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J D McChesney

Publications and source records attributed to J D McChesney.

At least 37 records · Page 2Linked to original sources
PubMed1991

Synthesis and the biological evaluation of the structural units of drummondin C.

Drummondin C (1) is an antibiotic isolated from a bioassay-directed fractionation of Hypericum drummondii (Grev. & Hook.)T.&G. It showed significant activity against the Gram-positive bacteria Staphylococcus aureus and Bacillus subtilis and the acid-fast bacterium Mycobacterium smegmatis. Two structural units of drummondin C, the 8-acetyl-5,7-dihydroxy-2,2-dimethylchromene (6) and 5-acetyl-3-methyl-filicinic acid (9), were synthesized to determine the relative importance of the two substructure portions to the antibiotic activity of the compound. The low antimicrobial activity of 6 and 9 demonstrates the necessity of both units for the antibiotic activity of drummondin C.

Anti-Bacterial Agents↗
PubMed1991

Hydroxylation and glucoside conjugation in the microbial metabolism of the diterpene sclareol.

1. The microbial metabolism of sclareol (1), a labdane diterpene ditertiary alcohol, was studied. Preliminary screening identified a number of microorganisms capable of metabolizing sclareol. 2. Preparative scale fermentation of growing cultures of Bacillus cereus UI-1477 resulted in the production of seven metabolites which have been characterized as 3 beta-hydroxysclareol (2), 2 alpha-hydroxysclareol (3), 18-hydroxysclareol (4), 2 alpha,18-dihydroxysclareol (6), 8 alpha,13 beta-dihydroxy-labd-14-en-3 beta-O-beta-D-glucoside (5), 8 alpha,13 beta-dihydroxy-labd-14-en-18-O-beta-D-glucoside (7), and 8 alpha,13 beta-dihydroxy-labd-14-en-2 alpha-O-beta-D-glucoside (10) by chemical, enzymic, and spectral data, especially 2D-n.m.r. techniques and thermospray liquid chromatography-mass spectrometry analysis.

Bacillus cereus↗
PubMed1990

Synthesis and antimalarial activity of (+)-deoxoartemisinin.

(+)-Deoxoartemisinin (2), a new and more active antimalarial agent, was successfully prepared from artemisinin in one step using NaBH4 and BF3.Et2O in THF. (-)-Deoxodeoxyartemisinin (5), a potential metabolite of deoxoartemisinin, was also prepared either from 2 or from artemisinic acid. 2 shows 8-fold increased antimalarial activity in vitro against chloroquine-resistant malaria as compared to artemisinin (1). Compound 2 possesses superior in vivo antimalarial activity to 1.

Animals↗
PubMed1990

Effect of aliphatic side-chain substituents on the antimalarial activity and on the metabolism of primaquine studied using mitochondria and microsome preparations.

The substitution of two deuterium atoms on the alpha-carbon of the primaquine side chain was found to produce a sevenfold decrease in the rate of conversion of primaquine to carboxyprimaquine by enzymatic oxidative deamination, but the deuterium substitution was found to have no significant effect on the in vitro antimalarial activity or on in vitro hepatocyte toxicity. Placing a single methyl group on the alpha-carbon was found to produce only a slight decrease in the rate of oxidative deamination. Although metabolic attack occurred adjacent to either the aniline nitrogen or the aliphatic amine, metabolic attack occurred primarily adjacent to the more basic nitrogen at the 1'-position, even when this position bore a methyl substituent. Primaquine, the alpha-dideutero analogue, and the alpha-methyl analogue were all found to have about the same in vitro antimalarial activity as determined in the liver hepatocyte assay.

Animals↗
PubMed1989

Thermospray mass spectroscopy/high performance liquid chromatographic identification of the metabolites formed from arteether using a rat liver microsome preparation.

Thermospray LC/MS methods with internal standardization were developed for the quantification of the antimalarial arteether and six of its metabolites at the 1-10 micrograms/ml level in liver microsome preparations without the use of solvent extraction. The thermospray mass spectra of arteether and most of its metabolites exhibited strong [M + NH4]+ and [M - OR]+ peaks arising from the molecular ion adduct and the loss of the alkoxy or hydroxy group of the side chain. In addition to the six metabolites for which authentic reference standards were available, three additional metabolites were detected. The major metabolites of arteether were found to be dihydroartemisinin, deoxydihydroartemisinin, 3-hydroxydeoxydihydroartemisinin, two isomers of hydroxyarteether, and 3-hydroxydeoxyarteether. Deoxyartheether was not found at significant concentrations in the microsome preparation.

