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Design, synthesis and biological evaluation of substituted 3-amino-N-(thiazol-2-yl)pyrazine-2-carboxamides as inhibitors of mycobacterial methionine aminopeptidase 1Juhás, Martin ...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 derivatives, as well as the correlation of enzyme inhibition with the in vitro growth inhibition activity is discussed.Source: Bioorganic chemistry. - ISSN 0045-2068 (Vol. 118, 2022, str. 1-9)Type of material - article, component part ; adult, seriousPublish date - 2022Language - englishCOBISS.SI-ID - 84883715
Author
Juhás, Martin |
Pallabothula S. K., Vinod |
Grabrijan, Katarina |
Šimovičová, Martina |
Janďourek, Ondřej |
Konečná, Klára |
Bárta, Pavel |
Gobec, Stanislav, 1970- |
Sosič, Izidor |
Zitko, Jan
Topics
Bakterijska rezistenca |
Tuberkuloza |
aminothiazole |
antimycobacterial |
enzyme inhibition |
methionine aminopeptidase 1 |
pyrazine |
aminotiazol |
antimikobakterijsko delovanje |
inhibicija encimov |
metionin aminopeptidaza 1 |
pirazin
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Database name | Field | Year |
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Links to authors' personal bibliographies | Links to information on researchers in the SICRIS system |
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Juhás, Martin | |
Pallabothula S. K., Vinod | |
Grabrijan, Katarina | 50814 |
Šimovičová, Martina | |
Janďourek, Ondřej | |
Konečná, Klára | |
Bárta, Pavel | |
Gobec, Stanislav, 1970- | 15284 |
Sosič, Izidor | 30816 |
Zitko, Jan |
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