Investigation of Novel Benzoxazole-Oxadiazole Derivatives as Effective Anti-Alzheimer’s Agents: In Vitro and In Silico Approaches

Abstract

Alzheimer’s disease (AD) is a progressive neurological illness that is distinguished clinically by cognitive and memory decline and adversely affects the people of old age. The treatments for this disease gained much attention and have prompted increased interest among researchers in this field. As a springboard to explore new anti-Alzheimer’s chemical prototypes, the present study was carried out for the synthesis of benzoxazole-oxadiazole analogues as effective Alzheimer’s inhibitors. In this research work, we have focused our efforts to synthesize a series of benzoxazole-oxadiazole (1–19) and evaluating their anti-Alzheimer properties. In addition, the precise structures of synthesized derivatives were confirmed with the help of various spectroscopic techniques including 1H-NMR, 13C-NMR and HREI-MS. To find the anti-Alzheimer potentials of the synthesized compounds (1–19), in vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), inhibitory activities were performed using Donepezil as the reference standard. From structure-activity (SAR) analysis, it was confirmed that any variation found in inhibitory activities of both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes were due to different substitution patterns of substituent(s) at the variable position of both acetophenone aryl and oxadiazole aryl rings. The results of the anti-Alzheimer assay were very encouraging and showed moderate to good inhibitory potentials with IC50 values ranging from 5.80 ± 2.18 to 40.80 ± 5.90 µM (against AChE) and 7.20 ± 2.30 to 42.60 ± 6.10 µM (against BuChE) as compared to standard Donepezil drug (IC50 = 33.65 ± 3.50 µM (for AChE) and 35.80 ± 4.60 µM (for BuChE), respectively. Specifically, analogues 2, 15 and 16 were identified to be significantly active, even found to be more potent than standard inhibitors with IC50 values of 6.40 ± 1.10, 5.80 ± 2.18 and 6.90 ± 1.20 (against AChE) and 7.50 ± 1.20, 7.20 ± 2.30 and 7.60 ± 2.10 (against BuChE). The results obtained were compared to standard drugs. These findings reveal that benzoxazole-oxadiazole analogues act as AChE and BuChE inhibitors to develop novel therapeutics for treating Alzheimer’s disease and can act as lead molecules in drug discovery as potential anti-Alzheimer agents.

Anti-Cholinergic Effects of the Phenolic Extract from the Astragalus crenatus Plant: A Computational and Network Pharmacology Study

“…These key residues can be clearly identified from the interactions with the co-crystallized inhibitors that are given in Table 3 and Table 4 . The conserved amino acids of the active site gorge that have been reported in the literature for AChE/BChE, respectively, include the catalytic and oxyanion hole residues Ser203/Ser198 and His447/His438; choline-binding pocket residues, which are Glu202/Glu197, Tyr337/Ala328, and Trp86/Trp82; and acyl-binding pocket residues, which are Trp236/Trp231, Phe338/Phe329, Phe297/Val288, and Phe295/Leu286 [ 32 ]. All the compounds selected as possible inhibitors of the two ChEs form interactions with at least one of their key amino acids ( Table 3 and Table 4 ).…”

In vitro biological studies and computational prediction-based analyses of pyrazolo[1,5-a]pyrimidine derivatives

“…15 Additionally, Alzheimer's disease therapy through acetylcholinesterase and butyrylcholinesterase inhibition mechanism action, such as rivastigmine drug, is classied as a phenylcarbamate category. 16 Cancer is a genetic disease caused (I) by errors that occur in cell division, (II) by DNA damage due to harmful substances, and (III) by inherited from parents. Therefore, the body's cells grow uncontrollably and sometimes spread to other parts; this is a cancer disease.…”

In-silico Molecular Docking Studies of Methyl Oxadiazole Hybrids Inhibiting Acetylcholinesterase for Alzheimer’s Disease Treatment

“…There are several explanations. There are various Alzheimer's theories 2 Several ideas have been proposed, such as the β-amyloid hypothesis, oligomer hypothesis, tau hypothesis, Ca 2+ dysregulation theory, presenilin hypothesis, and lysosome hypothesis. [3][4] AD requires low acetylcholine.…”