2. Academic Validation
  3. Design, synthesis and biological evaluation of substituted 3-amino-N-(thiazol-2-yl)pyrazine-2-carboxamides as inhibitors of mycobacterial methionine aminopeptidase 1

Design, synthesis and biological evaluation of substituted 3-amino-N-(thiazol-2-yl)pyrazine-2-carboxamides as inhibitors of mycobacterial methionine aminopeptidase 1

  • Bioorg Chem. 2022 Jan;118:105489. doi: 10.1016/j.bioorg.2021.105489.
Martin Juhás 1,  Vinod S K Pallabothula 2,  Katarina Grabrijan 3,  Martina Šimovičová 4,  Ondřej Janďourek 5,  Klára Konečná 6,  Pavel Bárta 7,  Pavla Paterová 8,  Stanislav Gobec 9,  Izidor Sosič 10,  Jan Zitko 11
Affiliations

Affiliations

  • 1 Charles University, Faculty of Pharmacy in Hradec Králové, Akademika Heyrovského 1203, 500 05 Hradec Králové, Czech Republic. Electronic address: [email protected].
  • 2 Charles University, Faculty of Pharmacy in Hradec Králové, Akademika Heyrovského 1203, 500 05 Hradec Králové, Czech Republic. Electronic address: [email protected].
  • 3 University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, SI-1000 Ljubljana, Slovenia. Electronic address: [email protected].
  • 4 Charles University, Faculty of Pharmacy in Hradec Králové, Akademika Heyrovského 1203, 500 05 Hradec Králové, Czech Republic. Electronic address: [email protected].
  • 5 Charles University, Faculty of Pharmacy in Hradec Králové, Akademika Heyrovského 1203, 500 05 Hradec Králové, Czech Republic. Electronic address: [email protected].
  • 6 Charles University, Faculty of Pharmacy in Hradec Králové, Akademika Heyrovského 1203, 500 05 Hradec Králové, Czech Republic. Electronic address: [email protected].
  • 7 Charles University, Faculty of Pharmacy in Hradec Králové, Akademika Heyrovského 1203, 500 05 Hradec Králové, Czech Republic. Electronic address: [email protected].
  • 8 University Hospital Hradec Králové, Department of Clinical Microbiology, Sokolská 581, 500 05 Hradec Králové, Czech Republic. Electronic address: [email protected].
  • 9 University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, SI-1000 Ljubljana, Slovenia. Electronic address: [email protected].
  • 10 University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, SI-1000 Ljubljana, Slovenia. Electronic address: [email protected].
  • 11 Charles University, Faculty of Pharmacy in Hradec Králové, Akademika Heyrovského 1203, 500 05 Hradec Králové, Czech Republic. Electronic address: [email protected].
PMID: 34826708 DOI: 10.1016/j.bioorg.2021.105489
Abstract

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb) is the number one cause of deaths due to a single infectious agent worldwide. The treatment of TB is lengthy and often complicated by the increasing drug resistance. New compounds with new mechanisms of action are therefore needed. We present the design, synthesis, and biological evaluation of pyrazine-based inhibitors of a prominent antimycobacterial drug target - mycobacterial methionine Aminopeptidase 1 (MtMetAP1). The inhibitory activities of the presented compounds were evaluated against the MtMetAP1a isoform, and all derivatives were tested against a broad spectrum of myco(bacteria) and fungi. The cytotoxicity of the compounds was also investigated using Hep G2 cell lines. Overall, high inhibition of the isolated Enzyme was observed for 3-substituted N-(thiazol-2-yl)pyrazine-2-carboxamides, particularly when the substituent was represented by 2-substituted benzamide. The extent of inhibition was strongly dependent on the used metal cofactor. The highest inhibition was seen in the presence of Ni2+. Several compounds also showed mediocre in vitro potency against Mtb (both Mtb H37Ra and H37Rv). Despite the structural similarities of Bacterial and Fungal MetAP1 to mycobacterial MtMetAP1, title compounds did not exert Antibacterial nor Antifungal activity. The reasons behind the higher activity of 2-substituted benzamido derivatives, as well as the correlation of Enzyme inhibition with the in vitro growth inhibition activity is discussed.

Keywords

Aminothiazole; Antimycobacterial; Enzyme inhibition; Methionine aminopeptidase 1; Pyrazine.

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