IN VITRO ACTIVITY OF CEPHALOSPORINS AGAINST MYCOBACTERIUM TUBERCULOSIS H37Rv: STRUCTURE-ACTIVITY RELATIONSHIPS

Abstract

Over 600 derivatives of cephalosporin C were screened for activity against Mycobacterium tuberculosis H37Rv by a 2-fold broth dilution method using DUBOS liquid medium. Among the most active derivatives were those in which a pyridyl or an aminomethylphenyl moiety was present in the 7-side chain. Structure-activity relationships have been determined for a number of such compounds of which 34 were considered in this report. In the pyridyl series, consideration was given to the effect on activity of the position of the nitrogen in the pyridine ring, N-alkylation and halogenation of this ring system, as well as the influence of a sulfur or an amino bridge in the 7-side chain. The most active derivative in the pyridyl series was a chlorinated analogue of cephapirin, 7-[(2, 6-dichloropyrid-4-yl) thioacetamido] cephalosporanic acid, whose minimal inhibitory concentration of 1.4 μg/ml was 10 times less than that of cephapirin and only twice that of dihydrostreptomycin. Several other derivatives in the pyridyl series whose activity was comparable to that of the chlorinated analogue of cephapirin had pyrid-4-ylaminoacetamido or 4-aminopyrid-l-ylacetamido 7-side chains. Relationships considered in the aminomethylphenyl series were the effect on activity of the position of the aminomethyl group on the phenyl ring, the presence or absence of a sulfur bridge in the 7-side chain, as well as the influence of substitutions of heterocyclic-thiomethyl groups for the acetoxymethyl moiety at the 3-position. All derivatives in this series having activity comparable to that of the chlorinated analogue of cephapirin contained an o-aminomethylphenylacetamido side chain at the 7-position.