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

Extensive research has been dedicated to develop compounds that can target multiple aspects of Alzheimer's disease (AD) treatment due to a growing understanding of AD's complex multifaceted nature and various interconnected pathological pathways. In the present study, a series of biological assays were performed to evaluate the potential of the tryptamine analogues synthesized earlier in our lab as multi-target-directed ligands (MTDLs) for AD. To assess the inhibitory effects of the compounds, various in vitro assays were employed. Three compounds, SR42, SR25, and SR10, displayed significant AChE inhibitory activity, with IC50 values of 0.70 µM, 0.17 µM, and 1.00 µM, respectively. These values superseded the standard drug donepezil (1.96 µM). In the MAO-B inhibition assay, SR42 (IC50 = 43.21 µM) demonstrated superior inhibitory effects as compared to tryptamine and other derivatives. Moreover, SR22 (84.08%), SR24 (79.30%), and SR42 (75.16%) exhibited notable percent inhibition against the COX-2 enzyme at a tested concentration of 100 µM. To gain insights into their binding mode and to validate the biological results, molecular docking studies were conducted. Overall, the results suggest that SR42, a 4,5 nitro-benzoyl derivative of tryptamine, exhibited significant potential as a MTDL and warrants further investigation for the development of anti-Alzheimer agents.

Fenugreek seed ethanolic extract inhibited formation of advanced glycation end products via scavenging reactive carbonyl intermediates.

Senescence is a natural phenomenon of growing old. It accelerates under certain conditions like diabetes mellitus resulting in early decline of bodily functions, which can be avoided by many claimed functional foods. The present study aims to investigate the anti-aging ability of Fenugreek seeds (Trigonellafoenum-graecum); a common ingredient of Indo-Pak cuisines. Briefly, the Fenugreek seeds extract (FgSE) in concentrationsof0.1, 0.5 and 1 mg/ml inhibited the formation of Advanced Glycation End products (AGEs) and fructosamine adducts in Bovine serum albumin (BSA)/fructose model in vitro. The BSA conformational analysis via Circular Dichorism and Congo red assays showed that it preserves secondary structure of BSA in aforementioned model. Although mechanistic studies revealed insignificant lysine blocking ability of Fenugreek by OPA assay, however carbonyl entrapping was found to be 24%, 34% and 42% at 0.1, 0.5 and 1 mg/ml, respectively. In vivo model of High Fructose diet (HFD) induced glycation, FgSE treatment in doses of 10, 25 & 50 mg/kg markedly improved Escape latency (p < 0.01) and preserved cognition in Morris Water Maze. Our data further exhibits significant decrease of CML (Nε-carboxymethyl lysine) levels in serum and hippocampus byFgSE treatment in comparison with HFD group. Therefore, we deduced that FgSE prevents glycation-induced memory decline via entrapping the reactive carbonyl intermediates, formed during production of AGEs. Hence, as a promising functional food it slows down the harmful process of glycation and aging associated morbidities.