Shakir_2025_RSC.Adv_15_101

It is believed that inflammation influences several physiological processes, including the function of the central nervous system. Moreover, the impairment of lipid mechanisms/pathways is associated with neurodegenerative disorders and onset of Alzheimer's disease (AD). AD is a chronic neurodegenerative disease representing the major cause of dementia worldwide. In this case, the overexpression of different pharmacological targets has been confirmed to address neuronal inflammation and AD, with acetylcholinesterase (AChE), monoamine oxidase-B (MAO-B), cyclooxygenase-2 (COX-2) and 5-lipoxygenase (LOX-5) being the most explored targets. Currently, the available treatments are only capable of alleviating the symptoms and not capable of delivering disease-modifying effects. Thus, the current research objective is to synthesize triazolo-thiadiazine derivatives of the deferasirox drug as multi-target compounds that could concurrently inhibit ChEs, MAOs, LOX-5 and COX-2. The synthesized derivatives were confirmed by FTIR, (1)H NMR, (13)C NMR and DEPT-135 spectroscopic techniques. During in vitro investigations, compound 11 was found to be the most potent inhibitor of all the targeted enzymes. Briefly, this compound exhibited inhibitory values (IC(50) +/- SEM) of 0.31 +/- 0.16, 0.13 +/- 0.16 and 0.94 +/- 0.16 microM against AChE, MAO-B and COX-2, respectively, suggesting that it is a lead molecule for the synthesis of more potential multi-targeted inhibitors. Several compounds, such as compound 9 and 13, showed dual inhibition potential in comparison to standard drugs. Furthermore, molecular docking analysis was performed to validate the in vitro results, where the potent compounds showed some significant interactions with the key amino acids present in the active site of the targeted enzymes. Furthermore, molecular dynamics (MD) simulation data and physicochemical properties supported deferasirox-substituted triazolo-thiadiazine as a promising horizon for the discovery and development of new molecules to treat multifactorial diseases associated with neuro-inflammation, such as AD.