Peptide conjugates of therapeutically used antitubercular isoniazid—design,synthesis and antimycobacterial effect

Tuberculosis (TB) is a bacterial infectious disease caused by Mycobacterium tuberculosis, a slow‐growing, powerful human pathogen which can survive in the host macrophages. In the chemotherapy of such intracellular pathogens it is necessary to achieve relatively high level of the drug in blood to attain therapeutically effective concentration in infected cells, which presumably has several serious side effects on healthy tissues. The elimination of M. tuberculosis from infected phagocytes could be more efficient with target cell‐directed delivery of antituberculars. A particularly promising approach is to conjugate a drug moiety to a peptide based carrier. The conjugates are chemically constructed to target release by hydrolysis (enzymatic and/or chemical) to liberate the active compound. Here we report the synthesis, characterisation and antimycobacterial evaluation of isoniazid (INH) peptide conjugates. As carrier moiety T‐cell epitope of immundominant 16‐kDa protein of M. tuberculosis and tuftsin‐derived peptides were used. To conjugate INH two synthetic methods were developed, where INH was coupled directly to the peptides or through a heterobifunctional reagent. We found that all of the INH conjugates were effective against M. tuberculosis and the minimal inhibitory concentration (MIC) values were comparable to the free INH moiety. Copyright © 2009 European Peptide Society and John Wiley & Sons, Ltd.