Antibacterial activity of 15-azasteroids alone and in combination with antibiotics.

A new class of 15-azasteroid analogues has been synthesized and tested for antimicrobial activity. The compounds 1, 10, 11, 11a-tetrahydro-7-methoxy-11a-methyl-2H-naphth (1,2-g) indol (methoxyimine) and 1,10,11,11a-tetrahydro-11a-methyl-2H-naphth (1,2-g) indol-7-ol (hydroxyimine) inhibit the growth of Bacillus subtillis and Escherichia coli at concentrations as low as 10-5 M. Addition of either compound to the growth medium casued a rapid inhibition in the transport of radioactive glucose, uracil and several amino acids. The inhibition of growth and substrate transport was reversed following removl of the steroid from the medium. The evidence is consistent with a site of steroid action at the cell periphery. Combining the methoxyimine with polyor circulin at subinhibitory concentrations produced greatly enhanced antimicrobial activity against Pseudomonas fluorescens. Similar action was observed against B. subtilis when the azasteroid was combined with vancomycin or chloramphenicol. The inhibitory action of other antibiotics such as penicillin or erythromycin was not affected by addition of the test compound. The results suggest formation of a molecular complex between the azasteroid and antibiotic which is responsible for the enhanced biological activity.

Synthesis and structure-activity relationships of heterocyclic compounds containing a trimethoxyarene function.

Pyrazole-, isoxazole-, and pyrazolone-containing systems were prepared from 3,4-dihydro-5,6,7-trimethoxy-1(2H)-naphthalenone, 3,4-dihydro-6,7,8-trimethoxy-1(2H)-naphthalenone, and 3,4-dihydro-6,7,8-trimethoxy-1(2H)-phenanthrone. Primarily, the pyrazoles displayed inhibition of growth in the microbial screens and in tissue culture. Correlation of the heteroatom distances between the oxygen atoms of two methoxy groups and a nitrogen atom in the pyrazole function with the percent plating efficiency on KB cell growth suggests increased inhibition as the (OA-N)/(OB-N) ratio deviates from one. No trend was observed in relating the OA-N-OB angle and activity for the examples studied.

Biological, proton-magnetic-resonance- and ultraviolet-spectroscopic evidence for a molecular complex of actinomycin D and 10,11-dihydro-3H-naphth (1,2-g)indazol-7-ol.

A proton-magnetic-resonance study of the complex formed between actinomycin D and 10,11-dihydro-3H-naphth[1,2-g]indazol-7-ol strongly suggests that the indazole lies above the phenoxazine ring of actinomycin D. The complex can be destroyed by addition of dimethyl sulphoxide or dimethylformamide. The actinomycin D-indazole complex inhibits growth of Pseudomonas fluorescens and raises the thermal denaturation response of DNA. These data support the hypothesis that a molecular complex is formed which readily inhibits cell growth and interacts with DNA.