Synthesis of Novel Pyrazinamide Derivatives Based on 3-Chloropyrazine-2-carboxamide and Their Antimicrobial Evaluation

Abstract

Aminodehalogenation of 3-chloropyrazine-2-carboxamide with variously substituted benzylamines yielded a series of fifteen 3-benzylaminopyrazine-2-carboxamides. Four compounds possessed in vitro whole cell activity against Mycobacterium tuberculosis H37Rv that was at least equivalent to that of the standard pyrazinamide. MIC values ranged from 6 to 42 µM. The best MIC (6 µM) was displayed by 3-[(4-methylbenzyl)amino]pyrazine-2-carboxamide (8) that also showed low cytotoxicity in the HepG2 cell line (IC50 ≥ 250 µM). Only moderate activity against Enterococcus faecalis and Staphylococcus aureus was observed. No activity was detected against any of tested fungal strains. Molecular docking with mycobacterial enoyl-ACP reductase (InhA) was performed to investigate the possible target of the prepared compounds. Active compounds shared common binding interactions of known InhA inhibitors. Antimycobacterial activity of the title compounds was compared to the previously published benzylamino-substituted pyrazines with differing substitution on the pyrazine core (carbonitrile moiety). The title series possessed comparable activity and lower cytotoxicity than molecules containing a carbonitrile group on the pyrazine ring.

Towards Novel 3-Aminopyrazinamide-Based Prolyl-tRNA Synthetase Inhibitors: In Silico Modelling, Thermal Shift Assay and Structural Studies

“…Both in the confirmed inhibitor 2a (crystallographic structure) and in our compounds of general structure 3, the substituent on the C2-carboxamide group exerts only non-specific hydrophobic interactions to the enzyme. For this reason, we also focused on our in-house derivatives of general structure 4 with an unsubstituted C2-carboxamide group [17]. For these, we generally observed worse docking scores (as expected because of the lower number of heavy atoms due to the lack of the substituent on the C2-carboxamide) and more flexibility in terms of different binding modes.…”

“…Pyrazinamide (PZA) is a clinically validated first-line antitubercular drug for the clinical treatment of active Mycobacterium tuberculosis infections and has also been considered as a bioactive chemical scaffold used for various chemical modifications [17][18][19][20][21][22]. Zitko's group reported a large series of pyrazinamide derivatives as part of efforts for the development of new antimicrobials, especially as antimycobacterial drugs [17,18]. The in-house library contains a series of 3-substituted-N-benzylpyrazine-2-carboxamide derivatives, which share high structural similarity with confirmed HcProRS inhibitor 2a.…”

Synthesis, Characterization and Antibacterial Evaluation of Some Azole Derivatives

“…Yield 68%; mp 140-142˚C; IR (KBr) cm tube was measured at 630 nm and compared with standard ampicillin. 25…”

Study The Effect of Factors on the Rate Constant (K) for Some Substituted Benzyl-amine Using Theoretical Calculations

“…Inter and intramolecular hydrogen bonding have been characterized [21]. Benzyl-amine was used to synthesize of compounds [22,23] which applied clinically to development of the anti-bacterial drugs [24][25][26]. Zeroorder kinetic was noticed in the hydrogenolysis of benzyl-amine which lead to adsorption of this compound at the surface [27].…”