Presence of N-heterocyclic ring systems as promising features in the molecular skeleton of FDA approved drugs, underlie the remarkable contributions of these heterocyclic nuclei in the field of medicine. Despite instability risks associated with COVID pandemic, the US FDA approved 50 drugs (36 NMEs and 14 biological products) in the year 2021. The active ingredients of 32 drugs out of these 36 NMEs (almost 89%) contain saturated, partially unsaturated and/or aromatic N-heterocyclic moieties in their molecular assemblies, hence dominating the medicinal approvals. While 27 molecules (75% of these NMEs drugs) are prominent small NMEs. Herein, we have considered profiling of those FDA approved 27 small-molecule drugs which are decorated with N-heterocycles as privileged scaffolds. These drugs are grouped on the basis of a number of N-heterocycles present in their structural framework. The spectrum of these drugs in terms of their structural features and medicinal importance is summarized in this review. Also, the pertinent analyses of their drug-likeliness conferring some general pharmacokinetic principles is highlighted.

Alzheimer’s disease (AD) is one of the progressive neurological disorders and the main cause of dementia all over the world. The multifactorial nature of Alzheimer’s disease is a reason for the lack of effective drugs as well as a basis for the development of new structural leads. In addition, the appalling side effects such as nausea, vomiting, loss of appetite, muscle cramps, and headaches associated with the marketed treatment modalities and many failed clinical trials significantly limit the use of drugs and alarm for a detailed understanding of disease heterogeneity and the development of preventive and multifaceted remedial approach desperately. With this motivation, we herein report a diverse series of piperidinyl-quinoline acylhydrazone therapeutics as selective as well as potent inhibitors of cholinesterase enzymes. Ultrasound-assisted conjugation of 6/8-methyl-2-(piperidin-1-yl)quinoline-3-carbaldehydes (4a,b) and (un)substituted aromatic acid hydrazides (7a-m) provided facile access to target compounds (8a-m and 9a-j) in 4–6 min in excellent yields. The structures were fully established using spectroscopic techniques such as FTIR, ¹H- and ¹³C NMR, and purity was estimated using elemental analysis. The synthesized compounds were investigated for their cholinesterase inhibitory potential. In vitro enzymatic studies revealed potent and selective inhibitors of AChE and BuChE. Compound 8c showed remarkable results and emerged as a lead candidate for the inhibition of AChE with an IC₅₀ value of 5.3 ± 0.51 µM. The inhibitory strength of the optimal compound was 3-fold higher compared to neostigmine (IC₅₀ = 16.3 ± 1.12 µM). Compound 8g exhibited the highest potency and inhibited the BuChE selectively with an IC₅₀ value of 1.31 ± 0.05 µM. Several compounds, such as 8a-c, also displayed dual inhibitory strength, and acquired data were superior to the standard drugs. In vitro results were further supported by molecular docking analysis, where potent compounds revealed various important interactions with the key amino acid residues in the active site of both enzymes. Molecular dynamics simulation data, as well as physicochemical properties of the lead compounds, supported the identified class of hybrid compounds as a promising avenue for the discovery and development of new molecules for multifactorial diseases, such as Alzheimer’s disease (AD).