3-Substituted N-Benzylpyrazine-2-carboxamide Derivatives: Synthesis, Antimycobacterial and Antibacterial Evaluation.
A series of substitutedN-benzyl-3-chloropyrazine-2-carboxamides were prepared as positional isomers of 5-chloro and 6-chloro derivatives, prepared previously. During the aminolysis of the acyl chloride, the simultaneous substitution of chlorine with benzylamino moiety gave rise toN-benzyl-3-(benzylamino)pyrazine-2-carboxamides as side products, in some cases. Although not initially planned, the reaction conditions were modified to populate this double substituted series. The final compounds were tested against four mycobacterial strains.N-(2-methylbenzyl)-3-((2-methylbenzyl)amino)pyrazine-2-carboxamide (1a) andN-(3,4-dichlorobenzyl)-3-((3,4-dichlorobenzyl)amino)pyrazine-2-carboxamide (9a) proved to be the most effective againstMycobacterium tuberculosisH37Rv, with MIC = 12.5 μg·mL-1. Compounds were screened for antibacterial activity. The most active compound was 3-chloro-N-(2-chlorobenzyl)pyrazine-2-carboxamide (5) againstStaphylococcus aureuswith MIC = 7.81 μM, andStaphylococcus epidermidiswith MIC = 15.62 μM. HepG2 in vitro cytotoxicity was evaluated for the most active compounds; however, no significant toxicity was detected. Compound9awas docked to several conformations of the enoyl-ACP-reductase ofMycobacterium tuberculosis. In some cases, it was capable ofH-bond interactions, typical for most of the known inhibitors.
Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic. semelkol@faf.cuni.cz.
Lucia
L
Semelková
Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic. JANDO6AA@faf.cuni.cz.
Ondřej
O
Janďourek
Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic. konecna@faf.cuni.cz.
Klára
K
Konečná
Department of Clinical Microbiology, University Hospital, Sokolská 581, 500 05 Hradec Králové, Czech Republic. pavla.paterova@fnhk.cz.
Pavla
P
Paterová
Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic. navratl2@faf.cuni.cz.
Lucie
L
Navrátilová
Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic. trejtnarf@faf.cuni.cz.
František
F
Trejtnar
Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic. kubicek@faf.cuni.cz.
Vladimír
V
Kubíček
Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic. kunes@faf.cuni.cz.
Jiří
J
Kuneš
Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic. dolezalm@faf.cuni.cz.
Martin
M
Doležal
Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic. jan.zitko@faf.cuni.cz.
Jan
J
Zitko
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D056945:Hep G2 Cells; D006801:Humans; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D011719:Pyrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects; D013212:Staphylococcus epidermidis / Q000187:drug effects; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D011719:Pyrazines
antibacterial activity; antimycobacterial activity; benzylamines; cytotoxicity; enoyl-ACP-reductase; molecular docking; pyrazinamide derivatives