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

Aliya Ibrar,Saifullah Mehsud,Ahmed Al-Harrasi,Syed M A Halimi,Ajmal Khan,Majid Ali,Imtiaz Khan,Rizwana Sarwar,Umar Farooq

doi:10.3389/fchem.2018.00061

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.

Highlights

Alzheimer’s disease (AD), the most common cause of dementia, is a neurodegenerative disorder mainly characterized by progressive deterioration of memory and cognition (Terry and Buccafusco, 2003)
One of the key therapeutic strategies adopted for primarily symptomatic AD is based on the cholinergic hypothesis targeting cholinesterase enzymes, two important enzymes from the group of serine hydrolases
Coumarinyl thiazole derivatives 6(a–o) were accessed through a multi-component reaction approach which starts with the preparation of 3-(2-bromoacetyl)-2H-chromen-2-one (3)

Summary

Introduction

Alzheimer’s disease (AD), the most common cause of dementia, is a neurodegenerative disorder mainly characterized by progressive deterioration of memory and cognition (Terry and Buccafusco, 2003). One of the key therapeutic strategies adopted for primarily symptomatic AD is based on the cholinergic hypothesis targeting cholinesterase enzymes (acetylcholinesterase and butyrylcholinesterase; Cummings et al, 2007), two important enzymes from the group of serine hydrolases. These serine hydrolases belong to the class of proteins known as the esterase/lipase family within the α/β-hydrolase fold superfamily (Cygler et al, 1993). AChE inhibitors currently approved as drugs for the treatment of Alzheimer’s disease are donepezil, rivastigmine, galantamine, and tacrine (Figure 1). In view of the limited number of cholinesterase inhibitors currently available for the treatment of AD, the search for new and potent inhibitors is of significant interest and a progressive area of current research

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Conclusion