Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 143, Issue -, Pages 1373-1386Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2017.10.036
Keywords
Benzothiazine; Monoamine oxidase; Molecular docking; Bioavailability
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Funding
- Higher Education Commission of Pakistan [20-3715/NRPU/RD/HEC/14/162, 20-3733/NRPU/RD/ 14/520]
- Government College University, Faisalabad, Pakistan
- Universiti Teknologi MARA [UiTM 600- IRMI/FRGS 5/3 (0119/201 6)]
- LESTARI [600-RMI/DANA5/3 LESTARI (92/2015)]
- Organization for the Prohibition of Chemical Weapons (OPCW), The Hague, The Netherlands
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Three series of 4-hydroxy-N'-[benzylidene/1-phenylethylidene]-2-H/methyl/benzyl-1,2-benzothiazine-3-carbohydrazide 1,1-dioxides (9-11)a-l were synthesized and unraveled to be highly potent dual inhibitors of monoamine oxidases (MAO-A and MAO-B). All the examined compounds demonstrated IC50 values in lower micro-molar range for both MAO-A as well as MAO-B. The most active MAO-A inhibitor was 4-hydroxy-N'-(1-phenylethylidene)-2H-benzo[e][1,2]thiazine-3-carbohydrazide 1,1-dioxide (9i) with an IC50 value of 0.11 +/- 0.005 mu M, whereas, methyl 4-hydroxy-2H-benzo[e][1,2]thiazine-3-carboxylate 1,1-dioxide (3) was the most active MAO-B inhibitor with an IC50 value of 0.21 +/- 0.01 mu M. Enzyme kinetics studies revealed that the most potent compounds inhibited both MAO enzymes (A & B) in a competitive fashion. Molecular docking studies were also performed to obtain an intuitive picture of inhibition potential for potent inhibitors. The high potency of these compounds is optimally combined with highly favorable ADME profile with predicted good oral bioavailability. (C) 2017 Elsevier Masson SAS. All rights reserved.
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