An Overview of 1,2,3-triazole-Containing Hybrids and Their Potential Anticholinesterase Activities

Abstract

Acetylcholine (ACh) neurotransmitter of the cholinergic system in the brain is involved in learning, memory, stress responses, and cognitive functioning. It is hydrolyzed into choline and acetic acid by two key cholinesterase enzymes, viz., acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). A loss or degeneration of cholinergic neurons that leads to a reduction in ACh levels is considered a significant contributing factor in the development of neurodegenerative diseases (NDs) such as Alzheimer’s disease (AD). Numerous studies have shown that cholinesterase inhibitors can raise the level of ACh and, therefore, enhance people’s quality of life, and, at the very least, it can temporarily lessen the symptoms of NDs. 1,2,3-triazole, a five-membered heterocyclic ring, is a privileged moiety, that is, a central scaffold, and is capable of interacting with a variety of receptors and enzymes to exhibit a broad range of important biological activities. Recently, it has been clubbed with other pharmacophoric fragments/molecules in hope of obtaining potent and selective AChE and/or BuChE inhibitors. The present updated review succinctly summarizes the different synthetic strategies used to synthesize the 1,2,3-triazole moiety. It also highlights the anticholinesterase potential of various 1,2,3-triazole di/trihybrids reported in the past seven years (2015-2022), including a rationale for hybridization and with an emphasis on their structural features for the development and optimization of cholinesterase inhibitors to treat NDs.

Pathogenesis of Alzheimer’s Disease and Diversity of 1,2,3-Triazole Scaffold in Drug Development: Design Strategies, Structural Insights, and Therapeutic Potential

“…1,2,3-Triazole is an exclusive five-membered heterocyclic nucleus majorly developed by click chemistry approach and first choice for development of multifunctional hybrids via molecular hybridization. 1,2,3-Triazole possesses low toxicity and higher stability in both acidic and basic conditions along with higher bioavailability . Most importantly, 1,2,3-triazole nucleus is a bioisostere of amide and an excellent example of peptide mimicry.…”

“…1,2,3-Triazole possesses low toxicity and higher stability in both acidic and basic conditions along with higher bioavailability. 77 Most importantly, 1,2,3-triazole nucleus is a bioisostere of amide and an excellent example of peptide mimicry. 1,4-Disubstituted triazole mimics the peptide bond or amide function in trans configuration that makes it an important nucleus in drug development strategies.…”

Stereochemical and Computational NMR Survey of 1,2,3-Triazoles: in Search of the Original Tauto-Conformers

“…In addition, the nitrogen atom in the triazole ring may be responsible, for example, for the enzyme−inhibitor interaction. 1,5,12,15,19 It is obvious that the 1,2,3-triazole ring with extraordinary structural features has great potential in drug development against numerous diseases as a pharmacophore, bioisostere, or structural platform. The recent evidence suggests that 1,2,3triazoles may increasingly appear in drug molecules in the near future along with a growing understanding of their important role in drug structures.…”

“…All 2D NMR spectra were recorded by using standard gradient Bruker pulse programs. The HMBC spectra were recorded with an acquisition time of 0.2 s, 17 and 20 kHz spectral width for 15 N and 13 C dimension, 1024 points in the 1 H dimension, a spectral width of 6000 Hz, 512 increments, and aiming at long-range coupling constant of 5 and 10 Hz for 15 N and 13 C, respectively, with a relaxation delay of 2 s. Two-dimensional 1 H− 1 H NOESY spectra were used to determine the configurational structure of the studied compounds (mixing time D8 = 0.6 s).…”

Novel Lawsone–Quinoxaline Hybrids as New Dual Binding Site Acetylcholinesterase Inhibitors

“…The 1,2,3-triazole heterocycle has been widely used in drug design, including new dual binding site AChE inhibitors, due to its facile synthesis, low toxicity, good pharmacokinetic profile, and resistance to acidic or basic conditions. The nitrogen atoms in the 1,2,3-triazole ring also contributed to enzyme–inhibitor interactions . The synthesized compounds were evaluated for AChE and BChE inhibition.…”