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.
Highlights
Mycobacterium tuberculosis is counted with justification among the most dangerous and successful microorganisms in today’s world, especially in developing countries which have become the reservoir of resistant strains [1]
The starting compound 5-chloro-6-methylpyrazine-2,3-dicarbonitrile and the final compounds 1–15 were synthesized according to the general procedure shown in Scheme 1
The aminodehalogenation reaction of this starting compound and ring-substituted benzylamines yielded a series of 15 secondary amines of which 14 were novel. 5-(Benzylamino)-6-methylpyrazine-2,3-dicarbonitrile (6) was previously synthesised by Takematsu et al and the reported melting point was 118–119 °C [30]
Summary
Mycobacterium tuberculosis is counted with justification among the most dangerous and successful microorganisms in today’s world, especially in developing countries which have become the reservoir of resistant strains (the most burdened countries are in South Africa and East Asia) [1]. This leads to inhibition of membrane transport and to cellular death [6,7,8] The gene encoding this enzyme is called pncA gene and its mutation is responsible for the origin of mycobacterial resistance to PZA [9]. Recent research has suggested a novel mechanism of action of PZA - inhibition of trans-translation This process is vital for survival and virulence of Mycobacteria and its inhibition leads to blockage of the proteosynthetic apparatus in ribosomes and to cellular death. The site of action of these PET inhibitors in the photosynthetic apparatus was situated predominantly on the donor side of PS2, in the section between oxygen evolving complex and intermediate D , i.e., tyrosine radical (TyrD) occurring on the 161st position in D2 protein These compounds can be considered as PS2 herbicides which could have adverse effect on plant growth. The structure-activity relationships between the chemical structure and in vitro biological activities of evaluated compounds are discussed
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