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

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

JOURNAL=Frontiers in Chemistry

VOLUME=6

YEAR=2018

URL=https://www.frontiersin.org/journals/chemistry/articles/10.3389/fchem.2018.00061

DOI=10.3389/fchem.2018.00061

ISSN=2296-2646

ABSTRACT=<p>In a continuation of our previous work for the exploration of novel enzyme inhibitors, two new coumarin-thiazole <bold>6(a–o)</bold> and coumarin-oxadiazole <bold>11(a–h)</bold> hybrids have been designed and synthesized. All the compounds were characterized by <sup>1</sup>H- and <sup>13</sup>C-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 <bold>6b</bold> was found as the most active member against AChE having IC<sub>50</sub> value of 0.87 ± 0.09 μM, while the compound <bold>6j</bold> revealed the same efficacy against BuChE with an IC<sub>50</sub> value of 11.01 ± 3.37 μM. In case of coumarinyl oxadiazole series, <bold>11a</bold> was turned out to be the lead candidate against AChE with an IC<sub>50</sub> value of 6.07 ± 0.23 μM, whereas compound <bold>11e</bold> was found significantly active against BuChE with an IC<sub>50</sub> 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 (<bold>6b</bold>, <bold>6h</bold>, <bold>6i</bold>, and <bold>6k</bold>) 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<sup>−1</sup>, 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 <bold>11(a–h)</bold> suggested that the compounds with high anti-butyrylcholinesterase activity (<bold>11e</bold>, <bold>11a</bold>, and <bold>11b</bold>) provided MOE score of −9.9, −7.4, and −8.2 Kcal.mol<sup>−1</sup>, respectively, with the active site of BuChE building π-π stacking with Trp82 and water bridged interaction.</p>