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Molecules 2014, 19(1), 651-671; doi:10.3390/molecules19010651
Article

N-Substituted 5-Amino-6-methylpyrazine-2,3-dicarbonitriles: Microwave-Assisted Synthesis and Biological Properties

1,* , 1
, 2
, 3
, 4
, 5
, 6
, 6
 and 7
1 Department of Medicinal Chemistry and Drug Analysis, Faculty of Pharmacy, Charles University in Prague, Heyrovskeho 1203, Hradec Kralove 50005, Czech Republic 2 Department of Biological and Medical Sciences, Faculty of Pharmacy, Charles University in Prague, Heyrovskeho 1203, Hradec Kralove 50005, Czech Republic 3 Department of Biophysics and Physical Chemistry, Faculty of Pharmacy, Charles University in Prague, Heyrovskeho 1203, Hradec Kralove 50005, Czech Republic 4 Department of Environmental Ecology, Faculty of Natural Sciences, Comenius University, Mlynska Dolina CH-2, Bratislava 842 15, Slovakia 5 Department of Inorganic and Organic Chemistry, Faculty of Pharmacy, Charles University in Prague, Heyrovskeho 1203, Hradec Kralove 50005, Czech Republic 6 Department of Biological Sciences, Cork Institute of Technology, Bishopstown, Cork, Ireland 7 Institute of Chemistry, Faculty of Natural Sciences, Comenius University, Mlynska Dolina CH-2, Bratislava 842 15, Slovakia
* Author to whom correspondence should be addressed.
Received: 2 December 2013 / Revised: 29 December 2013 / Accepted: 31 December 2013 / Published: 7 January 2014
(This article belongs to the Section Medicinal Chemistry)
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Abstract

In this work a series of 15 N-benzylamine substituted 5-amino-6-methyl-pyrazine-2,3-dicarbonitriles was prepared by the aminodehalogenation reactions using microwave assisted synthesis with experimentally set and proven conditions. This approach for the aminodehalogenation reaction was chosen due to its higher yields and shorter reaction times. The products of this reaction were characterized by IR, NMR and other analytical data. The compounds were evaluated for their antibacterial, antifungal and herbicidal activity. Compounds 3 (R = 3,4-Cl), 9 (R = 2-Cl) and 11 (R = 4-CF3) showed good antimycobacterial activity against Mycobacterium tuberculosis (MIC = 6.25 µg/mL). It was found that the lipophilicity is important for antimycobacterial activity and the best substitution on the benzyl moiety of the compounds is a halogen or trifluoromethyl group according to Craig’s plot. The activities against bacteria or fungi were insignificant. The presented compounds also inhibited photosynthetic electron transport in spinach chloroplasts and the IC50 values of the active compounds varied in the range from 16.4 to 487.0 µmol/L. The most active substances were 2 (R = 3-CF3), 3 (R = 3,4-Cl) and 11 (R = 4-CF3). A linear dependence between lipophilicity and herbicidal activity was observed.
Keywords: pyrazinamide derivatives; in vitro biological evaluation; microwave-assisted synthesis; tuberculosis; lipophilicity pyrazinamide derivatives; in vitro biological evaluation; microwave-assisted synthesis; tuberculosis; lipophilicity
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Jandourek, O.; Dolezal, M.; Paterova, P.; Kubicek, V.; Pesko, M.; Kunes, J.; Coffey, A.; Guo, J.; Kralova, K. N-Substituted 5-Amino-6-methylpyrazine-2,3-dicarbonitriles: Microwave-Assisted Synthesis and Biological Properties. Molecules 2014, 19, 651-671.

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