Mutagenic activity of isoxazolylnaphthoquinoneimines assayed by micronucleus bone marrow test.

Studies were undertaken to evaluate the ability of various quinoneimines to induce micronuclei in bone marrow cells as a measure of their genotoxicity. Accordingly, 2-hydroxy-N-(3,4-dimethyl-5-isoxazolyl)-1,4-naphthoquinone-4-imine (I), its 2-acetyl derivative (II) and 2-[(5-methyl-3-isoxazolyl)amino]-N-(5-methyl-3-isoxazolyl)-1 ,4- naphthoquinone-4-imine (III), as well as two of their precursors, 2-hydroxynaphthoquinone (NQ-2-OH) and 3,4-dimethyl-5-aminoisoxazole (DMAI) were given by intraperitoneal injection at 5, 50, 100 and 200 mg/Kg doses to S.J.L. Swiss mice with 24 h sampling time. Compounds I and II displayed highly significant differences at 50, 100 and 200 mg/kg doses (p < 0.01) and their mutagenic dose response curves correlated closely with an inverted U-shaped form whose interpretation is still the subject of controversy. NQ-2-OH only produced a significant increase in micronucleus frequency at 50 mg/kg, whereas no mutagenic activity was found for compound III and DMAI at the doses assayed. At 50 mg/kg the order of relative mutagenic potencies was I > II > NQ-2-OH. Mechanisms advanced to explain loss of drug activity at high doses include capture saturation, enzymatic induction during metabolism and participation of an independent defense system.

Mutagenic and analgesic activities of aniline derivatives.

Phenacetin (1), acetaminophen (2), acetanilide (3), 4-aminophenol (4), and aniline (5) were tested in S.J.L. Swiss mice for their mutagenic and analgesic activities. The S-analogues of 1 and 2, 4-mercaptoacetanilide (6) and 4-ethylthioacetanilide (7), respectively, were synthesized and tested in the same way to define if both activities could be separated by molecular modification. All the compounds tested exhibited analgesic activity with ED50 values ranging from 12.6 to 158.5 mg/kg. The compounds could be arranged in a decreasing order of analgesic activity as follows: 3 greater than 4 congruent to 5 congruent to 6 greater than 1 congruent to 7 greater than 2. All the compounds, except 6, were positive mutagens in the micronucleus test (statistically significant). The order of relative mutagenic potencies was 1 congruent to 7 greater than 4 greater than 2 congruent to 3 congruent to 5. A narrow dose-response curve relationship was found for 5 and its metabolite 4, the relative mutagenic potencies of which suggest ring hydroxylation as the major pathway of biotoxification. No parallelism was found between analgesic and mutagenic activities, so they could be separated by pharmacomodulation: 6 was more effective as an analgesic in the acetic acid test than 2, and no mutagenic activity was found at the doses assayed.

Studies on antimicrobial agents. 1. Synthesis and relation between the antimicrobial activities and certain physicochemical properties of some N'-(pyridinoacetyl) fatty acid hydrazides.

A new series of N'-(pyridinioacetyl)alkanoic and -benzoic acid hydrazides, as chloride salts, and some cyclic analogues produced ring closure have been synthesize and tested in a search for more effective germicides. Physicochemical parameters, such as surface tension, critical micelle concentration, and thermodynamic activity. (Ferguson values), were also determined. Staphylococcus aureus and Streptococcus pyogenes were the most susceptible of the organisms tested. N'-(Pyridinoacetyl)hexadecanoic acid hydrazide exhibited the highest toxicity to Staph. aureus and fungi. The mean surface tension of the equitoxic solutions is 59.8 +/- 0.3 dyn/cm for bacteria and 51.65 +/- 0.1 dyn/cm for fungi. N'-(Pyridinoacetyl)octadecanoic acid hydrazide and N'-(pyridinoacetyl)-9-ocadecenoic acid hydrazide exhibit the highest toxicity to S. pyogenes (1.1 x 10(-6) M). The surface tension of their equitoxic solutions and their Ferguson values indicate that these compounds may act through a different mechanism.