RESUMEN
One-pot intramolecular cyclization of novel sp3-enriched cyanoalkylsulfonyl fluorides into spirocyclic ß- or γ-sultams is disclosed. The method relies on nitrile group reduction followed by sulfonylation of amino group thus formed upon mild conditions (NaBH4, NiCl2·6H2O in MeOH). Cyclization proceeds smoothly with considerable efficiency (48-84%, 10 examples) on up to 30 g scale. The cyanoalkylsulfonyl fluoride intermediates can be obtained via S-nucleophilic substitution in ß-functionalized alkanenitriles or double alkylation of α-alkylthioacetonitrile, followed by oxidative chlorination with Cl2 and further reaction with KHF2. The title mono- and bifunctional sultams are advanced sp3-enriched building blocks for drug discovery and organic synthesis providing novel substitution patterns and frameworks mimicking saturated nitrogen heterocycles such as pyrrolidine/pyrrolidone.
RESUMEN
In the present paper, we report the synthesis via catalytic Michael reaction and biological results of a series of 3-heteryl substituted pyrrolidine-2,5-dione derivatives as moderate inhibitors against Mycobacterium tuberculosis H37Rv growth. Some of them present also inhibition activities against InhA.
Asunto(s)
Antituberculosos/química , Antituberculosos/farmacología , Proteínas Bacterianas/antagonistas & inhibidores , Mycobacterium tuberculosis/efectos de los fármacos , Oxidorreductasas/antagonistas & inhibidores , Pirrolidinas/química , Pirrolidinas/farmacología , Antituberculosos/síntesis química , Proteínas Bacterianas/metabolismo , Humanos , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Mycobacterium tuberculosis/crecimiento & desarrollo , Oxidorreductasas/metabolismo , Pirrolidinas/síntesis química , Relación Estructura-Actividad , Tuberculosis/tratamiento farmacológicoRESUMEN
We report here the discovery, synthesis and screening results of a series of 3-(9H-fluoren-9-yl)pyrrolidine-2,5-dione derivatives as a novel class of potent inhibitors of Mycobacterium tuberculosis H37Rv strain as well as the enoyl acyl carrier protein reductase (ENR) InhA. Among them, several compounds displayed good activities against InhA which is one of the key enzymes involved in the type II fatty acid biosynthesis pathway of the mycobacteria cell wall. Furthermore, some exhibited promising activities against M. tuberculosis and multi-drug resistant M. tuberculosis strains.
Asunto(s)
Antituberculosos/farmacología , Proteínas Bacterianas/antagonistas & inhibidores , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Oxidorreductasas/antagonistas & inhibidores , Pirrolidinonas/farmacología , Antituberculosos/síntesis química , Antituberculosos/química , Proteínas Bacterianas/metabolismo , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Cinética , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Mycobacterium tuberculosis/enzimología , Mycobacterium tuberculosis/crecimiento & desarrollo , Oxidorreductasas/metabolismo , Pirrolidinonas/síntesis química , Pirrolidinonas/química , Relación Estructura-ActividadRESUMEN
In the title compound, C12H17NO3, which was synthesized by Wagner-Meerwein rearrangement of the N-nitro-imine, the ring-junction C-C bond length is comparatively long [1.573â (2)â Å] due to a steric repulsion between the methyl groups at these atoms, which also leads to an increase in the C-C-C angles along this C4 chain [118.10â (13) and 115.04â (15) °, respectively]. In the crystal, N-Hâ¯O-C and N-Hâ¯O=C hydrogen bonds are formed between the amide group and the two O-atom acceptors of the lactone group, forming a chain along [001].
RESUMEN
In the title compound, C23H18FNO3, the tricyclic 9-fluorenyl system is approximately planar (r.m.s. deviation = 0.0279â Å). The N-C(=O) bond length is comparatively short [1.359â (3)â Å], which is typical for such conjugated systems. The N atom has a planar configuration [sum of bond angles= 359.8°] due to conjugation of its lone pair with the π-system of the carbonyl group. In the crystal, a three-dimensional network is formed through N-Hâ¯O and O-Hâ¯O hydrogen bonds between the amide and carb-oxy-lic acid groups and carbonyl O-atom acceptors.
RESUMEN
In the title compound, C(10)H(15)NO(5), the five-membered cyclo-pentane ring has an envelope conformation, with four atoms lying in a plane (mean deviation = 0.0213â Å), while the fifth atom deviates from this plane by 0.626â (2)â Å. A three-dimensional structure is formed through N-Hâ¯O and O-Hâ¯O hydrogen bonds between the amide and carb-oxy-lic acid groups and both carb-oxy-lic acid and amide O-atom acceptors.