Biological activity of new aza analogues of quinolones.

A series of novel derivatives of 4H-pyrido[1,2-]pyrimidine, 1,4-dihydro-4-oxo-1,5-naphthyridine and 1,4-dihydro-4-oxo-1,6-naphthyridine were prepared and their biological activity was compared with that of nalidixic acid. The in vitro antibacterial activity of the tested compounds was lower than that of nalidixic acid except for two agents, 1b and 2c, with a higher activity against Enterococcus faecalis. The compounds were tested for their ability to cure four plasmids from two species of Enterobacteriaceae. The derivatives eliminated three plasmids (pKM101, pBR322, F'lac) at one-half or one-quarter of the minimal inhibitory concentration. Plasmid RP4 was unaffected by the treatment. None of these compounds showed better antichloroplast activity than nalidixic acid.

Model-based relationship between physicochemical properties and inhibitory potency of alkylating 2-furylethylenes on yeast glycolysis.

Inhibitory effects of 35 2-furylethylenes, non-specific alkylating agents, on glycolysis in a respiratory mutant of Saccharomyces cerevisiae were correlated with their 1-octanol/water partition coefficients and the rate constants for reaction with 2-mercaptoacetic acid using physiologically based models. The simplest model explaining the data satisfactorily consists of two-step drug-receptor interaction involving reversible formation of a structurally non-specific non-covalent complex stabilized later covalently. The concentration of the free drug in the receptor surroundings was related to its initial concentration in external medium via a simple form of a disposition function constructed on the basis of time hierarchy of passive membrane transport, non-covalent binding to cell constituents and metabolic inactivation of the drug.

Relationships between structure of 5-nitro-2-furylethylenes and their SOS-function-inducing activities in Escherichia coli.

The SOS-function-inducing activities of 36 furylethylenes were characterized in Escherichia coli K12. The induction of the SOS function was assayed by monitoring the beta-galactosidase activity in the sulA::lacZ fusion strain PQ 37. To correct for the inhibitory effects of test compounds on mRNA or protein synthesis, the level of the constitutive alkaline phosphatase was assayed in parallel. Tested furylethylenes included nine alkylesters and eleven N-alkylamides of 5-nitro-2-furylacrylic acid (NFAA) and fourteen derivatives differing not only in substituents at exocyclic double bond, but also in the position 5 of the furan ring. The induction of the SOS-function by the derivatives depends on the presence of 5-nitrofuran centre in their molecule; side chains in the position 2 modify the degree of SOS response. SOS-inducing potency of n-alkyl congeners decreases with increasing lipophilicity. Effect of derivatives with branched alkyl substituents is lower than expected from the behavior of the n-alkyl homologues. All derivatives with positive effect on SOS-function in E. coli show mutagenic activity on Salmonella typhimurium TA98 in Ames test.

Structure-mutagenicity relationships of 5-nitro-2-furylethylenes in Salmonella typhimurium TA98.

Mutagenicity of three selected series of 2-furylethylene was determined by the Ames test. These included: nine alkylesters and eleven N-alkylamides of 5-nitro-2-furylacrylic acid (NFAA) and ten derivatives differing not only at exocyclic double bond, but also in the position 5 of the furan ring. Mutagenicity of the derivatives depends on the presence of the 5-nitro-furan centre in the molecule; side chains in the position 2 modify the degree of mutagenicity. Among the derivatives of NFAA tested as changing the substituents virtually does not affect chemical properties of the 5-nitrofuran ring. Mutagenicity of the n-alkyl congeners decreases linearly with increasing lipophilicity. Mutagenicity of the derivatives with branched alkyl substituents is lower than expected from the behaviour of the n-alkyl homologues.

Antimicrobial activity of methyl esters and nitriles of 2-cyano-3-(5'-R-2'-furyl)propenic acid.

Derivatives of 2-cyano-3-(2'-furyl)propenic acid with a markedly polarized double bond inhibit the growth of Chlorella pyrenoidosa, Saccharomyces cerevisiae, Candida albicans and Aspergillus niger at concentrations above 40 mumol/L. Their antibacterial activity (Escherichia coli B, Bacillus subtilis) is low. The biological effect increases with an increasing electron acceptor effect and decreasing hydrophobicity of the substituent on the furan ring. Substitution of methoxycarbony] group with cyano group in position 1 slightly increases the biological activity.