ABSTRACT
The combinatorial syntheses of a library of novel dihydrothiophenone-engrafted dispiro oxindole/indenoquinoxaline-pyrrolidine/pyrrolothiazole/indolizine hybrid heterocycles have been realized through a chemo-, regio-, and stereoselective multicomponent 1,3-dipolar cycloaddition strategy.
Subject(s)
Heterocyclic Compounds, Fused-Ring/chemical synthesis , Small Molecule Libraries/chemical synthesis , Spiro Compounds/chemical synthesis , Thiophenes/chemical synthesis , Combinatorial Chemistry Techniques , Cycloaddition Reaction , Humans , Magnetic Resonance Spectroscopy , Mass Spectrometry , Molecular Structure , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A facile and efficient synthesis of a library of novel chromeno[3,2-c]pyridines has been achieved from the reaction of various 3,5-((E)-arylidene)-1-alkylpiperidin-4-ones and cyclic 1,3-diketones. The reaction presumably occurred via tandem Michael addition-intramolecular O-cyclization-elimination sequence in a single operation.
Subject(s)
Pyridines/chemistry , Cyclization , Molecular Structure , Pyridines/chemical synthesisABSTRACT
A series of novel hybrid heterocycles comprising arylidene thiazolidine-2,4-dione and 1-cyclopropyl-2-(2-fluorophenyl)ethanone were synthesized. These compounds were evaluated for their antimycobacterial activity against Mycobacterium tuberculosis H37Rv in High Throughput Screen. Most of the hybrid arylidene thiazolidine-2,4-diones displayed moderate to good activity with MIC of less than 50 µM. Compound 1m exhibited maximum potency being 5.87 fold more active at EC50 and 6.26 fold more active at EC90 than the standard drug pyrimethamine.
Subject(s)
Anti-Bacterial Agents/pharmacology , Mycobacterium tuberculosis/drug effects , Thiazolidinediones/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Dose-Response Relationship, Drug , Microbial Sensitivity Tests , Molecular Structure , Structure-Activity Relationship , Thiazolidinediones/chemical synthesis , Thiazolidinediones/chemistryABSTRACT
The 1,3-dipolar cycloaddition of azomethine ylides generated in situ from the reaction of isatins or acenaphthylene-1,2-dione and 1,3-thiazolane-4-carboxylic acid to various exocyclic dipolarophiles synthesized from estrone afforded a library of novel C-16 spiro oxindole or acenaphthylene-1-one - 7-(aryl)tetrahydro-1H-pyrrolo[1,2-c][1,3]thiazole - estrone hybrid heterocycles. These reactions occur regio- and stereo-selectively affording a single isomer of the spiro estrones in excellent yields with the formation of two C-C and one C-N bonds along with the generation of four new contiguous stereo-centers in a single step.
Subject(s)
Heterocyclic Compounds/chemical synthesis , Pyrazoles/chemical synthesis , Spiro Compounds/chemical synthesis , Steroids/chemical synthesis , Thiazoles/chemical synthesis , Heterocyclic Compounds/chemistry , Pyrazoles/chemistry , Spiro Compounds/chemistry , Steroids/chemistry , Thiazoles/chemistryABSTRACT
An efficient one-pot four-component domino protocol for the combinatorial synthesis of novel 1,4-dihydropyrano[2,3-c]pyrazol-6-amines has been achieved. This transformation presumably occurs via cyclization-Knoevenagel condensation-Michael addition-tautomerism-intramolecular O-cyclization-elimination sequence of reactions. The significant features of this reaction include expedient one-pot process, short reaction time, no column chromatographic purification, excellent yield, and readily available starting materials.
Subject(s)
Amines/chemical synthesis , Combinatorial Chemistry Techniques/methods , Pyrazoles/chemical synthesis , Amines/chemistry , Cyclization , Pyrans/chemical synthesis , Pyrans/chemistry , Pyrazoles/chemistry , StereoisomerismABSTRACT
The 1,3-dipolar cycloaddition of azomethine ylides generated in situ from acenaphthenequinone and α-amino acids viz. 1,3-thiazolone-4-carboxylic acid and piperidine-2-carboxylic acid to a series of 1-methyl-3,5-bis[(E)-arylmethylidene]tetrahydro-4(1H)-pyridinones afforded novel spiro[5.2â³]acenaphthene-1â³-onespiro[6.3']-5'-arylmethylidene-1'-methylpiperidin-4'-one-7-aryltetrahydro-1H-pyrrolo[1,2-c][1,3]thiazoles and spiro[2.2â³]acenaphthene-1â³-onespiro[3.3']-5'-arylmethylidene-1'-methylpiperidin-4'-one-4-aryloctahydroindolizines respectively in quantitative yields. These compounds were evaluated for their AChE inhibitory activity and compound 3c was found to be the most potent with IC50 1.86 µmol/L.
