RESUMO
1-substituted indolizines with activity against Mycobacterium tuberculosis have been synthesized. The most active compounds carry an hydroxyphenylmethyl- or hydroxyalkyl substituent in the indolizine 1-position. The alkyl chain should be moderately long (C-5 or C-6). Aryl groups in the 2- and 3-position of the indolizine are also required. Removal of the 3-substituent resulted in significant loss of activity. A nitrile substituent in the 7-position is beneficial for both chemical stability and bioactivity. The compounds studied display a narrow antibacterial spectrum and appear to be quite selective antimycobacterial compounds. Moderate activity against certain pathogenic protozoa was also observed.
Assuntos
Antituberculosos/síntese química , Indolizinas/síntese química , Mycobacterium tuberculosis/efeitos dos fármacos , Animais , Antifúngicos/efeitos adversos , Antifúngicos/síntese química , Antifúngicos/química , Antifúngicos/farmacologia , Antiprotozoários/efeitos adversos , Antiprotozoários/síntese química , Antiprotozoários/química , Antiprotozoários/farmacologia , Antituberculosos/efeitos adversos , Antituberculosos/química , Antituberculosos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Indolizinas/efeitos adversos , Indolizinas/química , Indolizinas/farmacologia , Estrutura Molecular , Células VeroRESUMO
A number of indolizine 1-sulfonates have been prepared by cyclization of cyclopropenones with pyridines followed by trapping of the intermediate 1-indolizinol with a sulfonyl halide, and examined as inhibitors of 15-lipoxygenase (15-LO). The compounds display IC(50) values between 15 and 42 microM; all are more active than the well-known 15-LO inhibitor quercetin (IC(50) 51 microM). A wide variety of substituents are well tolerated. The enzyme inhibition was not affected by preincubation or the presence of a detergent and no significant particle formation was observed. Hence, inhibition from aggregates of indolizines, promiscuous inhibition, is highly unlikely.
Assuntos
Sulfonatos de Arila/farmacologia , Inibidores Enzimáticos/farmacologia , Glycine max/enzimologia , Indolizinas/farmacologia , Inibidores de Lipoxigenase , Sulfonatos de Arila/síntese química , Inibidores Enzimáticos/síntese química , Indolizinas/síntese químicaRESUMO
15-Lipoxygenase (15-LO) has been implicated in oxidation of low-density lipoproteins (LDL) and this enzyme may be involved in the development of atherosclerosis. We have examined 1-substituted indolizines as possible inhibitors of 15-LO from soy beans and from rabbit reticulocytes. Most compounds studied were significantly more active as inhibitors of 15-LO from soy beans than quercetin. The indolizines were slightly less potent inhibitors of the mammalian enzyme, but we found good correlation between inhibitory activity against both 15-LO enzymes studied. Several of the compounds were only weak DPPH scavengers and they may therefore be regarded as so-called non antioxidant inhibitors of 15-LO.
