In vitro and in vivo activities of syn2836, syn2869, syn2903, and syn2921: new series of triazole antifungal agents.

The in vitro and in vivo activities of four azole compounds belonging to a new series of 2(2,4-difluorophenyl)-3-(4-substituted piperazin-1-yl)-1-(1,2,4-triazol-1-yl) butanol antifungal agents is described. The compounds were selected from a library of azole compounds synthesized by our group. The in vitro activities of Syn2869, Syn2836, Syn2903, and Syn2921 against a panel of over 240 recently collected clinical isolates of yeast and molds were determined, and the results were compared with those obtained with fluconazole (FLC), itraconazole (ITC), and amphotericin B (AMB). The MICs at which 90% of the isolates were inhibited (MIC(90)s) for the four test compounds for strains of Candida spp. ranged from <0.048 to 0.78 microg/ml. All compounds were also active against FLC-resistant Candida albicans and other Candida sp. strains. Moreover, MIC(90)s for strains of Cryptococcus neoformans, Aspergillus spp., Trichophyton spp., and Microsporum spp. were also low and ranged from <0.048 to 0.39 microg/ml. The test compounds produced a fungistatic pattern during the time-kill kinetic studies. In vivo studies indicated that all four test compounds have good efficacies against C. albicans in a murine systemic infection model and significantly improved the survival rates of the infected mice. The results for Syn2903 were similar to those for FLC, while the other compounds were slightly less effective but had ranges of activities similar to the range of activity of ITC. The compounds were also evaluated against an Aspergillus fumigatus systemic infection. Syn2903 was also superior to ITC, whereas the efficacy data for the other compounds were similar to those for ITC. It was concluded from the data generated for this new series of azole compounds in the studies described above that further pharmacokinetic and toxicologic evaluations are warranted prior to selection of a candidate compound for preclinical testing.

Indonesian Medicinal Plants. XIV. Characterization of 3'-O-Caffeoylsweroside, a new secoiridoid glucoside, and kelampayosides A and B, two new phenolic apioglucosides, from the bark of Anthocephalus chinensis (Rubiaceae).

A new secoiridoid glucoside named 3'-O-caffeoylsweroside (1), and two new phenolic apioglucosides, named kelampayoside A (4) and kelampayoside B (6), together with eleven known compounds (five iridoids and six alkaloids), were isolated from the bark of Anthocephalus chinensis (Rubiaceae), an Indonesian medicinal plant from Sumatra Island, Indonesia. The chemical structures of 1, 4 and 6 have been elucidated respectively as 3'-O-caffeoylsweroside (1), antiarol 1-O-beta-D-apiofuranosyl (1 --> 6)-beta-D-glucopyranoside (4), and antiarol 1-O-beta-D-5"-O-caffeoylapiofuransoyl (1 --> 6)-beta-D-glucopyranoside (6) on the bases of their chemical and physiochemical properties. Among fourteen constituents characterized, cadambine (13), one of the major indole alkaloid constituents of A. chinensis, was shown to exhibit moderate growth-inhibitory activity against the malarial parasite Plasmodium falciparum (a chloroquine-resistant K1 strain) cultured in human erythrocytes.

Indonesian medicinal plants. VIII. Chemical structures of three new triterpenoids, bruceajavanin A, dihydrobruceajavanin A, and bruceajavanin B, and a new alkaloidal glycoside, bruceacanthinoside, from the stems of Brucea javanica (Simaroubaceae).

Three new apotirucallane-type triterpenoids named bruceajavanin A (1) dihydrobruceajavanin A (2) and bruceajavanin B (3), and a novel beta-carboline alkaloidal glycoside named bruceacanthinoside (4) were isolated from the stems of Brucea javanica (Simaroubaceae), a traditional medicine used to treat malaria in the Bengkulu area, Sumatra, Indonesia. Their chemical structures have been elucidated on the bases of their chemical and physicochemical properties. Bruceajavanin A (1), dihydrobruceajavanin A (2) and bruceacanthinoside (4) were shown to inhibit growth of the cultured malarial parasite Plasmodium falciparum K1 of a chloroquine-resistant strain.

Dehatrine, an antimalarial bisbenzylisoquinoline alkaloid from the Indonesian medicinal plant Beilschmiedia madang, isolated as a mixture of two rotational isomers.

Through bioassay-guided separations of the chemical constituents of the Indonesian medicinal plant Beilschmiedia madang BL. a bisbenzylisoquinoline alkaloid was obtained as the major antimalarial principle. The physicochemical properties of the alkaloid were consistent with the proposed structure of dehatrine. However, the alkaloid isolated by us was shown to be a mixture of two rotational isomers. The X-ray crystallographic analysis of 1 has shown that two rotamers are incorporated in a single crystal in 1:1 ratio. The complex NMR spectrum of 1 has also been defined as a mixture of two rotamers by extensive use of 2D (COSY and COLOC) techniques. Dehatrine has been shown to significantly inhibit the growth of cultured Plasmodium falciparum K1 strain (cholorquine resistant) with similar activity to quinine.

[Therapeutic efficacy of cefodizime in combination with minocycline against systemic infection caused by methicillin-resistant Staphylococcus aureus in immunocompromised tumour bearing mice].

The in vivo synergistic effect of cefodizime (CDZM) in combination with minocycline (MINO) against methicillin-resistant Staphylococcus aureus (MRSA) was investigated. A study of fractional effective dose (FED) index showed that either synergistic or additive effect was observed between CDZM and MINO. The postantibiotic effect (PAE) of MINO was not altered by the addition of CDZM. However, a strong synergistic bactericidal effect of CDZM and MINO against MRSA CT-18 was observed for more than 14 hours in the presence of immunocompromised tumour bearing murine polymorphonuclear leukocytes (PMN). These results suggest that the strong therapeutic efficacy of CDZM in combination with MINO was caused by synergistic bactericidal effect of the 2 drugs in the presence of PMN.