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The halogenated 6-spiroepoxypenicillins are a series of novel semisynthetic beta-lactam compounds with highly conformationally restricted side chains incorporating an epoxide. Their biological activity profiles depend crucially on the configuration at position C-3 of that epoxide. In derivatives with aromatic-containing side chains, e.g., anilide, the 3R-compounds possess notable Gram-positive antibacterial activity and potent beta-lactamase inhibitory properties. The comparable 3S-compounds are antibacterially inactive, but retain beta-lactamase inhibitory activity. Using the molecular simulation programs COSMIC and ASTRAL, we attempted to map a putative, lipophilic accessory binding site on the PBPs that must interact with the side-chain aromatic residue. Comparative computer-assisted modelling of the 3R-, and 3S-anilides, along with benzylpenicillin, indicated that the available conformational space at room temperature for the side chains of the 3R- and the 3S-anilides was mutually exclusive. The conformational space for the more flexible benzylpenicillin could accommodate the side chains of both the constrained penicillin derivatives. By a combination of van der Waals surface calculations and a pharmacophoric distance approach, closely coincident conformers of the 3R-anilide and benzylpenicillin were identified. These conformers must be related to the antibacterial, 'bioactive' conformer for the classical beta-lactam antibiotics. From these proposed bioactive conformations, a model for the binding of benzylpenicillin to the PBPs relating the three-dimensional arrangement of a putative lipophilic S2-subsite, specific for the side-chain aromatic moiety, and the 3 alpha-carboxylate functionality is presented.
A direct central nervous system (CNS)-related component of the cardiovascular actions of converting enzyme (CE) inhibitors will be governed by the ability of these drugs to gain access to the brain. We investigated the inhibitory effect of the two CE inhibitors ramipril and Hoe 288 on CE activity in different brain regions and in the cerebrospinal fluid of rats. One-week oral gavage treatment with ramipril (10 mg/kg/day) and Hoe 288 (10 mg/kg/day) resulted in a marked inhibition of CE activity in the brain cortex (90 and 91%, respectively), the hypothalamus (78 and 82%, respectively), and in the brainstem (67 and 66%, respectively). The complete blockade of plasma CE activity was paralleled by a 84% inhibition of CE activity in cerebrospinal fluid. Both CE inhibitors failed significantly to inhibit CE activity in the striatum. Our results demonstrate that the CE inhibitors Hoe 288 and ramipril were able to pass the blood-brain barrier (BBB) to inhibit central CE activity. The penetration of CE inhibitors into the CNS appears to depend on the lipophilicity of the drugs and on the mode of drug application. The possibility that an inhibition of CE activity in circumventricular organs outside the BBB such as the subfornical organ and the organum vasculosum of the lamina terminalis may be sufficient to explain the central effects of orally applied CE inhibitors is discussed.
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FR-111142 is a new angiogenesis inhibitor produced by a fungus Scolecobasidium arenarium F-2015. FR-111142 inhibited endothelial cell proliferation in vitro and angiogenesis in the growing chick chorioallantoic membrane model in vivo. Further, FR-111142 also suppressed the solid tumor growth in mice.
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The effect of the beta-lactone antibiotic diffusomycin (oxazolomycin) was investigated against vaccinia (Lister), herpes simplex type 1 (Kupka), influenza A (WSN; H1N1), and Coxsackie A9 viruses. Diffusomycin reduced significantly the plaque formation of enveloped DNA and RNA viruses by more than 90% in the range of the maximally tolerated dose. As could be shown with vaccinia virus, the antiviral action was not caused by virucidal effect on virions or by interaction with virus adsorption and penetration. In one-step growth cycle assays diffusomycin prevented the replication of herpes simplex type 1, vaccinia and influenza A viruses in a dose-dependent manner. The replication of influenza A viruses was blocked immediately after addition of the compound during zero to six hr p.i. Partial reversibility of the antiviral action was established by washing off the antibiotic from chicken embryo cells (CEC) infected with influenza A virus. Finally, replication of Coxsackie A9 virus was not inhibited by diffusomycin. Electron-optical studies revealed a reduced synthesis of HSV-1 nucleocapsids in dependence on the concentration of the compound.
