Synthesis, monoamine oxidase inhibition activity and molecular docking studies of novel 4-hydroxy-N′-[benzylidene or 1-phenylethylidene]-2-H/methyl/benzyl-1,2-benzothiazine-3-carbohydrazide 1,1-dioxides

• Published in: European Journal of Medicinal Chemistry
• Main Author: Saddique F.A.; Zaib S.; Jalil S.; Aslam S.; Ahmad M.; Sultan S.; Naz H.; Iqbal M.; Iqbal J.
• Format: Article
• Language: English
• Published: Elsevier Masson s.r.l. 2018
• Online Access: https://www.scopus.com/inward/record.uri?eid=2-s2.0-85032899006&doi=10.1016%2fj.ejmech.2017.10.036&partnerID=40&md5=3910ef9cb034e3be2e6b7fbde44e28c9

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 μM, 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 μM. 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. © 2017 Elsevier Masson SAS