The directed synthesis of anti-tubercular quinolones targeted against M. tuberculosis gyrase and featuring amino acid or peptide side chains for enhanced uptake, represent an attractive approach to developing potent, clinically useful, anti-tubercular agents. Quinolones with broad spectrum activity do show modest, but potentially clinically useful, activity against both sensitive and multiple drug resistant M. tuberculosis. Thus, quinolones do represent another means of chemotherapeutic intervention in active tuberculosis. There has not been any effort directed solely towards identifying the structural features of quinolones which may enhance their anti-tubercular activity. It is the aim of this project to examine the quinolone nucleus with various substitutions to determine which contribute specifically to cellular antitubercular activity. Parke-Davis has in its chemical library over 24OO quinolone examples to accomplish this task. Further and in conjunction with research performed in Projects I and II, M. tuberculosis gyrase will be used in biochemical studies to further optimize the quinolone SAR. Additionally, the concept of facilitated uptake via amino acid or peptide transporters will be addressed by the new synthesis of specific amino acid or peptide prodrugs of optimized quinolones. Parke- Davis has extensive experience in the synthesis of amino acid prodrugs of quinolones to support this effort. Along with these biochemical studies, quinolone resistance mechanisms will be studied in addition to determining the frequency of resistance to these optimized examples. After this optimization process is completed, examples will be tested in in vivo experimentation to determine efficacy and tolerance.
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