Abstract
A series of twelve amides was synthesized via aminolysis of substituted pyrazinecarboxylic acid chlorides with substituted benzylamines. Compounds were characterized with analytical data and assayed in vitro for their antimycobacterial, antifungal, antibacterial and photosynthesis-inhibiting activity. 5-tert-Butyl-6-chloro-N-(4-methoxybenzyl)pyrazine-2-carboxamide (12) has shown the highest antimycobacterial activity against Mycobacterium tuberculosis (MIC = 6.25 µg/mL), as well as against other mycobacterial strains. The highest antifungal activity against Trichophyton mentagrophytes, the most susceptible fungal strain tested, was found for 5-chloro-N-(3-trifluoromethylbenzyl)-pyrazine-2-carboxamide (2, MIC = 15.62 µmol/L). None of the studied compounds exhibited any activity against the tested bacterial strains. Except for 5-tert-butyl-6-chloro-N-benzylpyrazine-2-carboxamide (9, IC50 = 7.4 µmol/L) and 5-tert-butyl-6-chloro-N-(4-chlorobenzyl)pyrazine-2-carboxamide (11, IC50 = 13.4 µmol/L), only moderate or weak photosynthesis-inhibiting activity in spinach chloroplasts (Spinacia oleracea L.) was detected.
Highlights
Tuberculosis (TB) is considered to be one of the most frequent and widespread nowadays infectious diseases especially in developing countries
We focused on binuclear pyrazinamide analogues containing the -CONH-CH2- bridge, namely on N-benzylpyrazine-2-carboxamides
A series of twelve binuclear pyrazinamide analogues containing -CONH-CH2- bridges was synthesized by the condensation of substituted pyrazine-2-carboxylic acid chlorides with the corresponding benzylamines
Summary
Tuberculosis (TB) is considered to be one of the most frequent and widespread nowadays infectious diseases especially in developing countries. PZA, as a prodrug that requires bacterial enzymes to generate the biologically active molecule, enters mycobacterial cell via passive diffusion and it is activated by pyrazinamidase/nicotinamidase (EC 3.5.1.19) to form pyrazinoic acid (POA) [5]. The demonstration that PZA and POA inhibit Mycobacterium tuberculosis fatty acid synthase-I (FAS-I) in whole-cell and cell-free assays suggests that the disruption might be a consequence of the inhibition of membrane synthesis [8,9,10]. Reversible binding of both PZA and POA to M. tuberculosis FAS-I has been definitively confirmed by Saturation Transfer Difference
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