Ultrasound-Assisted Synthesis of Piperidinyl-Quinoline Acylhydrazones as New Anti-Alzheimer’s Agents: Assessment of Cholinesterase Inhibitory Profile, Molecular Docking Analysis, and Drug-like Properties

Abstract

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).

Discovery of Hydrazone Scaffolds as Potent and Selective Multitarget‐Directed Ligands for the Treatment of Neurodegenerative Disorders

“…Thiophene ring also showed amide‐π stacked interaction with Gly116 amino acid residue with a distance of 5.48 Å. Moreover, Phe398 displayed π‐sigma interaction (4.93 Å) with the sulfur atom in the thiophene moiety which also makes a conventional hydrogen bond with the oxygen atom of Ser198 with a distance of 3.71 Å, which are in agreement with the previous studies [41,42] . A π‐alkyl linkage was formed between Leu286 and thiophene ring with a distance of (4.83 Å).…”

“…Subsequently, π-alkyl interactions were also observed between various amino acid residues such as Trp86 (4.73 Å), Val294 (5.32 Å) and Pro31 (4.49 Å), and such interactions are in agreement to previous results. [41] Additionally, Phe295 showed π-donor hydrogen bond with a distance of 3.60 Å (Figure 10).…”

“…Moreover, Phe398 displayed π-sigma interaction (4.93 Å) with the sulfur atom in the thiophene moiety which also makes a conventional hydrogen bond with the oxygen atom of Ser198 with a distance of 3.71 Å, which are in agreement with the previous studies. [41,42] A π-alkyl linkage was formed between Leu286 and thiophene ring with a distance of (4.83 Å). On the other hand, chloro substituent at the aryl ring of hydrazone exhibited π-alkyl interactions with Trp82 (4.41 Å) and Trp430 (6.37 Å), respectively, in addition to van der Waals interaction with Ser79 with a distance of 3.44 Å. Aryl ring itself also formed a π-anion contact with Asp70 (3.64 Å) as shown in Figure 12.…”