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

• DOI: 10.1016/j.ejmech.2017.10.036
• Publication Date: 2017-10-19T07:45:14Z
• Authors: Furqan Ahmad Sadd...; Sumera Zaib; Saquib Jalil; Sana Aslam; Matloob Ahmad; Sadia Sultan; Humera Naz; Mazhar Iqbal; Jamshed Iqbal
• Keywords: 0301 basic medicine; 0303 health sciences; Monoamine Oxidase Inhibitors; Protein Conformation; Thiazines; Chemistry Techniques, Synthetic; Benzylidene Compounds; Rats; 3. Good health; Molecular Docking Simulation; Structure-Activity Relationship; 03 medical and health sciences; Hydrazines; Animals; Humans; Monoamine Oxidase

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.