Biomedical subjects

R Ciabatti

Publications and source records attributed to R Ciabatti.

At least 37 records · Page 2Linked to original sources

PubMed1993

Chemical modifications of the antibiotic purpuromycin.

Purpuromycin, isolated in our laboratories from the culture broth of Actinoplanes ianthinogenes, is very active in vitro against Gram-positive bacteria and fungi and shows variable activity against Gram-negative bacteria. Its poor bioavailability, probably due to its insolubility in aqueous media at physiological pH's, and the fact that its activity is antagonized by serum, led us to plan a chemical program with the aim of understanding the relevance of the substituents for the antibiotic activity. The original 7-methoxycarbonyl group was transformed into more hydrophilic groups by hydrolysis, by reduction and by ammonolysis or in esters with different degree of lipophilicity and steric hindrance. Almost all of the derivatives retained activity against Gram-positive bacteria but lost activity against Escherichia coli and Trichophyton mentagrophytes. Like purpuromycin, all of the derivatives show a reduced activity in the presence of serum.

Anti-Bacterial Agents↗

PubMed1992

Synthesis and antibacterial activity of a series of basic amides of teicoplanin and deglucoteicoplanin with polyamines.

Basic carboxamides of teicoplanin A2 (CTA) and its aglycon (TD) are prepared by condensation of the 63-carboxyl function of these antibiotics with linear or branched polyamines. The antimicrobial activities of some of the resulting compounds were better than those of the unmodified antibiotics. The presence of more than one basic group in the amidic chain enhanced the in vitro activity of some TD-amides against Gram-negative bacteria; two of these derivatives were also effective in vivo against Escherichia coli septicemia in the mouse. Among the CTA derivatives, the amide with spermine showed some unexpected in vitro activity against Gram-negatives. Both CTA- and TD-amides with polyamines are very soluble in water over a wide range of pH and are very hydrophilic.

Amides↗

PubMed1992

Isolation, structure determination and biological activity of A-16686 factors A' 1, A' 2 and A' 3 glycolipodepsipeptide antibiotics.

When Actinoplanes strain ATCC 33076, the producer of A-16686 A1, A2 and A3 complex, is fermented in a suitable medium three additional factors, designated A' 1, A' 2 and A' 3 are produced. These were isolated and characterized, and were shown to differ from the parent components of the original complex by lacking one mannose unit. Bioconversion of A factors into A' factors was achieved by incubation with the mycelium of Actinoplanes ATCC 33076. Factor A' 2 has better antibacterial activity than A2 against some bacteria.

Actinomycetales↗

PubMed1992

Synthesis and biological activity of O56-substituted carboxyesters and carboxamides of teicoplanin aglycone.

A series of O56-substituted carboxyester or carboxyamide derivatives of deglucoteicoplanin (TD) was prepared by condensation of the 56-hydroxyl function with various alkylating agents of general formula RBr, where R represents functional groups with different physico-chemical properties. The modifications at position 56 influenced the antimicrobial activity of the new derivatives; activity depended on the structure of various R groups, their ionic properties, and their steric hindrance. The activity of the new compounds did not show any significant improvement when compared with TD. The physico-chemical and antibacterial properties of the synthesized compounds are reported.

Anti-Bacterial Agents↗

PubMed1990

Carboxyhydrazides of the aglycone of teicoplanin. Synthesis and antibacterial activity.

The condensation of the terminal carboxyl group of the deglucoteicoplanin (TD) with various substituted hydrazines produced hydrazide derivatives having different physico-chemical properties. This chemical modification of the carboxyl function does not affect the ability of teicoplanin antibiotics to interfere in bacterial cell-wall synthesis. The antibacterial activity of deglucoteicoplanin hydrazides (V) were found to depend mostly on their ionic character. All the hydrazides were slightly more active than TD on Escherichia coli. Those possessing an additional basic group were more in vitro active than TD against Gram-negative microorganisms. In Experimental Streptococcus pyogenes septicemia in the mouse, basic hydrazides were more active than other derivatives when administered subcutaneously although they are as potent as TD.

Animals↗

PubMed1990

Ramoplanin: a review of its discovery and its chemistry.

Ramoplanin is a novel antibacterial agent with characteristics that make it suitable for development as a topical treatment for acne, infected wounds, and for treatment of antibiotic-associated diarrhoea. In this paper, the authors will review the discovery process and the descriptive chemistry of this novel molecular entity.

Anti-Bacterial Agents↗

PubMed1989

Thioureas and isothiouronium salts of the aglycone of teicoplanin. I. Synthesis and biological activity.

