Abstract
A series of 18 N-alkyl substituted 3-aminopyrazine-2-carboxamides was prepared in this work according to previously experimentally set and proven conditions using microwave assisted synthesis methodology. This approach for the aminodehalogenation reaction was chosen due to higher yields and shorter reaction times compared to organic reactions with conventional heating. Antimycobacterial, antibacterial, antifungal and photosynthetic electron transport (PET) inhibiting in vitro activities of these compounds were investigated. Experiments for the determination of lipophilicity were also performed. Only a small number of substances with alicyclic side chain showed activity against fungi which was the same or higher than standards and the biological efficacy of the compounds increased with rising lipophilicity. Nine pyrazinamide derivatives also inhibited PET in spinach chloroplasts and the IC50 values of these compounds varied in the range from 14.3 to 1590.0 μmol/L. The inhibitory activity was connected not only with the lipophilicity, but also with the presence of secondary amine fragment bounded to the pyrazine ring. Structure-activity relationships are discussed as well.
Highlights
Pyrazinamide (PZA) is considered to be one of the most important drugs in the World
These strains were resistant to all known first- and second-line antituberculosis agents and posed a threat to epidemiologists all over the World. They have practically disappeared with the discovery and approval of the new anti-tuberculosis agent bedaquiline for their therapy because it is active against the resistant Mycobacterium tuberculosis [3]
We focus on the synthesis of pyrazine derivatives with aliphatic or alicyclic side chains and their antimycobacterial, antibacterial, antifungal and photosynthetic electron transport (PET)-inhibiting activities
Summary
Pyrazinamide (PZA) is considered to be one of the most important drugs in the World. It has numerous uses and the pyrazine ring is contained in many natural compounds. PZA is classified as the first-line antituberculotic agent that is unique for its therapeutic properties It acts in acidic environment as a bactericidal sterilising drug that is able to kill the dormant forms of tubercle bacilli, especially in combination with rifampicin. The gene encoding pyrazinamidase is known as pncA gene and its mutation leads to the resistance of mycobacteria to pyrazinamide [8] Another theory propounded the inhibition of fatty acid synthase I (FAS I) (EC 2.3.1.85). A recent theory introduced by Zhang et al proposed the inhibition of trans-translation as the main way of PZA action This cellular process is essential for survival and virulence of mycobacteria and its interruption leads to fatal blockade of proteosynthesis. We focus on the synthesis of pyrazine derivatives with aliphatic or alicyclic side chains and their antimycobacterial, antibacterial, antifungal and PET-inhibiting activities
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