ABSTRACT
Guided by the metabolism information of SQ109, derivatives with substituted geranylamine moiety or substituted admantane ring of SQ109 were synthesized and evaluated as antituberculosis agents. Among all tested compounds, compound 11c showed the most potent antituberculosis activity with MIC value of 0.3 microM against Mycobacterium tuberculosis H37Rv.
Subject(s)
Antitubercular Agents/chemistry , Antitubercular Agents/pharmacology , Diamines/chemistry , Diamines/pharmacology , Mycobacterium tuberculosis/drug effects , Antitubercular Agents/chemical synthesis , Diamines/chemical synthesis , Microbial Sensitivity Tests , Structure-Activity Relationship , Tuberculosis/drug therapyABSTRACT
The low bioavailability of SQ109 in rats, resulting from first-pass effect in the liver, may be remedied by prodrug strategy. Based on esterase-sensitive carbamate prodrug strategy, a novel series of prodrugs of SQ109 has been reported. Bioavailability of SQ109 after administration of prodrug 7a was 91.4% compared with 21.4% after oral administration of SQ109. After oral administration of compound 7a, the parent drug SQ109 exhibited preferential tissue distribution into lung and spleen, the target organs of tubercular infection and replication.