A series of thiourea and isothiouronium salt derivatives of the aglycone of teicoplanin was prepared by reaction of the terminal amino group with isothiocyanates, followed by S-alkylation of the thiourea compounds. Unexpectedly, the two classes of derivatives show a similar in vitro antibacterial activity against Gram-positive bacteria. Thiourea compounds, due to the lack of a positively charged N-terminus group, have a 10-fold lower binding constant to Ac-D-Ala-D-Ala, a bacterial cell-wall model, than the parent antibiotic and isothiouronium salt derivatives.

Anti-Bacterial Agents↗

PubMed1989

An unexpected intramolecular cyclization of isothiouronium teicoplanins. II. Reaction mechanism and biological activity.

N15-Isothiouronium derivatives of teicoplanin and its aglycone submitted to alkaline condition give rise to an intramolecular cyclization. The structures of the new gamma-lactam derivatives were determined by using 1H NMR, IR and fast atom bombardment mass spectra. The cyclization mechanism was interpreted on the basis of the identification of the intermediate structure. The poor in vitro antibacterial activity of the new cyclic compounds and the negligible affinity for the synthetic peptidoglycan model Ac2-L-Lys-D-Ala-D-Ala is probably due to the lack of the N-17 amidic proton and to the lack of the basic character of the nitrogen in position 15.

Anti-Bacterial Agents↗

PubMed1989

Ramoplanin (A-16686), a new glycolipodepsipeptide antibiotic. III. Structure elucidation.

By combination of chemical, 1H and 13C NMR, and mass spectrometric studies, the structures of the three components of the antibiotic ramoplanin (A-16686), produced by Actinoplanes sp. ATCC 33076, have been elucidated. All the components have structures formed by a common depsipeptide skeleton carrying a dimannosyl group and are differentiated by the presence of various acylamide moieties, derived from C8, C9 and C10 fatty acids.

Amino Acid Sequence↗

PubMed1989

Ramoplanin (A-16686), a new glycolipodepsipeptide antibiotic. IV. Complete sequence determination by homonuclear 2D NMR spectroscopy.

Homonuclear 2D NMR spectroscopy double quantum filter correlation spectroscopy (DQF-COSY), relayed-COSY, nuclear Overhauser enhancement spectroscopy (NOESY), and DQF-relayed-NOESY) allowed the complete determination of the core depsipeptide of antibiotic ramoplanin (A-16686). In particular, the DQF-relayed-NOESY experiments were essential in assigning the single signals close to the diagonal.

Amino Acid Sequence↗

PubMed1988

X-ray structure determination of mexiprostil, a new gastroprotective 16-methoxy-16-methyl-PGE1 analogue.

Mexiprostil is a new gastroprotective 16-methoxy-16-methyl-PGE1 methyl ester. To assign the absolute configuration at C-15, a crystalline high-melting C-1 ester analog 5 11,15-dihydroxy-16-methoxy-16-methyl-9-oxoprost-13-en-1-oic acid 4-(4-bromobenzamide)phenyl ester (15R, 16R) was prepared and submitted to single crystal X-ray analysis. Since C-8, C-11, C-12 and C-16 are shown to have R configurations, the X-ray diffraction results established that the configuration at C-15 is also R.

Alprostadil↗

PubMed1988

Prolyl derivatives of enalapril as potential angiotensin converting enzyme inhibitors.

The synthesis of a new class of potential angiotensin converting enzyme (ACE) inhibitors, analogs of enalapril, is reported. In these molecules the C-terminal amino acidic sequence Ala-Pro of enalapril was replaced by the sequence Pro-Pro. The compounds were tested both in vitro and in vivo. They showed no in vivo activity but only a week in vitro inhibitory activity.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1987

Metabolic oxidation of the pyrrole ring: structure and origin of some urinary metabolites of the anti-hypertensive pyrrolylpyridazinamine, mopidralazine. III: Studies with the 13C-labelled drug.

The metabolism of the anti-hypertensive drug, mopidralazine, N-(2',5'-dimethyl-1H-pyrrol-1-yl)-6-(4"-morpholinyl)-3-pyridazinamine, was reinvestigated in rats using the [2'(5')-13CH3]-labelled drug to determine the significance of the pharmacologically active intermediate 3-hydrazino-6-(4-morpholinyl)pyridazine. The previously proposed mesonic structure of the major metabolite I, i.e., 5'-hydroxy-3',6'-dimethyl-1'-[6-(4"-morpholinyl)-3-pyridazinyl]pyrida zinium hydroxide inner salt, was confirmed by chemical synthesis, X-ray diffraction analysis and 1H n.m.r. of the [3',6'-13CH3]-labelled metabolite I. Metabolite II, 3-methyl-6-(4-morpholinyl)-triazolo [4,3-6 b]pyridazine and metabolite VII, 3-methyl-7-(4-morpholinyl)-3H-pyridazino[1,6-c]pyridazine, were shown to retain the 13CH3 labelling of mopidralazine, whereas metabolite X, 3-acetyl-hydrazino-6-(4-morpholinyl)-pyridazine, loses the labelling, indicating that their formation involves two different pathways. It is hypothesized that the oxidation of the pyrrole leads to ring opening followed by a chemical rearrangement giving rise directly to metabolites II and VII or, with the intermediacy of the pharmacologically active 3-hydrazino-6-(4-morpholinyl) derivative and an enzymic acetylation or conjugation with pyruvic acid, to metabolites X, II and VII.

