Metabolism of antimalarial sesquiterpene lactones.

Metabolism of artemisinin derivatives, which are antimalarial sesquiterpenes, appeared to lead to the production of the more polar metabolites in general. Presence of the endoperoxide moiety in the A/B ring structure seems crucial for the expression of antimalarial activity of these compounds. Microbial models served as effective predictors for the mammalian metabolism of artemisinin derivatives as well as producing quantities of metabolites for reference standards and structure elucidation studies. Combination of 2D-NMR and Thermospray HPLC/MS techniques was very useful for the structure elucidation of metabolites.

Photooxidation products of primaquine. Structure, antimalarial activity and hemolytic effects.

Photooxidation of primaquine (1) and 5-hydroxyprimaquine (5) afforded a blue dye for which o-quinone structure 4 was elaborated. Similar oxidation of N-ethoxyacetylprimaquine (10) afforded o-quinone 11. Tissue schizontocidal activity of 4 and 11, and bisquinolylmethine 3 prepared earlier, showed that none of them had noteworthy antimalarial activity, but all three produced methemoglobin.

Microbial models of mammalian metabolism of xenobiotics: An updated review.

The utilization of microbes as models for mammalian metabolism of xenobiotics has been well established since the concept was first introduced by Smith and Rosazza in the early seventies. The core assumption of this concept rests on the fact that fungi are eukaryotic organisms that possess metabolizing enzyme systems similar to those present in mammalian systems. Hence, the outcome of xenobiotic metabolism in both systems is expected to be similar, if not identical, and, thus, fungi can be used to predict the outcome of mammalian metabolism of various xenobiotics, including drugs. Utilizing microbial models offers a number of advantages over the use of animals in metabolism studies, mainly reduction in use of animals, ease of setup and manipulation, higher yield and diversity of metabolite production, and lower cost of production. In a continuation to our contribution to this field, this review will outline the results of studies that were conducted over the last seven years to emphasize the similarities between the microbial and mammalian metabolic pathways of xenobiotics through the endorsement of the concept of microbial models of mammalian metabolism .

Copyrine alkaloids: synthesis, spectroscopic characterization, and antimycotic/antimycobacterial activity of A- and B-ring-functionalized sampangines.

Several A- and B-ring-substituted sampangines were synthesized and evaluated for antifungal and antimycobacterial activity against AIDS-related opportunistic infection pathogens. Electrophilic halogenation provided a channel for structural elaboration of the sampangine B-ring at position 4, while the synthesis of A-ring 3-substituted sampangines and benzo[4,5]sampangine (24) were achieved from the corresponding functionalized cleistopholines. Two-dimensional NMR spectroscopy was used to rigorously characterize the A- and B-ring substituent patterns. Structure-activity relationship studies revealed the activity of the sampangines was enhanced by the presence of a substituent at position 3 or by a 4,5-benzo group.

Alkaloids from Haplophyllum tuberculatum.

Two new alkaloids, haplotubinone (3) and haplotubine (4), were isolated from the aerial parts of Haplophyllum tuberculatum together with the known lignan diphyllin. The structures of the new alkaloids were established by spectroscopic methods in conjunction with X-ray crystallographic analysis of 3. In addition, the amide N-(2-phenylethyl)-benzamide has been identified in this source for the first time.

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.

Antibacterial and antifungal activity of liriodenine and related oxoaporphine alkaloids.

Liriodenine was evaluated for its antibacterial and antifungal activity against several microorganisms. Other related oxoaporphine alkaloids also were evaluated. Attempts to prepare oxoaporphine alkaloids from N-acetylnoraporphines were unsuccessful, but an unexpected phenanthrene alkaloid was obtained. A novel N-demethylation reaction was noted when oxogaucine methiodide and liriodenine methiodide were treated with alumina.

Microbial transformations and 13C-NMR analysis of colchicine.

Several microorganisms were screened for their ability to biotransform colchicine, and two were selected for preparative scale fermentations. Streptomyces spectabilis and Streptomyces griseus both produced O2-demethylcolchicine and O3-demethylcolchicine but in different amounts. The 13C-NMR assignments of colchicine, O10-demethylcolchicine, and trimethylcolchicinic acid are reported and were used to help identify the structures of the metabolites.

Metabolism of phencyclidine by microorganisms.

A number of microorganisms were screened for their ability to metabolize phencyclidine. Two microorganisms, Beauveria sulfurescens and Cunninghamella echinulata, produced hydroxylated metabolites, which were identified as 1-(1-phenylcyclohexyl)-4-hydroxypiperidine and 4-phenyl-4-piperidinocyclohexanol by high-pressure liquid chromatographic analysis.

