Tuberculosis is caused by Mycobacterium tuberculosis, an intracellular pathogen that can survive in host cells, mainly in macrophages. An increase of multidrug-resistant tuberculosis qualifies this infectious disease as a major public health problem worldwide. The cellular uptake of the antimycobacterial agents by infected host cells is limited. Our approach is to enhance the cellular uptake of the antituberculars by target cell-directed delivery using drug-peptide conjugates to achieve an increased intracellular efficacy. In this study, salicylanilide derivatives (2-hydroxy-N-phenylbenzamides) with remarkable antimycobacterial activity were conjugated to macrophage receptor specific tuftsin based peptide carriers through oxime bond directly or by insertion of a GFLG tetrapeptide spacer. We have found that the in vitro antimycobacterial activity of the salicylanilides against M. tuberculosis H37Rv is preserved in the conjugates. While the free drug was ineffective on infected macrophage model, the conjugates were active against the intracellular bacteria. The fluorescently labelled peptide carriers that were modified with different fatty acid side chains showed outstanding cellular uptake rate to the macrophage model cells. The conjugation of the salicylanilides to tuftsin based carriers reduced or abolished the in vitro cytostatic activity of the free drugs with the exception of the palmitoylated conjugates. The conjugates degraded in the presence of rat liver lysosomal homogenate leading to the formation of an oxime bond-linked salicylanilide-amino acid fragment as the smallest active metabolite.

Department of Organic and Bioorganic Chemistry Faculty of Pharmacy Charles University Heyrovského 1203 500 05 Hradec Králové Czech Republic

Laboratory for Mycobacterial Diagnostics and Tuberculosis Regional Institute of Public Health in Ostrava Partyzánské náměstí 7 702 00 Ostrava Czech Republic

Laboratory of Bacteriology Korányi National Institute for Tuberculosis and Respiratory Medicine Pihenő út 1 Budapest H 1122 Hungary

MTA ELTE Research Group of Peptide Chemistry Pázmány Péter sétány 1 A P O Box 32 1518 H 1117 Budapest 112 Hungary

MTA ELTE Research Group of Peptide Chemistry Pázmány Péter sétány 1 A P O Box 32 1518 H 1117 Budapest 112 Hungary; Laboratory of Bacteriology Korányi National Institute for Tuberculosis and Respiratory Medicine Pihenő út 1 Budapest H 1122 Hungary

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New Salicylanilide Derivatives and Their Peptide Conjugates as Anticancer Compounds: Synthesis, Characterization, and In Vitro Effect on Glioblastoma