Animals↗

PubMed1986

Angiotensin converting enzyme inhibitors as antihypertensive agents: 1-[(2-mercaptocycloalkyl)carbonyl]-L-prolines.

The synthesis of 1-[(2-mercaptocyclopentyl)carbonyl]-L-prolines, 1-[(2-mercaptocyclobutyl)carbonyl]-L-prolines and related benzoyl derivatives as pure isomers is described. The abilities of all the compounds to inhibit angiotensin converting enzyme (ACE) in vitro and in vivo and to lower the systolic blood pressure in renal hypertensive dogs were determined. Three of them, namely 1-[[2-(benzoylthio)cyclopentyl]carbonyl]-L-proline (10f(R,S], 1-[(2-mercaptocyclopentyl)carbonyl]-L-proline (10g(R,S], and 1-[[2-(benzoylthio)cyclobutyl]carbonyl]-L-proline (16f(R,S], were found to be as potent as captopril in reducing blood pressure. The influence of chirality and ring size on the ACE inhibition is described.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1986

Structure-activity studies of 16-methoxy-16-methyl prostaglandins.

The synthesis of the pure diastereoisomer of 16-methoxy-16-methyl-PGF2 alpha, -PGE2, and -PGE1 is described. The absolute configuration of C-16 was established by chemical methods, while the absolute C-15 configurations of the diastereoisomers were assigned tentatively on the basis of their chromatographic behavior and NMR spectra. The synthetic prostaglandin analogues were evaluated for antisecretory, antifertility, and diarrheogenic effects. Both the C-15 and C-16 configurations were found to be critical for the biological activities. These studies indicate that the introduction of the methyl and methoxy groups at C-16 into the prostaglandin analogues markedly increases the ratio of antisecretory to diarrheogenic action. One of the PGE1 derivatives, 9f(15 alpha, 16R) (MDL 646, mexiprostil), was selected for further pharmacological evaluation and is currently under clinical investigation.

Alprostadil↗

PubMed1985

Imidazolyl derivatives of enalapril as potential angiotensin converting enzyme inhibitors.

The synthesis of a few derivatives of the angiotensin converting enzyme inhibitor enalapril is described. In these molecules the chelating carbethoxy group is substituted with an imidazolyl one. The compounds were tested both in vitro and in vivo. None of them showed in vivo activity but only a marginal in vitro inhibitory activity.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1985

Metabolic pathways of the anti-hypertensive agent, N-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(4-morpholinyl)-3-pyridazinamine hydrochloride. II: Studies in the dog.

The metabolic fate of a new anti-hypertensive, 1-pyrrolyl-pyridazinamine, was studied in male Beagle dogs given both p.o. and i.v. doses of the 14C-labelled drug (1 mg/kg). The compound given as a single i.v. injection disappeared from the central compartment with a half-life of about 0.9 h. Plasma levels of total 14C were represented mostly by metabolites. Eight urinary metabolites designated as metabolites I, II and XI-XVI were purified and their structures assigned by means of u.v., i.r., n.m.r. and mass spectrometry. Quantitatively the primary metabolic attack involved the morpholine moiety of the molecule which undergoes oxidative opening. A minor pathway afforded the cleavage of the pyrrole followed by chemical rearrangements to form six-membered sidnone-like products or a triazole derivative. The major (XIII) and three minor metabolites were studied for their antihypertensive activity in rats and were shown to be inactive.

Administration, Oral↗

PubMed1984

Studies on the luteolytic activity of MDL-646, a new gastroprotective PGE1 analogue, in the hamster.

MDL-646, 11,15-dihydroxy-16-methyl-16-methoxy-9-oxo- prost -13-en-1-oic acid methyl ester, is one of the most active members of a new class of PGE1 analogues with potent gastric cytoprotective and antisecretory activity. The potential luteolytic activities of MDL-646 and its corresponding PGE2 derivative, L 14224 were assessed from their ability to terminate pregnancy and to reduce plasma progesterone levels in the hamster. PGE1 and PGE2 were used as reference compounds. The biological and biochemical data clearly demonstrate that these 16-methyl-16-methoxy PGE derivatives, given s.c. or p.o. either once or for 3 days, have no luteolytic effects up to a daily dose of 2-2.5 mg/kg, and are therefore at most 1/2 to 1/4 as luteolytic as the parent natural PGEs. The dissociation between gastroprotective and luteolytic activity was interpreted to indicate that these new PGE derivatives have a specific action.

Abortion, Spontaneous↗