Study of the metabolic conversion of imipramine and desipramine to N-nitrosodesipramine by bacteria using a nitrogen-selective GC analysis.

A GC method using dual nitrogen selective and flame ionization detectors was developed for the determination of N-nitrosodesipramine using N-butyryldesipramine as the internal standard. The precision of the method was found to be +/- 5.0% and the accuracy was +/- 4.9%. The method could be used to detect 10 ng/ml of N-nitrosodesipramine in bacterial cultures. When desipramine and sodium nitrite were incubated with aerobic or anaerobic bacteria, the nitrosamine level was found to be 10-300 times higher than the controls. When imipramine and potassium nitrate were incubated with a mixed anaerobic culture, the level of N-nitrosodesipramine was found to be 4.5 times higher than the control.

Metabolism of imipramine by microorganisms.

The microbial metabolism of imipramine was studied using selected fungal organisms. The major microbial metabolites were isolated, and their structures were established by spectroscopic analyses (particularly 13C-NMR) and by comparison with authentic samples. The microbial metabolites identified included 2-hydroxyimipramine, 10-hydroxyimipramine, iminodibenzyl, imipramine-N-oxide, and desipramine; these metabolites also have been found in mammalian metabolism studies.

Microbial metabolism of bornaprine, 3-(diethylamino)propyl 2-phenylbicyclo[2.2.1]heptane-2-carboxylate.

Metabolism studies of the anticholinergic drug, bornaprine [3-(diethylamino)propyl 2-phenylbicyclo[2.2.1]heptane-2-carboxylate, an epimeric mixture], in rats, dogs, and humans have been conducted previously, but the identities of the metabolites were not established. Using an in vitro microbial system to study the metabolism of bornaprine resulted in the isolation of four metabolites whose structures were rigorously established using spectroscopic techniques, especially 13C NMR. The four metabolites found were hydroxylated at C-5 or C-6 in the bicyclic ring.

Antimicrobial properties of alkaloids from Xanthorhiza simplicissima.

The organic extract of the whole plant Xanthorhiza simplicissima was found to exhibit good activity against the AIDS-related opportunistic pathogens Candida albicans, Cryptococcus neoformans, and Mycobacterium intracellularae. Bioassay-directed fractionation of the extract led to the isolation of the known alkaloid berberine as the major active component. A second alkaloid of the isohomoprotoberberine family, puntarenine, was isolated from this plant family for the first time. Puntarenine also showed marginal activity against the dermatophytic fungus Trichophyton mentagrophytes and the yeast Saccharomyces cerevisiae.

Two antimicrobial alkaloids from heartwood of Liriodendron tulipifera L.

Alcoholic extracts of the heartwood of Liriodendron tulipifera have demonstrated antimicrobial activity against Staphylococcus aureus, Mycobacterium smegmatis, Candida albicans, and Aspergillus niger. The antimicrobial activity was associated only with the alkaloidal fraction. Separation of the active alkaloidal fraction by chromatography led to the isolation and identification of dehydroglaucine and liriodenine as the active components. Several other alkaloidal derivatives were prepared and tested. In addition to the active alkaloids, michelabine was also identified in the tertiary nonphenolic base fraction along with the lignan, lirioresinol-B-dimethyl ether, and two N-acetylnoraporphine alkaloids from the nonbasic fraction.

Demethylation of imipramine by enteric bacteria.

The ability of a number of aerobic and anaerobic bacteria to N-demethylate imipramine (I) to desipramine (II) has been investigated. Of the bacteria investigated, almost half were known inhabitants of the human GI tract. More than half of the enteric bacteria studied were capable of N-demethylating imipramine (I) to desipramine (II) to some extent in at least one medium. It was found that the medium in which the organism was grown had a significant effect on the N-demethylase activity observed.

Antimicrobial properties of Honduran medicinal plants.

Ninety-two plants used in the traditional pharmacopoeia of the Pech and neighboring Mestizo peoples of central Honduras are reported. The results of in vitro antimicrobial screens showed that 19 of the extracts from medicinal plants revealed signs of antifungal activity while 22 demonstrated a measurable inhibitory effect on one or more bacterial cultures. Bioassay-guided fractionation of extracts from Mikania micrantha, Neurolaena lobata and Piper aduncum produced weak to moderately active isolates. The broad spectrum of activity of the extracts helps to explain the widespread use of these plants for wound healing and other applications.