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
Abstract 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 IC 50 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)-2 H -benzo[ e ][1,2]thiazine-3-carbohydrazide 1,1-dioxide ( 9i ) with an IC 50 value of 0.11 ± 0.005 μM, whereas, methyl 4-hydroxy-2 H -benzo[ e ][1,2]thiazine-3-carboxylate 1,1-dioxide ( 3 ) was the most active MAO-B inhibitor with an IC 50 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. Highlights Three series of benzothiazine-3-carbohydrazide were synthesized. Potent inhibitors of monoamine oxidases were unraveled. Kinetics studies were carried out for potent inhibitors of MAO-A & MAO-B. Molecular docking studies further supported the in vitro results. Compounds exhibited favorable ADME profile with good oral bioavailability. Graphical abstract [DISPLAY OMISSION]
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