Antimicrobial activity of trifluoromethyl ketones and their synergism with promethazine.

The antimicrobial effects of 30 trifluoromethyl ketones [1-30] were studied on various representative bacteria. Of the ketones, 4,4,4-trifluoro-1-phenyl-1,3-butanedione [10], 1,1,1-trifluoro-3-(4,5-dimethyloxazol-2-yl)-2-propanone [11] and 1-(2-benzoxazolyl)-3,3,3-trifluoro-2-propanone [18] were found to exhibit potent antibacterial activity against the Gram-positive Bacillus megaterium and Corynebacterium michiganese, but not against Gram-negative bacteria such as Pseudomonas aeruginosa and Serratia marcescens. Compounds 11 and 18 inhibited the Escherichia coli. Compound 18 was also effective against yeasts. The combination of promethazine with 18 was significantly synergistic against E. coli strains, especially the proton pump deficient mutant. The results suggest that membrane transporters are the target of trifluoromethyl ketones. The inhibition was more marked in the proton pump deficient E. coli mutant than in the wild type, which suggested that the antibacterial effect of trifluoromethyl ketones is partly prevented by the proton pump system.

Biological activity of kiwifruit peel extracts.

Various bioactive substances in kiwifruit extracts were fractionated by organic solvent extractions, followed by silica gel and ODS chromatographies. Both cytotoxic activity and multi-drug resistance reversal activity were found in the less polar fractions. Cytotoxic activity was not always parallel the radical intensity. Antibacterial activity was distributed into various fractions and all fractions were inactive against Candida albicans and H. pylori. Only 70% methanol extracts showed anti-human immunodeficiency virus activity, and produced a broad ESR signal under alkaline conditions, in a fashion similar to lignin. These fractions also effectively scavenged O(2)(-) produced by the xanthine-xanthine oxidase reaction, suggesting a bimodal (pro-oxidant and antioxidant) action. These data suggest a medicinal efficacy of kiwifruit peel extracts.

Guanine-cytosine rich regions of plasmid DNA can be the target in anti-plasmid effect of phenothiazines.

The antiplasmid effects of promethazine on E. coli is the consequence of special complex formed with a covalently closed circular (ccc) form of plasmid DNA. The exact target in this macromolecule, however, was not clarified until recently. Caffeine and the chemically similar guanosine-5'- monophosphate (GMP) could compete with the antiplasmid effect of promethazine, showing that promethazine or other phenothiazines preferentially bind to xanthine type molecules. Among the xanthines, GMP was more effective at complex-forming than adenosine-5'-monophosphate (AMP). In addition, the Z-DNA was more susceptible than B-DNA. Therefore, one could suppose that guanine-cytosine (G-C) rich regions have higher affinity than adenine-thymine (A-T) rich region on phenothiazines. Because the G-C rich regions have a special role in the DNA stability via three hydrogen bonds, we suppose that these regions could have a key role in some biological effects such as antiplasmid and anticancer activity.

Plasmid elimination and immunomodulation by 3-benzazepines in vitro.

For studying the mechanisms of biological activity on 3-benzazepines, antimicrobial effect, F'lac plasmid elimination activity (a plasmid curing effect on F'lac plasmid) and antibody-dependent cellular cytotoxicity (ADCC) test were performed. A weak antiplasmid effect was found at sub-inhibitory concentrations. A combination of [KF4] with verapamil [2] did not alter the ineffectivity, however, [KF4] could inhibit the antiplasmid effect of promethazine, as compared to the control (promethazine alone) plasmid curing effect. A competition between promethazine and [KF4] might exist in plasmid elimination effect. ADCC activity of human leukocytes was enhanced by KF1, KF2, KF3, DA and NE at 1.0 microgram/mL concentrations. The majority of 3-benzazepines [KS02, KM57, KN50, KE04, KI10, KP80] was ineffective for plasmid curing, however, inhibited the ADCC reaction, but they did not show a real dose-dependent effect.

6,12-dihydro-1-benzopyrano[3,4-b][1,4]benzothiazin-6-ones: synthesis and mdr reversal in tumor cells.

Six 6,12-dihydro-1-benzopyrano[3,4-b][1,4]benzothiazin-6-ones and three coumarins were systematically investigated for reversal of multidrug resistance of bacteria and cancer cells in model experiments. 7-Methylcoumarin was able to eliminate the E. coli plasmid significantly; however, the other derivatives were ineffective. Four of 6,12-dihydro-1-benzopyrano[3,4-b] [1,4]benzothiazin-6-ones had a moderate effect on the multidrug resistance efflux pump of mouse lymphoma cells in vitro. Despite of the similarity of resistance mechanisms of bacteria and tumor cells, the reversal of drug resistance in bacteria and in cancer cells is not uniform because the structure-activity requirements are apparently different.