ABSTRACT
Certain nitrothiazole derivatives, such as niridazole (Ba 32644, Ambilhar), exert pronounced activities against several trichomonad strains when tested under anaerobic conditions comparable to those of the nitroimidazole derivatives. Few compounds of the nitrothiazole group, however, are markedly less active in vitro. The in vivo activity of the nitrothiazole derivatives as determined in mice infected subcutaneously with T. foetus, is as good as that of metronidazole. A nitrothiazole derivative with a laminar side chain is inactive in vivo after oral administration, although it shows pronounced antitrichomonad activity in vitro.
Subject(s)
Antitrichomonal Agents/pharmacology , Thiazoles/pharmacology , Trichomonas Infections/drug therapy , Animals , Antitrichomonal Agents/therapeutic use , Chemical Phenomena , Chemistry , Mice , Nitro Compounds/pharmacology , Trichomonas Infections/parasitology , Trichomonas Infections/pathology , Trichomonas vaginalis/drug effectsABSTRACT
Niridazole (Ambilhar) and three other newly synthesized nitrothiazole derivatives were highly active against 19 microaerophilic campylobacters (minimum concentration required to inhibit 50% of strains [MIC50], 0.0075 to 0.015 mg/liter). There were, however, considerable differences in the susceptibility among strains tested, and one nitrothiazole derivative was rather inactive (MIC50, 2 mg/liter). Nitroimidazole derivatives, such as metronidazole and tinidazole, were less active (MIC50, 2 and 4 mg/liter, respectively). The nitrofuran derivatives, such as nitrofurazone and nitrofurantoin, were also less active (MIC50, 1 mg/liter). Niridazole and another potent nitrothiazole derivative killed the campylobacters rapidly at low concentrations. In contrast, much higher concentrations of metronidazole were required to achieve bactericidal values.
Subject(s)
Anti-Bacterial Agents/pharmacology , Campylobacter fetus/drug effects , Campylobacter/drug effects , Niridazole/pharmacology , Microbial Sensitivity Tests , Nitrofurans/pharmacology , Nitroimidazoles/pharmacologyABSTRACT
Hypoglycemic sulfonyliminoimidazolidines were shown to stimulate insulin release in vitro (rabbit pancreas) and in vivo (normal rats) comparable to tolbutamide and to inhibit glucose oxidation in isolated rat fat cells in vitro similar to phenformin. These results support the hypothesis that the hypoglycemic effect of the compounds in normal and in diabetic animals may be due to a combination of mechanisms operative in sulfonylureas and biguanides. Determination of the three-dimensional structure of the potent analogue 1 by X-ray crystallography enabled us to identify specific regions of the molecule presumed to be involved in the molecular mode of action of sulfonyl-iminoimidazolidines.
Subject(s)
Hypoglycemic Agents/chemical synthesis , Imidazoles/chemical synthesis , Imidazolidines , Animals , Biological Assay , Imidazoles/pharmacology , Insulin/metabolism , Insulin Secretion , Islets of Langerhans/drug effects , Islets of Langerhans/metabolism , Molecular Conformation , Rabbits , Structure-Activity Relationship , X-Ray DiffractionABSTRACT
A series of 1-[[p-[2-(acylamino)ethyl]phenyl]sulfonyl]-2-iminoimidazolidines has been synthesized. Compounds from this new class of oral hypoglycemic agents lower blood glucose in normal and in streptozotocin-diabetic rats. Potent analogues were obtained by modification of the acyl residue. 1-[[p-[2-(Crotonylamino)ethyl]phenyl]-sulfonyl]-3-cyclohexyl-2-iminoimidazolidine (44) turned out to be the most potent compound in the normal rat (20 times tolbutamide), and 1-[[p-[2-(5-methylisoxazole-3-carboxamido)ethyl]phenyl]sulfonyl]-3-cyclohexyl-2-imino-imidazolidine (30) displayed the highest potency in the diabetic rat (similar to phenformin).
