Synthesis and Biological Evaluation of N-Alkyl-3-(alkylamino)-pyrazine-2-carboxamides

Abstract

A series of N-alkyl-3-(alkylamino)pyrazine-2-carboxamides and their N-alkyl-3-chloropyrazine-2-carboxamide precursors were prepared. All compounds were characterized by analytical methods and tested for antimicrobial and antiviral activity. The antimycobacterial MIC values against Mycobacterium tuberculosis H37Rv of the most effective compounds, 3-(hexylamino)-, 3-(heptylamino)- and 3-(octylamino)-N-methyl-pyrazine-2-carboxamides 14‒16, was 25 μg/mL. The compounds inhibited photosystem 2 photosynthetic electron transport (PET) in spinach chloroplasts. This activity was strongly connected with the lipophilicity of the compounds. For effective PET inhibition longer alkyl chains in the 3-(alkylamino) substituent in the N-alkyl-3-(alkylamino)pyrazine-2-carboxamide molecule were more favourable than two shorter alkyl chains.

Keywords: alkylation; aminodehalogenation; antimycobacterial activity; inhibition of photosynthetic electron transport; pyrazinamide; pyrazine; structure-activity relationships.

Scheme 1

Synthesis of final compounds 1–30.

Figure 1

Plot of experimentally measured log k parameter on calculated log P.

Figure 2

Dependence of antimycobacterial activity of tested compounds against M. tuberculosis H37Rv on log k.

Figure 3

Dependence of antifungal activity of tested compounds against T. mentagrophytes on log k.

Figure 4

Dependence of PET-inhibiting activity on lipophilicity of studied compounds expressed as log k.

Figure 5

(A) Fluorescence emission spectra of aromatic amino acids in suspension of spinach chloroplasts without and with compound 16 (c = 0, 10, 25, 49, 74 and 123 μmol/L; the curves from top to bottom); (B) Dependence of intensity of aromatic amino acids fluorescence emission band (expressed as % of control) at 340 nm in suspension of spinach chloroplasts on the concentration of studied compounds: 27 and 16. Excitation wave length λ = 275 nm; chlorophyll concentration 10 mg/L.