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[New heterocyclic derivatives of benzimidazole with germicidal activity. II. Mechanism of action of fluoro-5-(nitro-2'-furyl)-2-benzimidazole in B. subtilis and C. albicans].

Study of the microbiological activity of 5-fluoro-(2'-nitrofuryl)-2-benzimidazole F-O-NO2 (I) was continued. The substance was tested on cultures of B. subtilis and C. albicans. From the microbial strains studied, the mortality rate, the minimum inhibitory and bacterial concentrations and the cytotoxicity were determined. The action mechanism was studied using tritiated leucin, uracil and thymidine. Acute toxicity in the mouse (DL50 = 275 mg/kg) was also determined. The germicidal activity of (II), homologous N-ethyl derivative of (I), was also studied. On the basis of the results obtained, a possible mechanism of action of compound (I) is discussed.

Animals↗

New heterocyclic derivatives of benzimidazole with germicidal activity--XI--Experimental validation of OSAR prediction on antibacterial and antimycotic activity of benzimidazole derivatives.

In continuation of previous studies, Authors describe the synthesis of three new derivatives of 2-(5'-nitro-2'-furyl) benzimidazole, having hydroxy, methoxy or amino group at position 5. The new compounds, synthesized as suggested by a previous chemometric study, were tested in vitro against 5 Gram + and 4 Gram- strains and the mycete C. albicans. Two derivatives (R = OH, NH2) showed a good degree of antibacterial activity, especially the 5-hydroxy derivative, but they were practically inactive against the mycete; these results are in agreement with the prediction of chemometric study.

Anti-Bacterial Agents↗

New heterocyclic derivatives of benzimidazole with germicidal activity. X-In vivo toxicity of 5-fluoro-2-(5'-nitro-2'-furyl)-benzimidazole (F-O-NO2); preliminary observations.

The in vivo toxicity of 5-fluoro-2-(5'-nitro-2'-furyl) benzimidazole vehiculated in liposomes (L-FONO2), induced in mice by intraperitoneal injection, was evaluated. Toxicity was tested looking at the liver and kidney damage by determining some specific functional parameters (seric urea, seric GPT and urinary beta-NAG): no modifications were observed after administration of L-FONO2 for seven days.

Acetylglucosaminidase↗

Pharmacological profile of a highly potent and long-acting angiotensin II receptor antagonist, 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4- yl]methyl]-1H-benzimidazole-7-carboxylic acid (CV-11974), and its prodrug, (+/-)-1-(cyclohexyloxycarbonyloxy)-ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5- yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate (TCV-116).

The angiotensin II (AII) antagonistic action of 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-1H-benzi mid azole-7 - carboxylic acid (CV-11974) was examined in in vitro assay systems, including AII receptor binding assay using membrane fractions of bovine adrenal cortex or rabbit aorta and AII-induced contraction assay using rabbit aortic strips, and CV-11974 and its prodrug, (+/-)1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H- benzimidazole-7-carboxylate (TCV-116), were examined in an in vivo system of AII-induced pressor response in conscious rats. DuP 753 or EXP3174 (the main active metabolite of DuP 753) was used as the reference compound. CV-11974 inhibited the binding of [125I] AII to the bovine adrenal cortical membrane and rabbit aortic membrane with IC50 values of 1.12 x 10(-7) and 2.86 x 10(-8) M, respectively. Similar results were obtained with EXP3174. CV-11974 interacted with AII in these membrane fractions with subtype 1 receptor in a competitive manner. CV-11974 at 10(-5) M did not affect the binding of [125I]AII to subtype 2 (AT2) receptor in bovine cerebellum. CV-11974 selectively inhibited the AII-induced contraction of rabbit aortic strips in a noncompetitive manner (pD' 2, 9.97); it had no effects on the contraction induced by norepinephrine, KCl, serotonin, prostaglandin F2 alpha or endothelin. EXP3174 showed a pD'2 value of 8.95 for the AII-induced contraction. CV-11974 given intravenously and TCV-116 given orally inhibited the AII-induced pressor response in rats with ID50 values of 0.033 mg/kg and 0.069 mg/kg, respectively. These effects of CV-11974 and TCV-116 were 12 and 48 times more potent than those of EXP3174 and DuP 753, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Cortex↗

Effect of repeated benzimidazole treatments with increasing dosages on the phenotype of resistance and the beta-tubulin codon 200 genotype distribution in a benzimidazole-resistant cyathostomin population.

This study was designed to investigate the effect of repeated treatments with increasingly high fenbendazole (FBZ) dosages on the phenotype and genotype of a benzimidazole (BZ)-resistant cyathostomin population. An experimentally infected horse was treated repeatedly with FBZ dose rates between 7.5 and 30.0 mg/kg body weight (bw) over approximately 2 years. Faecal egg counts (FECs) and larval cultures were performed weekly. A total of 45 faecal egg count reduction tests (FECRTs) were analysed, revealing a high variability during the course of experiment with a mean value in faecal egg count reduction (FECR) of -17% (S.D. +/- 78). The FECR was always < 90%, providing the evidence of BZ resistance. Nine egg hatch tests were performed during the course of the experiment and revealed LD(50) values between 0.20 and 0.31 microg/ml thiabendazole (TBZ) and LD(96) values of > 0.36 microg/ml TBZ, confirming the phenotype of resistance. The LD(99) varied between 0.40 and 0.63 microg/ml TBZ. Despite consecutive treatments, no noticeable increase of the LD(50), LD(96) and LD(99) values was detected for the duration of the experiment. The molecular analysis of the codon 200 of 106 third stage larvae (L3) was carried out following repeated treatments with 30 mg FBZ/kg bw. Out of these larvae 32% were homozygous TTC/TTC, 60% showed the heterozygous TTC/TAC genotype, and 8% were homozygous TAC/TAC. The resulting allele frequencies were 62% for TTC and 38% for TAC. These findings suggest that repeated BZ treatments with increasing dosages do not alter significantly the FECRT and EHT characteristics of a BZ-resistant cyathostomin population. Furthermore, it may also be concluded that, in contrast to sheep trichostrongyles, such a selection regime does not result in beta-tubulin codon 200 TAC allele autocracy.

Alleles↗

Effect on contractility of skinned fibres from mammalian heart and smooth muscle by a new benzimidazole derivative, 4,5-dihydro-6-[2-(4-methoxyphenyl)-1H-benzimidazol-5-yl]-5-methy l-3(2H )- pyridazinone.

The positive inotropic drug 4,5-dihydro-6-[2-(4-methoxyphenyl)-1H-benzimidazol-5-yl]methyl-3(2 H)- pyridazinone (UD-CG 115 BS) enhances calcium induced contraction of skinned fibres from cardiac muscle probably by increasing the calcium sensitivity of troponin. Submaximal calcium induced contraction of skinned fibres from a smooth muscle (guinea-pig taenia coli) are slightly inhibited.

Animals↗