2-Chlorotyrosine and 2-bromotyrosine, as well as the previously reported 2-fluorotyrosine, were synthesized by hydrolysis of the condensation products from the appropriate benzyl bromide and ethyl acetamidomalonate and were compared with the corresponding 3-halotyrosines as growth inhibitors of Escherichia coli 9723, Streptococcus faecalis 8043 and Lactobacillus plantarum 8014. In contrast to the 2- and 3-fluorotyrosines which were equally effective as growth inhibitors, the 2-chloro- and 2-bromotyrosines were much more effective than the 3-chloro- and 3-bromotyrosines in inhibiting the growth of the three microorganisms. For each of the assay organisms, the growth inhibitions of all three 2-halotyrosines were reversed competitively in varying degrees by tyrosine.

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The effects of a chloro substituent upon the microbiological activities of 3-amino-3,4-dihydro-1-hydroxycarbostyril were determined. The 5-, 6-, and 7-chloro analogs were synthesized by reductive cyclizations of the appropriately chloro-substituted o-nitrophenylalanines, while the 8-chloro analog was obtained from the N-trifluoroacetyl-3-chloro-2-nitrophenylalanine ethyl ester. All of these compounds were observed to inhibit the growth of Escherichia coli 9723, Leuconostoc dextranicum 8086, and Lactobacillus plantarum 8014. The relative inhibitory activities of the chloro analogs were 7-Cl greater than 6-Cl greater than 8-Cl greater than 5-Cl in E. coli and 7-Cl greater than 6-Cl greater than 8-Cl = 5-Cl in L. dextranicum and L. plantarum. In each of the three microorganisms, the 7-Cl analog was a more effective growth inhibitor than the parent unsubstituted compound. The growth inhibitory activities of this class of compounds were demonstrated to be much more effective than those of the four corresponding lactams, the 5-, 6-, 7-, and 8-chloro analogs of 3-amino-3,4-dihydrocarbostyril.

Against Enterobacter aerogenes 13048, Serratia marcescens 13880, Klebsiella pneumoniae 10031, Pseudomonas aeruginosa 10145, Escherichia coli 9723, Lactobacillus casei 7469, Lactobacillus plantarum 8014, Leuconostoc dextranicum 8086, and Streptococcus faecalis 8043, the mean minimal inhibitory concentrations of three cyclic hydroxamic acids, 3-amino-3,4-dihydro-1-hydroxycarbostyril, the 6-chloro analog, and the 7-chloro analog, were 0.6, 0.6, and 0.2 ug/ml, and those of the corresponding lactams, 3-amino-3,4-dihydrocarbostyril, the 6-chloro analog, and the 7-chloro analog, were 60, 60, and 6 ug/ml, respectively. Under the same assay conditions the mean minimal inhibitory concentrations of chloramphenicol and kanamycin were both 2 pug/ml. In addition, the cyclic hydroxamic acids but not the lactams inhibited the growth of Candida albicans at miniimal inhibitory concentrations ranging from 20 to 200 pg/ml, at pH 7, as compared with that of amphotericin B, at 2 pg/ml.

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