In vitro biological evaluation of new antimycobacterial salicylanilide-tuftsin conjugates

• Published in: European journal of medicinal chemistry Vol. 133; pp. 152 - 173
• Main Authors: Baranyai, Zsuzsa, Kratky, Martin, Vosatka, Rudolf, Szabo, Eleonora, Senoner, Zsuzsanna, David, Sandor, Stolarikova, Jitina, Vinsova, Jarmila, Bosze, Szilvia
• Format: Journal Article
• Language: English
• Published: PARIS Elsevier 16.06.2017
• Subjects: Animals; Antitubercular Agents - chemistry; Antitubercular Agents - pharmacokinetics; Antitubercular Agents - pharmacology; Cell Line; Chemistry, Medicinal; Humans; Life Sciences & Biomedicine; Mycobacterium - drug effects; Mycobacterium Infections - drug therapy; Mycobacterium tuberculosis - drug effects; Pharmacology & Pharmacy; Rats; Salicylanilides - chemistry; Salicylanilides - pharmacokinetics; Salicylanilides - pharmacology; Science & Technology; Tuberculosis - drug therapy; Tuberculosis, Multidrug-Resistant - drug therapy; Tuftsin - analogs & derivatives; Tuftsin - pharmacokinetics; Tuftsin - pharmacology; MYCOBACTERIUM-TUBERCULOSIS; LIQUID MEDIUM; DRUG-DELIVERY; Intracellular bacteria; SIMPLE CULTURE TECHNIQUE; RECEPTOR; Fatty acid side chain; FATTY-ACIDS; PHAGOCYTOSIS STIMULATING PEPTIDE; Cellular uptake; Tuftsin based carrier; Salicylanilide; ISOCITRATE LYASE; LIPOPEPTIDE CONJUGATE; Antimycobacterial activity; CELL-LINE
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2017.03.047

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 H(37)Rv 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. (C) 2017 Published by Elsevier Masson SAS.