title: Design, Synthesis, and Evaluation of 2-Amino-6-nitrobenzothiazole-Derived Hydrazones as MAO Inhibitors: Role of the Methylene Spacer Group.
abstract: A series of 2-amino-6-nitrobenzothiazole-derived extended hydrazones were designed, synthesized, and investigated for their ability to inhibit monoamine oxidase A and B (MAO-A/MAO-B). The compounds were found to exhibit inhibitory activities in the nanomolar to micromolar range. Some of the compounds showed excellent potency and selectivity against the MAO-B isoform. N'-(5-Chloro-2-oxoindolin-3-ylidene)-2-(6-nitrobenzothiazol-2-ylamino)acetohydrazide (compound 31) showed the highest MAO-B inhibitory activity (IC50 =1.8±0.3 nm, selectivity index [SI]=766.67), whereas compound 6 [N'-(1-(4-bromophenyl)ethylidene)-2-(6-nitrobenzothiazol-2-ylamino)acetohydrazide] was found to be the most active MAO-A inhibitor (IC50 =0.42±0.003 μm). Kinetic studies revealed that compounds 6 and 31 exhibit competitive-type reversible inhibition against both MAO-A and MAO-B, respectively. Structure-activity relationship (SAR) studies disclosed several structural aspects significant for potency and the contribution of the methylene spacer toward MAO-B inhibitory potency, with minimal or no neurotoxicity. Molecular modeling studies yielded a good correlation between experimental and theoretical inhibitory data. Binding pose analysis revealed the significance of cumulative effects of π-π stacking and hydrogen bond interactions for effective stabilization of virtual ligand-protein complexes. Further optimization studies of compound 31, including co-crystallization of inhibitor-MAO-B complexes, are essential to develop these compounds as potential therapeutic agents for MAO-B-associated neurodegenerative diseases.
authors.affiliation: Pharmaceutical Chemistry Research Laboratory, Department of Pharmaceutics, Indian Institute of Technology, Banaras Hindu University, Varanasi, 221005, Uttar Pradesh, India), Fax.
authors.forename: Rati K P
authors.initials: RK
authors.lastname: Tripathi
authors.affiliation: Pharmaceutical Chemistry Research Laboratory, Department of Pharmaceutics, Indian Institute of Technology, Banaras Hindu University, Varanasi, 221005, Uttar Pradesh, India), Fax. asraja.phe@iitbhu.ac.in.
authors.forename: Senthil R
authors.identifier: 0000-0002-6008-4571
authors.initials: SR
authors.lastname: Ayyannan
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D052160:Benzothiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D020134:Catalytic Domain; D003010:Clorgyline / Q000494:pharmacology; D015195:Drug Design; D006835:Hydrazones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D006860:Hydrogen Bonding; D007700:Kinetics; D008024:Ligands; D062105:Molecular Docking Simulation; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D010672:Phenytoin / Q000633:toxicity; D051381:Rats; D012642:Selegiline / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000928:Antidepressive Agents; D052160:Benzothiazoles; D006835:Hydrazones; D008024:Ligands; D008996:Monoamine Oxidase Inhibitors; C000622565:N'-(1-(4-bromophenyl)ethylidene)-2-(6-nitrobenzothiazol-2-ylamino)acetohydrazide; C000622564:N'-(5-chloro-2-oxoindolin-3-ylidene)-2-(6-nitrobenzothiazol-2-ylamino)acetohydrazide; D012642:Selegiline; D010672:Phenytoin; D003010:Clorgyline
keywords: 6-nitrobenzothiazole; MAO inhibitors; hydrazones; molecular docking; monoamine oxidase