Synthesis and biological activity of new salicylanilide N,N-disubstituted carbamates and thiocarbamates

• Published in: Bioorganic & medicinal chemistry Vol. 22; no. 15; pp. 4073 - 4082
• Main Authors: Krátký, Martin, Volková, Marie, Novotná, Eva, Trejtnar, František, Stolaříková, Jiřina, Vinšová, Jarmila
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.08.2014; Elsevier
• Subjects: Anti-Infective Agents - chemical synthesis; Anti-Infective Agents - chemistry; Anti-Infective Agents - pharmacology; Antimicrobial activity; Antimycobacterial activity; Biochemistry & Molecular Biology; Carbamates - chemical synthesis; Carbamates - chemistry; Carbamates - pharmacology; Cell Survival - drug effects; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Cytotoxicity; Fungi - drug effects; Gram-Positive Bacteria - drug effects; Hep G2 Cells; Humans; Isocitrate Lyase - antagonists & inhibitors; Isocitrate Lyase - metabolism; Isocitrate lyase inhibition; Life Sciences & Biomedicine; Methicillin-Resistant Staphylococcus aureus - drug effects; Microbial Sensitivity Tests; Mycobacterium avium - drug effects; Mycobacterium kansasii - drug effects; Pharmacology & Pharmacy; Physical Sciences; Salicylanilide carbamate; Salicylanilide thiocarbamate; Salicylanilides - chemistry; Science & Technology; Structure-Activity Relationship; Thiocarbamates - chemical synthesis; Thiocarbamates - chemistry; Thiocarbamates - pharmacology; Salicylanilide carbamate; Cytotoxicity; Antimicrobial activity; Isocitrate lyase inhibition; Antimycobacterial activity; Salicylanilide thiocarbamate; MYCOBACTERIUM-TUBERCULOSIS; DRUG; ACTIVATION; DESIGN; ESTER PRODRUGS; INHIBITION; RESISTANCE; ISOCITRATE LYASE; AGENTS; DERIVATIVES
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2014.05.064

The development of novel antimicrobial drugs represents a cutting edge research topic. In this study, 20 salicylanilide N,N-disubstituted carbamates and thiocarbamates were designed, synthesised and characterised by IR, 1H NMR and 13C NMR. The compounds were evaluated in vitro as potential antimicrobial agents against Mycobacterium tuberculosis and nontuberculous mycobacteria (Mycobacterium avium and Mycobacterium kansasii) as well as against eight bacterial and fungal strains. Additionally, we investigated the inhibitory effect of these compounds on mycobacterial isocitrate lyase and cellular toxicity. The minimum inhibitory concentrations (MICs) against mycobacteria were from 4μM for thiocarbamates and from 16μM for carbamates. Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus, were inhibited with MICs from 0.49μM by thiocarbamates, whilst Gram-negative bacteria and most of the fungi did not display any significant susceptibility. All (thio)carbamates mildly inhibited isocitrate lyase (up to 22%) at a concentration of 10μM. The (thio)carbamoylation of the parent salicylanilides led to considerably decreased cytotoxicity and thus improved the selectivity indices (up to 175). These values indicate that some derivatives are attractive candidates for future research.