N -Pyrazinoyl Substituted Amino Acids as Potential Antimycobacterial Agents-The Synthesis and Biological Evaluation of Enantiomers

• Published in: Molecules (Basel, Switzerland) Switzerland), 2020-03, Vol.25 (7), p.1518
• Main Authors: Juhás, Martin, Kučerová, Lucie, Horáček, Ondřej, Janďourek, Ondřej, Kubíček, Vladimír, Konečná, Klára, Kučera, Radim, Bárta, Pavel, Janoušek, Jiří, Paterová, Pavla, Kuneš, Jiří, Doležal, Martin, Zitko, Jan
• Format: Article
• Language: English
• Subjects: amino acids; Amino Acids - chemistry; Amino Acids - pharmacology; Anti-Bacterial Agents - pharmacology; antibacterial; antimycobacterial; Antitubercular Agents - pharmacology; Aspergillus flavus - drug effects; Candida albicans - drug effects; Cell Survival - drug effects; Chromatography, Liquid; cytotoxicity; Gas Chromatography-Mass Spectrometry; Hep G2 Cells; Humans; Hydrogen-Ion Concentration; Magnetic Resonance Spectroscopy; Microbial Sensitivity Tests; Mycobacterium smegmatis - drug effects; Mycobacterium tuberculosis - drug effects; Optical Rotation; Pseudomonas aeruginosa - drug effects; pyrazinamide; Pyrazinamide - chemistry; Pyrazinamide - pharmacology; Staphylococcus aureus - drug effects; tuberculosis; Tuberculosis - drug therapy
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules25071518

Tuberculosis is an infectious disease caused by (Mtb), each year causing millions of deaths. In this article, we present the synthesis and biological evaluations of new potential antimycobacterial compounds containing a fragment of the first-line antitubercular drug pyrazinamide (PZA), coupled with methyl or ethyl esters of selected amino acids. The antimicrobial activity was evaluated on a variety of (myco)bacterial strains, including Mtb H37Ra , and fungal strains, including and . Emphasis was placed on the comparison of enantiomer activities. None of the synthesized compounds showed any significant activity against fungal strains, and their antibacterial activities were also low, the best minimum inhibitory concentration (MIC) value was 31.25 µM. However, several compounds presented high activity against Mtb. Overall, higher activity was seen in derivatives containing ʟ-amino acids. Similarly, the activity seems tied to the more lipophilic compounds. The most active derivative contained phenylglycine moiety (PC-ᴅ/ʟ-Pgl-Me, MIC < 1.95 µg/mL). All active compounds possessed low cytotoxicity and good selectivity towards Mtb. To the best of our knowledge, this is the first study comparing the activities of the ᴅ- and ʟ-amino acid derivatives of pyrazinamide as potential antimycobacterial compounds.