In this study, a series of nitrogen-based novel heterocyclic compounds were synthesized and characterized by elemental analysis, IR and NMR spectra. The novel synthesized nitrogen-based novel heterocyclic compounds were evaluated against the acetylcholinesterase (AChE) and α-glycosidase enzymes. These compounds showed IC50 values in range of 0.76–28.04 μM against AChE as a cholinergic enzyme, and 26.10–82.17 μM against α-glycosidase as a hydrolytic enzyme. On the other hand, they demonstrated Ki values between 1.25±0.22–25.36±4.72 μM against AChE, and 25.07±4.57–78.55±17.04 μM against α-glycosidase enzymes. The synthesized nitrogen-based novel heterocyclic compounds exhibited effective inhibition profiles against both indicated metabolic enzymes. These results may contribute to the development of new drugs particularly to treat some disorders, which widespread display in the world including Alzheimer's disease and diabetes. Furthermore, molecular docking calculations were made to compare the theoretical biological activities of nitrogen-based novel heterocyclic compounds against proteins including enzymes. After these calculations, ADME/T analysis was performed to examine the drug properties of nitrogen-based novel heterocyclic compounds. 

Synthesis, Characterization, Molecular Docking, Acetylcholinesterase and α‐Glycosidase Inhibition Profiles of Nitrogen‐Based Novel Heterocyclic Compounds

In addition to the first synthesis of the natural bromophenol butyl 2-(3,5-dibromo-4-hydroxyphenyl)acetate (1), indene derivatives 34 and 35 were synthesized from 3-phenylpropenal derivatives in BBr3 medium. Five known natural bromophenols and some derivatives were synthesized by known methods. Cholinesterase (ChEs) inhibitors reduce the breakdown of acetylcholine and are used in the treatment of Alzheimer's disease (AD) and dementia symptoms. The inhibition effects of all obtained compounds were examined towards acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and α-glycosidase enzymes. All synthesized compounds demonstrated the strong inhibition effects against both cholinergic enzymes. For determination of Ki values of novel bromophenols Lineweaver-Burk graphs were obtained. Ki values were found in the ranging of 0.13-14.74 nM for AChE, 5.11-23.95 nM for BChE, and 63.96-206.78 nM for α-glycosidase, respectively. All bromophenols and their derivatives exhibit effective inhibition profile when compared to positive controls.

Synthesis and Biological Activity of Some Bromophenols and Their Derivatives Including Natural Products.

A variety of azaheterocycle-fused piperidines and pyrrolidines bearing CF3 and CHF2 functionalities were obtained using CF3SO2Na and CHF2SO2Na by visible light photocatalysis. This protocol involves a radical cascade cyclization via tandem tri- and difluoromethylation-arylation of pendent unactivated alkenes. Benzimidazole, imidazole, theophylline, purine, and indole serve as applicable anchors, thereby enriching the structural diversity of piperidine and pyrrolidine derivatives. This method features mild, additive-free and transition metal-free conditions.

Photocatalytic synthesis of azaheterocycle-fused piperidines and pyrrolidines via tandem difunctionalization of unactivated alkenes.

Multi-target directed ligands (MTDLs) have recently attracted significant interest due to their exceptional effectiveness against multi-factorial Alzheimer's disease. The present work described the development of pyrazine-based MTDLs using multicomponent Petasis reaction for the dual inhibition of tau-aggregation and human acetylcholinesterase (hAChE). The molecular structure of synthesized ligands was validated by 1H & 13C NMR and mass spectrometry. The screened compounds were shown to have a strong inhibitory effect at 10 μM concentration against tau-oligomerization and hAChE, but only moderate inhibitory activity against Aβ42. Among all the compounds, the half-maximal inhibitory concentration (IC50) for 21 and 24 against hAChE were 0.71 μM and 1.09 μM, respectively, while they displayed half-maximal effective concentrations (EC50) values of 2.21 μM and 2.71 μM for cellular tau-oligomerization, respectively. Additionally, an MTT experiment using tau-expressing SH-SY5Y neuroblastoma cells revealed that 21 was more neuroprotective than the FDA-approved medication donepezil. Furthermore, an MD simulation study was performed to investigate the dynamics and stability of AChE-21 and AChE-24 complexes in an aqueous environment. The MM-PBSA calculations were performed to evaluate the binding of 21 and 24 with AChE, and the relative binding energy was calculated as -870.578 and -875.697 kJ mol-1, respectively. As a result, the study offered insight into the design of new MTDLs and highlighted 21 as a potential roadblock to the development of anti-AD medications. 

Multicomponent Petasis reaction for the identification of pyrazine based multi-target directed anti-Alzheimer's agents: In-silico design, synthesis, and characterization

Synthesis and Pharmacological Evaluation of Novel Triazole-Pyrimidine Hybrids as Potential Neuroprotective and Anti-neuroinflammatory Agents

Dual targeting of acetylcholinesterase and tau aggregation: Design, synthesis and evaluation of multifunctional deoxyvasicinone analogues for Alzheimer’s disease

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Dual targeting of acetylcholinesterase and tau aggregation: Design, synthesis and evaluation of multifunctional deoxyvasicinone analogues for Alzheimer’s disease