Animals↗
PubMed1989

Nonsurgical management of an isolated interhemispheric subdural hematoma sequentially followed by CT.

Using transaxial CT scan, we diagnosed a patient with head injury as having an isolated interhemispheric subdural hematoma, on the basis of the widening of the superior sagittal sinus. The diagnosis was confirmed by coronal views. The patient was managed nonsurgically and gradual reabsorption of the hematoma was documented by CT. During the latter stages of reabsorption, two parallel lines were noted on the transaxial views as the subdural collection became smaller and drew away from the sagittal sinus. We conclude that an unusual widening of the superior sagittal sinus on transaxial CT scan warrants suspecting an interhemispheric subdural hematoma. Because the hematoma may be obscured by the overlying clot, coronal views may also be valuable.

Female↗
PubMed1988

Differential metabolism of the enantiomers of primaquine.

When racemic primaquine was administered to rats, the majority of the residual primaquine excreted in urine was found to be the (+)-isomer. Using a liver microsome preparation, there was no selectivity in the metabolism of the (+)- and (-)-isomers; however, a liver fraction containing mitochondria and microsomes did show selectivity. In the latter preparation, there was a marked preference for the conversion of (-)-primaquine to (-)-carboxy-primaquine.

Animals↗
PubMed1986

Novel sulfur-containing microbial metabolite of primaquine.

Microbial metabolism studies of the antimalarial drug primaquine, using Streptomyces roseochromogenus (ATCC 13400) have produced an N-acetylated metabolite and a methylene-linked dimeric product, both of which have been previously reported, and a novel sulfur-containing microbial metabolite. The structure of the metabolite as a sulfur-linked dimer was proposed on the basis of spectral and chemical data. The molecular formula C34H44N6O4S was established from field-desorption mass spectroscopy and analytical data. The 1H- and 13C-nuclear magnetic resonance spectral data firmly established that the novel metabolite was a symmetrically substituted dimer of primaquine N-acetate with a sulfur atom linking the two units at C-5. The metabolite has been shown to be a mixture of stereoisomers which can equilibrate in solution. This observation was confirmed by microbial synthesis of the metabolite from optically active primaquine.

Chemical Phenomena↗
PubMed1985

A simple colorimetric method for the determination of primaquine metabolites in urine.

A simple method of screening large numbers of urine samples for the presence of primaquine metabolites has been developed using a commercially available diazonium salt reagent and an extraction cartridge. The extraction requires only 1.0 ml of urine and is selective for acidic or neutral primaquine metabolites. With primaquine-dosed rats, primaquine metabolites could be detected 36 hours after administration of the drug. The sensitivity of the method was found to be approximately 400 mug/l.

Animals↗
PubMed1984

Excretion, distribution, and metabolism of primaquine in rats.

The metabolism of the 8-aminoquinoline antimalarial drug, primaquine (I) was studied using rats. The drug was administered intravenously, intraperitoneally, and orally, and blood samples were collected at various time intervals. Primaquine was metabolized by oxidative deamination to give 8-(3-carboxy-l- methylpropylamino )-6- methoxyquinoline (III). The plasma levels of both primaquine and its metabolite were determined by HPLC. The tissue distributions of radioactive primaquine after intravenous, intraperitoneal, and oral administrations were also determined. Significant concentrations of radioactivity were found in the lungs, adrenal glands, and liver. In addition, a significant portion of the dose was found to be excreted in the feces within 24 h after administration of the drug by either of the three routes.

Administration, Oral↗
PubMed1984

Bromo-6-methoxy-8-aminoquinolines: preparation and 13C-NMR assignments.

Preparation of all possible monobromo-6-methoxy-8-aminoquinolines is reported. These materials provided an opportunity to assess the effect of bromine substitution on 13C-NMR chemical shift patterns. An explanation of the isomerization of 5-bromo-6-methoxy-8-acetamidoquinoline to 7-bromo-6-methoxy-8-aminoquinoline during hydrolysis is presented.

Aminoquinolines↗
PubMed1984

Microbial transformation of primaquine by Candida tropicalis.

