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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 1. 2022

Martin Juhás, and Vinod S K Pallabothula, and Katarina Grabrijan, and Martina Šimovičová, and Ondřej Janďourek, and Klára Konečná, and Pavel Bárta, and Pavla Paterová, and Stanislav Gobec, and Izidor Sosič, and Jan Zitko
Charles University, Faculty of Pharmacy in Hradec Králové, Akademika Heyrovského 1203, 500 05 Hradec Králové, Czech Republic. Electronic address: juhasm@faf.cuni.cz.

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.

UI MeSH Term Description Entries
D008826 Microbial Sensitivity Tests Any tests that demonstrate the relative efficacy of different chemotherapeutic agents against specific microorganisms (i.e., bacteria, fungi, viruses). Bacterial Sensitivity Tests,Drug Sensitivity Assay, Microbial,Minimum Inhibitory Concentration,Antibacterial Susceptibility Breakpoint Determination,Antibiogram,Antimicrobial Susceptibility Breakpoint Determination,Bacterial Sensitivity Test,Breakpoint Determination, Antibacterial Susceptibility,Breakpoint Determination, Antimicrobial Susceptibility,Fungal Drug Sensitivity Tests,Fungus Drug Sensitivity Tests,Sensitivity Test, Bacterial,Sensitivity Tests, Bacterial,Test, Bacterial Sensitivity,Tests, Bacterial Sensitivity,Viral Drug Sensitivity Tests,Virus Drug Sensitivity Tests,Antibiograms,Concentration, Minimum Inhibitory,Concentrations, Minimum Inhibitory,Inhibitory Concentration, Minimum,Inhibitory Concentrations, Minimum,Microbial Sensitivity Test,Minimum Inhibitory Concentrations,Sensitivity Test, Microbial,Sensitivity Tests, Microbial,Test, Microbial Sensitivity,Tests, Microbial Sensitivity
D009169 Mycobacterium tuberculosis A species of gram-positive, aerobic bacteria that produces TUBERCULOSIS in humans, other primates, CATTLE; DOGS; and some other animals which have contact with humans. Growth tends to be in serpentine, cordlike masses in which the bacilli show a parallel orientation. Mycobacterium tuberculosis H37Rv
D011719 Pyrazines A heterocyclic aromatic organic compound with the chemical formula C4H4N2. Pyrazine
D004305 Dose-Response Relationship, Drug The relationship between the dose of an administered drug and the response of the organism to the drug. Dose Response Relationship, Drug,Dose-Response Relationships, Drug,Drug Dose-Response Relationship,Drug Dose-Response Relationships,Relationship, Drug Dose-Response,Relationships, Drug Dose-Response
D004791 Enzyme Inhibitors Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. Enzyme Inhibitor,Inhibitor, Enzyme,Inhibitors, Enzyme
D000626 Aminopeptidases A subclass of EXOPEPTIDASES that act on the free N terminus end of a polypeptide liberating a single amino acid residue. EC 3.4.11. Aminopeptidase
D000995 Antitubercular Agents Drugs used in the treatment of tuberculosis. They are divided into two main classes: "first-line" agents, those with the greatest efficacy and acceptable degrees of toxicity used successfully in the great majority of cases; and "second-line" drugs used in drug-resistant cases or those in which some other patient-related condition has compromised the effectiveness of primary therapy. Anti-Tuberculosis Agent,Anti-Tuberculosis Agents,Anti-Tuberculosis Drug,Anti-Tuberculosis Drugs,Antitubercular Agent,Antitubercular Drug,Tuberculostatic Agent,Tuberculostatic Agents,Antitubercular Drugs,Agent, Anti-Tuberculosis,Agent, Antitubercular,Agent, Tuberculostatic,Anti Tuberculosis Agent,Anti Tuberculosis Agents,Anti Tuberculosis Drug,Anti Tuberculosis Drugs,Drug, Anti-Tuberculosis,Drug, Antitubercular
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D015195 Drug Design The molecular designing of drugs for specific purposes (such as DNA-binding, enzyme inhibition, anti-cancer efficacy, etc.) based on knowledge of molecular properties such as activity of functional groups, molecular geometry, and electronic structure, and also on information cataloged on analogous molecules. Drug design is generally computer-assisted molecular modeling and does not include PHARMACOKINETICS, dosage analysis, or drug administration analysis. Computer-Aided Drug Design,Computerized Drug Design,Drug Modeling,Pharmaceutical Design,Computer Aided Drug Design,Computer-Aided Drug Designs,Computerized Drug Designs,Design, Pharmaceutical,Drug Design, Computer-Aided,Drug Design, Computerized,Drug Designs,Drug Modelings,Pharmaceutical Designs
D015394 Molecular Structure The location of the atoms, groups or ions relative to one another in a molecule, as well as the number, type and location of covalent bonds. Structure, Molecular,Molecular Structures,Structures, Molecular

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