Combined in Vitro and in Silico Studies for the Anticholinesterase Activity and Pharmacokinetics of Coumarinyl Thiazoles and Oxadiazoles

Abstract

In a continuation of our previous work for the exploration of novel enzyme inhibitors, two new coumarin-thiazole 6(a–o) and coumarin-oxadiazole 11(a–h) hybrids have been designed and synthesized. All the compounds were characterized by 1H- and 13C-NMR spectroscopy and elemental analysis. New hybrid analogs were evaluated against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in order to know their potential for the prevention of Alzheimer's disease (AD). In coumarinyl thiazole series, compound 6b was found as the most active member against AChE having IC50 value of 0.87 ± 0.09 μM, while the compound 6j revealed the same efficacy against BuChE with an IC50 value of 11.01 ± 3.37 μM. In case of coumarinyl oxadiazole series, 11a was turned out to be the lead candidate against AChE with an IC50 value of 6.07 ± 0.23 μM, whereas compound 11e was found significantly active against BuChE with an IC50 value of 0.15 ± 0.09 μM. To realize the binding interaction of these compounds with AChE and BuChE, the molecular docking studies were performed. Compounds from coumarinyl thiazole series with potent AChE activity (6b, 6h, 6i, and 6k) were found to interact with AChE in the active site with MOE score of −10.19, −9.97, −9.68, and −11.03 Kcal.mol−1, respectively. The major interactions include hydrogen bonding, π-π stacking with aromatic residues, and interaction through water bridging. The docking studies of coumarinyl oxadiazole derivatives 11(a–h) suggested that the compounds with high anti-butyrylcholinesterase activity (11e, 11a, and 11b) provided MOE score of −9.9, −7.4, and −8.2 Kcal.mol−1, respectively, with the active site of BuChE building π-π stacking with Trp82 and water bridged interaction.

SAR-mediated Similarity Assessment of the Property Profile for New, Silicon-Based AChE/BChE Inhibitors

“…On the other hand, tacrine is only about four times better at the inhibition of AChE [53]. However, there have been published several studies describing the less significant selectivity of carbamate inhibitors towards AChE or BChE [24,54,55,56,57]. As mentioned above, reaching the site of action is key for drugs; in the case of anti-AD drugs, this is penetration into the CNS via the BBB.…”

Combining In Silico and In Vitro Studies to Evaluate the Acetylcholinesterase Inhibitory Profile of Different Accessions and the Biomarker Triterpenes of Centella asiatica

“…%I: [(A c − A s )/(A c )] × 100 (1) where (%I): Percentage inhibition A c : Absorbance of negative control A s : Absorbance of sample…”

“…Alzheimer's Disease (AD) is a neurodegenerative disease which is the common cause of dementia and is mainly differentiated by progressive deterioration of memory and cognition [1]. It is characterized by low levels of the neurotransmitter acetylcholine (ACh), neuro-inflammation, and oxidative stress in the brain region [2].…”

Design, Synthesis, and Structure–Activity Relationships of Thiazole Analogs as Anticholinesterase Agents for Alzheimer’s Disease

“…Heterocyclic rings are frequently used as the main structure in the design of biological compounds [ 25 ]. It has been demonstrated in several studies that compounds carrying a thiazole ring are effective against neurodegenerative disorders caused by low cholinergic neurotransmitter levels [ 26 , 27 , 28 , 29 , 30 , 31 ]. In this paper, we aim to present the new thiazole derivatives as ChE inhibitors.…”