The microbial metabolism of primaquine, a 6-methoxy-8-aminoquinoline antimalarial agent, was investigated. The yeast Candida tropicalis was found to convert primaquine to the previously reported N-acetylated derivative. On continued incubation of C. tropicalis in the presence of the N-acetylated derivative, a minor dimeric metabolite was formed. The proposed structure of the metabolite was based primarily on the analysis of its spectroscopic properties (1H and 13C nuclear magnetic resonance spectra and field-desorption mass spectrum). The structure of the metabolite was proven by direct comparison with an authentic sample of the minor dimeric metabolite prepared by treatment of the N-acetylated derivative with formaldehyde in the presence of formic acid in methanol.

Acetylation↗
PubMed1984

Production of a novel dimeric metabolite of primaquine by Streptomyces rimosus.

Primaquine, an 8-amino-6-methoxyquinoline antimalarial agent, was subjected to metabolic studies with microorganisms. Streptomyces rimosus converted primaquine to the previously reported N-acetyl derivative. Continued incubation of S. rimosus resulted in the formation of a minor dimeric metabolite. The structure of the minor dimeric metabolite was proposed based primarily on its spectral data (1H and 13C nuclear magnetic resonance spectra and mass spectrum). The proposed structure of the metabolite was confirmed by synthesis of the dimer by treatment of primaquine-N-acetate with potassium ferricyanide in a biphasic chloroform-aqueous sodium bicarbonate system with a phase-transfer catalyst. Since (+/-)-primaquine was used for both the microbial transformation and synthesis, a diastereomeric mixture of symmetrical dimers was formed in each case. The metabolite sample was identical to the synthetic sample, as shown by direct comparison (thin-layer chromatography, co-thin-layer chromatography, high-pressure liquid chromatography, co-high-pressure liquid chromatography, 1H nuclear magnetic resonance spectra, and mass spectrum).

Chromatography, High Pressure Liquid↗
PubMed1983

Picrotoxin-like lactones.

Preparation of some simple lactone analogues of picrotoxin and their biological evaluation is reported. Certain analogues possessed activity, but at potencies insufficient to warrant further work.

Alkylation↗
PubMed1982

High-performance liquid chromatographic analysis of the metabolism of primaquine and the identification of a new mammalian metabolite.

Using rats that had been dosed with 20 mg/kg of primaquine diphosphate (11.4 mg/kg free base), it was found that the drug underwent a metabolic oxidative deamination to give 8-(3-carboxy-1-methylpropylamino)-6-methoxyquinoline. The presence of this new mammalian metabolite was verified using high-performance liquid chromatographic, gas chromatographic, and mass spectral methods. A quantitative high-performance liquid chromatographic method for the determination of primaquine and the carboxylic acid metabolite in plasma using only 50 microliters of whole blood from the rat was developed and the method could be used to detect levels as low as 0.05 microgram/ml of the metabolite. Following intravenous administration of the drug, it was found that the plasma levels of primaquine fell very rapidly and after 30 min, the levels of the metabolite were much higher than those of primaquine.

Animals↗
PubMed1981

Primaquine: metabolism by microorganisms and 13C nuclear magnetic resonance assignments.

Primaquine (I), a 6-methoxy-8-aminoquinoline derivatives used for the treatment of malaria, has been subjected to metabolic studies using microorganisms. A total of 77 microorganisms (fungi and Streptomyces spp.) were evaluated for their ability to metabolize primaquine. Of these, 23 were found to convert primaquine to one or more metabolites (thin-layer chromatography analysis). Preparative scale fermentation of primaquine with four different microorganisms resulted in the isolation of two metabolites, identified as 8-(4-acetamido-1-methylbutylamino)-6-methoxyquinoline (II) and 8-(3-carboxyl-1-methylpropylamino)-6-methoxyquinoline (III). The structures of the metabolites were proposed based primarily on a comparison of the 13C nuclear magnetic resonance spectra of II and the methyl ester of III (IV) with that of primaquine. The structures of both metabolites II and III were confirmed by direct comparison with authentic samples.

Aspergillus flavus↗
PubMed1981

Considerations about the structure-activity relationships of 8-aminoquinoline antimalarial drugs.

A discussion of the structure-activity relationships (SAR) of 8-aminoquinoline antimalarial drugs is presented. Consideration is given to the potential role of metabolic transformations in the in vivo activation of 8-aminoquinolines. It is emphasized that the mechanism of action of 8-aminoquinoline agents has not yet been established and thus any analysis of SAR must be speculative.

Aminoquinolines↗