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

Abstract

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 l-amino acids. Similarly, the activity seems tied to the more lipophilic compounds. The most active derivative contained phenylglycine moiety (PC-d/l-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 d- and l-amino acid derivatives of pyrazinamide as potential antimycobacterial compounds.

Improving Antimicrobial Activity and Physico-Chemical Properties by Isosteric Replacement of 2-Aminothiazole with 2-Aminooxazole

“…Antimicrobial activity and cytotoxicity screenings were performed as published previously [ 24 , 56 ]. The full description of the used methodology is available in the Supplementary Materials .…”

Synthesis, Biological Evaluation, and In Silico Modeling of N-Substituted Quinoxaline-2-Carboxamides

“…In compound 20, the extended linker (extra methylene group) caused the deviation in the position of the quinoxaline core, which led to the loss of interaction with Arg325. This unfavorable shift was observed for all docked poses of title compounds with the extended linker (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31).…”

“…†† Selectivity index (SI) = IC 50 (µM)/MIC Mtb H37Ra (µM). ††† PZA is inactive at pH 6.6 (pH of testing medium), activity is observed in acidic medium (MIC at pH of 6 is <3.91 µg/mL) [ 16 ]. * Structure of compound 6 .…”

“…Based on the observed whole-cell antimycobacterial activity (Table 1), we chose compound 2 as a representative of the N-phenyl subseries (1-14, excl. 6) and compound 20 as a representative of the N-benzyl series (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31). These prototypic compounds were docked into mycobacterial DprE1 (pdb id: 4P8N).…”