A series of 60 newly synthesized and known quinolone antibacterials, including quinoline- and 1,8-naphthyridine-3-carboxylic acids, pyrido[2,3-d]pyrimidine-6-carboxylic acids, and some monocyclic 4-pyridone-3-carboxylic acids, were tested and compared in a newly established, easy to perform, DNA gyrase assay. The results were correlated with minimum inhibitory concentrations (MICs) against a variety of organisms. Among the known quinolones were 14 clinically significant drugs (oxolinic acid, norfloxacin, ciprofloxacin, enoxacin, etc.) which were used as standards and compared side-by-side. The study focused on the changes in DNA gyrase inhibition brought about by certain features of the molecules, namely, the C6-fluorine or the nature of the C7 substituent. The intrinsic gyrase inhibition of the fused parent rings, quinoline vs. naphthyridine vs. pyrido[2,3-d]pyrimidine, was also explored. In all cases, loss of enzyme inhibition produced poor MICs, but some compounds with good DNA gyrase inhibition did not correspondingly inhibit bacterial growth. Possible explanations for this phenomena and the benefits of a DNA gyrase-MIC strategy for developing future structure-activity relationships are discussed.

A series of 18 1-substituted 7-[3-[(ethylamino)methyl]-1- pyrrolidinyl]-6,8-difluoro-1,4-dihydro-4-oxo-3-quinoline- carboxylic acids (N1 analogues of CI-934) were synthesized and evaluated for antibacterial activity and DNA-gyrase inhibition. Correlations between the inhibition of DNA gyrase and antibacterial potency were established. A quantitative structure-activity relationship (QSAR) was derived by using the antibacterial potency for each of 11 strains of bacteria and the Gram-negative mean. The equations indicated that antibacterial potency was strongly dependent on STERIMOL length and width and the level of unsaturation of the N1 substituent. Some strains also showed a dependence on the presence of heteroatoms (O, N, S) in the N1 group. No significant correlations between gyrase inhibition and combinations of these parameters were found. These QSAR results are discussed in conjunction with the conformational analyses from molecular modeling studies. The substituent that most enhanced the activity of the quinolone in all regards was the cyclopropyl group. This analogue, 1-cyclopropyl-7-[3-[(ethylamino)-methyl]-1-pyrrolidinyl]-6, 8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (PD 117558), demonstrated outstanding broad spectrum activity both in vitro and in vivo when compared to relevant standards.

The reactions of benzyne with a variety of organic substrates provide excellent undergraduate laboratory experiments. Wittig and Knauss2 have re-

have the proper oxidation potential to reduce the enzyme bound NAD"1" to NADH and, thereby, cause irreversible (KCñt) inhibition of AdoHcy hydrolase.In a separate study, we have reported that compounds 1 and 2 have potent antiviral activity against vaccinia virus, while demonstrating reduced host cell cytotoxicity. 32 The results from this study and others studies10 conducted in our laboratory strongly suggest that AdoHcy hydrolase is the molecular target for the antiviral effects seen with compounds 1 and 2, as well as with NpcA. These data also support the hypothesis of Glazer and Knode21 that the cytotoxicity associated with NpcA, which is reduced in compounds 1 and 2, is in part a result of the formation of NpcATP by adenosine kinase and its conversion to NpcMet by AdoMet synthetase.

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