RESUMEN
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.
Asunto(s)
Compuestos Heterocíclicos de Anillos Fusionados/síntesis química , Bibliotecas de Moléculas Pequeñas/síntesis química , Compuestos de Espiro/síntesis química , Tiofenos/síntesis química , Técnicas Químicas Combinatorias , Reacción de Cicloadición , Humanos , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Estructura Molecular , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Piridinas/química , Ciclización , Estructura Molecular , Piridinas/síntesis químicaRESUMEN
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.
Asunto(s)
Antibacterianos/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Tiazolidinedionas/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Relación Dosis-Respuesta a Droga , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Relación Estructura-Actividad , Tiazolidinedionas/síntesis química , Tiazolidinedionas/químicaRESUMEN
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.
Asunto(s)
Compuestos Heterocíclicos/síntesis química , Pirazoles/síntesis química , Compuestos de Espiro/síntesis química , Esteroides/síntesis química , Tiazoles/síntesis química , Compuestos Heterocíclicos/química , Pirazoles/química , Compuestos de Espiro/química , Esteroides/química , Tiazoles/químicaRESUMEN
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.
Asunto(s)
Aminas/síntesis química , Técnicas Químicas Combinatorias/métodos , Pirazoles/síntesis química , Aminas/química , Ciclización , Piranos/síntesis química , Piranos/química , Pirazoles/química , EstereoisomerismoRESUMEN
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.
Asunto(s)
Acetilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/farmacología , Piperidinas/farmacología , Pirroles/farmacología , Tiazoles/farmacología , Animales , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Relación Dosis-Respuesta a Droga , Electrophorus , Modelos Moleculares , Estructura Molecular , Piperidinas/síntesis química , Piperidinas/química , Pirroles/síntesis química , Pirroles/química , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/químicaRESUMEN
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.
Asunto(s)
Antibióticos Antituberculosos/química , Benzopiranos/química , Oxadiazoles/química , Óxidos/química , Piridinas/química , Antibióticos Antituberculosos/síntesis química , Antibióticos Antituberculosos/farmacología , Pruebas de Sensibilidad Microbiana , Conformación Molecular , Mycobacterium tuberculosis/efectos de los fármacos , Nitrilos/química , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Antibacterianos/química , Antibacterianos/farmacología , Piperidonas/química , Piperidonas/farmacología , Pirrolidinas/química , Pirrolidinas/farmacología , Antibacterianos/síntesis química , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Infecciones por Mycobacterium no Tuberculosas/tratamiento farmacológico , Mycobacterium smegmatis/efectos de los fármacos , Mycobacterium tuberculosis/efectos de los fármacos , Piperidonas/síntesis química , Pirrolidinas/síntesis química , Compuestos de Espiro/síntesis química , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , Tuberculosis/tratamiento farmacológicoRESUMEN
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.