A number of tetrahydrofuran analogues of 2'-methylspiro[1-azabicyclo[2.2.2]octane-3,4'-[1,3]dioxolane] (1) have been prepared with the aim to obtain information about the relative importance of each of the oxygens in 1 for efficacy and for selectivity. In addition, the dimethyl and desmethyl analogues of 1 were prepared. The new compounds were compared to cis- and trans-1 with regard to their ability to displace (-)-[3H]-3-quinuclidinyl benzilate ((-)-[3H]QNB) from muscarinic receptors in cerebral cortex, heart, parotid gland, and urinary bladder from guinea pigs. Functional studies were made on isolated guinea pig bladder and ileum. The new compounds exhibited both lower affinity and efficacy than cis-1. A conformational study was performed, and the effects of steric and electronic factors on the biological activity of the compounds are discussed.
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Inhibition of brain converting enzyme (CE) has been implicated in the antihypertensive action of some CE inhibitors. However, it is still a matter of debate whether these drugs gain access to the central nervous system upon systemic administration. In this study in rats we investigated the ability of p.o. applied CE inhibitors to penetrate from blood into cerebrospinal fluid (CSF) by analyzing the inhibition of CE activity in the CSF after acute bolus and after 1 week overnight treatment with enalapril, ramipril and Hoe 288. Penetration into the CSF closely paralleled the lipid solubility of the drugs. The most lipophilic drug, Hoe 288 (10 mg/kg), inhibited CE activity in the CSF after acute (66%) and after chronic (30%) p.o. treatment. Ramipril (10 mg/kg), being less lipophilic than Hoe 288, was only effective after acute bolus administration (59% inhibition), whereas the most hydrophilic drug, enalapril (30 mg/kg), did not reduce CE activity in the CSF after either regimen. The CE inhibition in the CSF after acute p.o. treatment with ramipril and Hoe 288 was dose-dependent with threshold doses of 3 to 10 mg/kg (ramipril) and less than 1 mg/kg (Hoe 288). The presence of ramipril and Hoe 288 in the CSF was also demonstrated by the inhibitory effect of heat-inactivated CSF from CE inhibitor-treated rats on purified CE from rabbit lung. A comparison of the in vitro activities of the three prodrugs and their parent diacids against CE in plasma and in CSF and against purified CE revealed hydrolysis of the prodrugs to their parent diacids in plasma and CSF.(ABSTRACT TRUNCATED AT 250 WORDS)
In order to search for new antitumor drugs, sixteen N',N"-dispirotripiperazine derivatives were synthesized from N',N"-dispirotripiperazinium dichloride dihydrochloride by substitution, acylation and Mannich reaction. Six compounds were selected for preliminary pharmacological test. The result showed that five compounds possess inhibitory action against carcinoma S37 in rats. The inhibitory activity of compounds VI and X was 55.0% and 41.9% respectively.
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Paraherquamides B (2, C27H33N3O4), C (3, C28H33N3O4), D (4, C28H33N3O5), E (5, C28H35N3O4), F (6, C28H35N3O3), and G (7, C28H35N3O4) are novel metabolites of Penicillium charlesii. The structures of these compounds have been determined by NMR and MS analysis.
Some hepatic effects of the hypolipidemic agents 3,9-di-3-pyridyl-2,4,8,10-tetraoxaspiro-5,5-undecane (compound A) and 2-(4-dibenzofuranyloxy)-2-methylpropionic acid (compound B) were investigated in male rats. The animals were treated orally with these drugs and a reference compound-clofibrate for 10 weeks, the daily doses being 250, 300 and 300 mg/kg body weight respectively. All three drugs caused hepatomegaly with a normal microscopic appearance in liver cells. In rats given compound A, part of some liver cells could be occupied by numerous membranes of smooth endoplasmic reticulum. The hepatocytes of the rats treated with compound B or clofibrate showed a marked increase in microbody profiles and an elevated hepatic catalase activity in comparison to the control animals. Neither the microbodies nor the catalase activity were affected by compound A. Hypolipidemic effects were demonstrated with all three compounds, the most potent activity being shown by compound B. Treatment with this agent resulted in significantly higher catalse activity than with clofibrate.
The synthesis and local anesthetic properties of five 1-dealkyloxindole-3-spiropyrrolidines and six 1-dealkyloxindole-3-spiropiperidines are described. The compounds studied include members of all five possible positional isomers of the two classes of spirooxindoles; all showed local anesthetic activity by the rat sciatic nerve block method. The coincidence of the least variability in the relative positions of basic nitrogen, amide carbonyl, and aromatic ring (compounds 1 and 6) with lowest normalized toxicity is noteworthy.