Subject(s)
Acetylcholinesterase/metabolism , Cholinesterase Inhibitors/pharmacology , Piperidines/pharmacology , Pyrroles/pharmacology , Thiazoles/pharmacology , Animals , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Dose-Response Relationship, Drug , Electrophorus , Models, Molecular , Molecular Structure , Piperidines/chemical synthesis , Piperidines/chemistry , Pyrroles/chemical synthesis , Pyrroles/chemistry , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/chemistryABSTRACT
The 1,3-dipolar cycloaddition of nitrile oxides generated in situ from benzohydroximinoyl chloride and triethylamine to 2-aminopyranopyridine-3-carbonitriles and 2-aminochromene-3-carbonitriles occurred chemoselectively furnishing novel 1,2,4-oxadiazole-pyranopyridine/chromene hybrid heterocycles in moderate yields. In vitro screening of these compounds against Mycobacterium tuberculosis H37Rv (MTB) disclosed that the 1,2,4-oxadiazole-pyranopyridine hybrids display enhanced activity relative to the 1,2,4-oxadiazole-chromene hybrids. Among the compounds screened, 3-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]-4-(2,4-dichlorophenyl)-8-[(E)-(2,4-dichlorophenyl)-methylidene]-6-methyl-5,6,7,8-tetrahydro-4H-pyrano[3,2-c]pyridin-2-amine (MIC: 0.31 µM) is 1.2, 15.2 and 24.6 times more active than standard antitubercular drugs, viz. isoniazid, ciprofloxacin and ethambutol, respectively.
Subject(s)
Antibiotics, Antitubercular/chemistry , Benzopyrans/chemistry , Oxadiazoles/chemistry , Oxides/chemistry , Pyridines/chemistry , Antibiotics, Antitubercular/chemical synthesis , Antibiotics, Antitubercular/pharmacology , Microbial Sensitivity Tests , Molecular Conformation , Mycobacterium tuberculosis/drug effects , Nitriles/chemistry , Structure-Activity RelationshipABSTRACT
An efficient synthesis of 1-methyl-3-[(E)-arylmethylidene]tetrahydro-4(1H)-pyridinones was achieved by the reaction of 1-methyl-4-piperidone and aromatic aldehydes in the presence of pyrrolidine under solvent-free microwave irradiation. These dipolarophiles upon cycloaddition with nitrile oxide and azomethine ylides afford stereoselectively novel spiro-isoxazolines, pyrrolizines and pyrrolidines respectively in excellent yields. The spiro compounds were screened for their in vitro activity against Mycobacterium tuberculosis H37Rv (MTB), multi-drug resistant M. tuberculosis (MDR-TB) and Mycobacterium smegmatis (MC(2)) using agar dilution method. Among the synthesized compounds, 1-methyl-4-(2,4-dichlorophenyl)pyrrolo(spiro[2.3'']oxindole)spiro[3.3']-1'-methylpiperidin-4'-one was found to be the most active with a minimum inhibitory concentration (MIC) of 1.76 and 0.88 microM against MTB and MDR-TB respectively.
Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Piperidones/chemistry , Piperidones/pharmacology , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , Anti-Bacterial Agents/chemical synthesis , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure , Mycobacterium Infections, Nontuberculous/drug therapy , Mycobacterium smegmatis/drug effects , Mycobacterium tuberculosis/drug effects , Piperidones/chemical synthesis , Pyrrolidines/chemical synthesis , Spiro Compounds/chemical synthesis , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , Tuberculosis/drug therapyABSTRACT
The 1,3-dipolar cycloaddition of azomethine ylides derived from acenaphthenequinone and alpha-amino acids viz. sarcosine, phenylglycine, 1,3-thiazolane-4-carboxylic acid and proline to a series of 2,6-bis[(E)-arylmethylidene]cyclohexanones afforded novel spiro-heterocycles chemo-, regio- and stereoselectively in quantitative yields. These compounds were screened for their in vitro activity against Mycobacterium tuberculosis H37Rv (MTB) using agar dilution method. Two compounds, 4-(2,4-dichlorophenyl)-5-phenylpyrrolo(spiro[2.2'']acenaphthene-1''-one)spiro[3.2']-6'-(2,4-dichlorophenylmethylidene)cyclohexanone (4i) and spiro[5.2'']acenaphthene-1''-onespiro[6.2']-6'-(2,4-dichlorophenylmethylidene)cyclohexanone-7-(2,4-dichlorophenyl)tetrahydro-1H-pyrrolo[1,2-c][1,3]thiazole (5i) display maximum activity in vitro with a MIC value of 0.40microg/mL against MTB and were 4 and 15.6 times more potent than ethambutol and pyrazinamide, respectively.
