Antimicrobial drug resistance is currently one of the most critical health issues. Pathogens resistant to last-resort antibiotics are increasing, and very few effective antibacterial agents have been introduced in recent years. The promising drug candidates are often discontinued in the primary stages of the drug discovery pipeline due to their unspecific reactivity (PAINS), toxicity, insufficient stability, or low water solubility. In this work, we investigated a series of substituted N-oxazolyl- and N-thiazolylcarboxamides of various pyridinecarboxylic acids. Final compounds were tested against several microbial species. In general, oxazole-containing compounds showed high activity against mycobacteria, especially Mycobacterium tuberculosis (best MICH37Ra = 3.13 µg/mL), including the multidrug-resistant strains. Promising activities against various bacterial and fungal strains were also observed. None of the compounds was significantly cytotoxic against the HepG2 cell line. Experimental measurement of lipophilicity parameter log k'w and water solubility (log S) confirmed significantly (typically two orders in logarithmic scale) increased hydrophilicity/water solubility of oxazole derivatives in comparison with their thiazole isosteres. Mycobacterial β-ketoacyl-acyl carrier protein synthase III (FabH) was suggested as a probable target by molecular docking and molecular dynamics simulations.

• Keywords
• aminooxazole, aminothiazole, antimycobacterial activity, docking, isostere, molecular docking, molecular dynamics, pyridine, water solubility,
• Publication type
• Journal Article MeSH

Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis (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, M. smegmatis, M. aurum, Staphylococcus aureus, Pseudomonas aeruginosa, and fungal strains, including Candida albicans and Aspergillus flavus. 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.

• Keywords
• amino acids, antibacterial, antimycobacterial, cytotoxicity, pyrazinamide, tuberculosis,
• MeSH
• Amino Acids chemistry   pharmacology   MeSH
• Anti-Bacterial Agents pharmacology   MeSH
• Antitubercular Agents pharmacology   MeSH
• Aspergillus flavus drug effects   MeSH
• Hep G2 Cells MeSH
• Candida albicans drug effects   MeSH
• Chromatography, Liquid MeSH
• Hydrogen-Ion Concentration MeSH
• Humans MeSH
• Magnetic Resonance Spectroscopy MeSH
• Microbial Sensitivity Tests MeSH
• Mycobacterium smegmatis drug effects   MeSH
• Mycobacterium tuberculosis drug effects   MeSH
• Optical Rotation MeSH
• Gas Chromatography-Mass Spectrometry MeSH
• Pseudomonas aeruginosa drug effects   MeSH
• Pyrazinamide chemistry   pharmacology   MeSH
• Staphylococcus aureus drug effects   MeSH
• Tuberculosis drug therapy   MeSH
• Cell Survival drug effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Amino Acids MeSH
• Anti-Bacterial Agents MeSH
• Antitubercular Agents MeSH
• Pyrazinamide MeSH