ABSTRACT
Here we first time report an unprecedented and unnatural six-membered 1,5-oxaza spiroquinone scaffold with structural novelty, a convenient and efficient synthetic route was developed for the synthesis of new 1,5-oxaza spiroquinone derivatives (1a-1r) in high yields from readily available starting materials. The logic of the present work consists of (1) the identification of a promising unprecedented scaffold from privileged scaffolds of biological active molecules through our 'Chemistry-oriented Synthesis' (ChOS) approach, a compensatory strategy for target-based drug discovery, (2) the positioning of the identified 1,5-oxaza spiroquinone scaffold on neuroinflammation and neurodegenerative disease through nitric oxide (NO) inhibitory activity without cytotoxicity in hyper-activated microglia (IC50 of NO production: 0.07-1.82⯵M) to establish structure-activity relationship (SAR), (3) the investigation on the possibility as a selective kinase inhibitor related to neurodegenerative diseases (eg. JNK1, CDK2, DAPK1) through kinase full panel screening of the most potent compound 1n, and (4) the evaluation on in vivo efficacy of the compound 1n through Y-maze test.
Subject(s)
Drug Discovery , Neuroprotective Agents/chemical synthesis , Quinones/chemical synthesis , Spiro Compounds/chemical synthesis , Inflammation/drug therapy , Microglia/metabolism , Microglia/pathology , Neurodegenerative Diseases/drug therapy , Neuroprotective Agents/chemistry , Neuroprotective Agents/pharmacology , Nitric Oxide/pharmacology , Protein Kinase Inhibitors/pharmacology , Quinones/chemistry , Quinones/pharmacology , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , Structure-Activity RelationshipABSTRACT
Novel 2,3-dihydrofuran derivatives were synthesized through a tandem Knoevenagel-Michael cyclization in good yield by reacting α-tosyloxy ketone, 5,5-dimethyl-1,3-cyclohexanedione, and various aldehydes in the presence of phthalazine in acetonitrile. These compounds were subjected to inâ vitro antibacterial screening against eight micro-organisms by using diffusion method and also inâ vitro cytotoxicity screening against four human cancerous cell lines by applying MTT assay. Some of the compounds showed impressive activities.
Subject(s)
Anti-Bacterial Agents/pharmacology , Antineoplastic Agents, Phytogenic/pharmacology , Bacteria/drug effects , Furans/pharmacology , Ketones/chemistry , Tosyl Compounds/chemistry , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Antineoplastic Agents, Phytogenic/chemical synthesis , Antineoplastic Agents, Phytogenic/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Cyclization , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Furans/chemical synthesis , Furans/chemistry , Humans , Microbial Sensitivity Tests , Molecular Structure , Structure-Activity RelationshipABSTRACT
A practical stereoselective synthesis of (6S)-5,6,dihydro-6-[(2R)-2-hydroxy-6-phenyl hexyl]-2H-pyran-2-one, a potent natural antifungal compound, is described. The sequence involves diastereoselective iodine-induced electrophilic cyclization, epoxide ring opening with a vinyl Grignard reagent and ring closing metathesis (RCM) as the key steps.
