component from CA-4 (as depicted in Fig.…”