Design, synthesis, anti-inflammatory evaluation, and molecular modelling of new coumarin-based analogs combined curcumin and other heterocycles as potential TNF-α production inhibitors <i>via</i> upregulating Nrf2/HO-1, downregulating AKT/mTOR signalling pathways and downregulating NF-κB in LPS induced macrophages
Creators: name: Ghany, Lina M. A. Abdel
name: Beshay, Botros Y.
name: Moustafa, Amal M. Youssef
name: Maghrabi, Ali Hassan Ahmed
name: Ali, Eman Hussain Khalifa
name: Saleem, Rasha Mohammed
name: Zaki, Islam
name: Ryad, Noha
Publisher: name: Taylor & Francis
Year: 2023
Subjects: subject: Biophysics
subject: Biochemistry
subject: Microbiology
subject: FOS: Biological sciences
subject: Pharmacology
subject: Biotechnology
subject: Environmental Sciences not elsewhere classified
subject: Chemical Sciences not elsewhere classified
subject: Ecology
subject: Immunology
subject: FOS: Clinical medicine
subject: Biological Sciences not elsewhere classified

description: 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 <b>14b</b>, which contained 3,4-dimethoxybenzylidene hydrazinyl, demonstrated the highest anti-inflammatory activity with an EC<sub>50</sub> value of 5.32 μM. The anti-inflammatory effects of <b>14b</b> 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 <b>14b</b> and dexamethasone bind to the same TNF-α pocket, suggesting that <b>14b</b> has potential as a therapeutic agent superior to dexamethasone for TNF-α. Three series of curcumin-based analogs, incorporating other heterocycles, were synthesised with the intention of exploring their potential as anti-inflammatory agents. Subsequently, these analogs underwent biological assessment in macrophages induced by LPS to determine their anti-inflammatory efficacy. Among the fourteen coumarin derivatives synthesised, the most potent anti-inflammatory activity was observed in the coumarin compound <b>14b</b>, which featured a 3,4-dimethoxybenzylidene hydrazinyl moiety, with an EC<sub>50</sub> value of 5.32 μM. The anti-inflammatory effects of compound 14b were achieved through the modulation of signalling pathways such as AKT/mTOR and Nrf2/HO-1, as well as the downregulation of NF-kβ, resulting in decreased production of pro-inflammatory cytokines including IL-6, IL-1β, and TNF-α. Molecular modelling studies revealed that both compound <b>14b</b> and dexamethasone bind to the same binding site on TNF-α, suggesting that <b>14b</b> has the potential to serve as a therapeutic agent for TNF-α and other pro-inflammatory cytokines that surpasses that of dexamethasone.