Synthesis, Antimycobacterial, Antifungal and Photosynthesis-Inhibiting Activity of Chlorinated N-phenylpyrazine-2-carboxamides †

Martin Dolezal,Vladimir Buchta,Josef Jampilek,Katarina Kralova,Jan Zitko,Jiri Kunes,Zdenek Osicka,Jiri Dohnal,Marcela Vejsova

doi:10.3390/molecules15128567

Abstract

A series of sixteen pyrazinamide analogues with the -CONH- linker connecting the pyrazine and benzene rings was synthesized by the condensation of chlorides of substituted pyrazinecarboxylic acids with ring-substituted (chlorine) anilines. The prepared compounds were characterized and evaluated for their antimycobacterial and antifungal activity, and for their ability to inhibit photosynthetic electron transport (PET). 6-Chloro-N-(4-chlorophenyl)pyrazine-2-carboxamide manifested the highest activity against Mycobacterium tuberculosis strain H37Rv (65% inhibition at 6.25 μg/mL). The highest antifungal effect against Trichophyton mentagrophytes, the most susceptible fungal strain tested, was found for 6-chloro-5-tert-butyl-N-(3,4-dichlorophenyl)pyrazine-2-carboxamide (MIC = 62.5 μmol/L). 6-Chloro-5-tert-butyl-N-(4-chlorophenyl)pyrazine-2-carboxamide showed the highest PET inhibition in spinach chloroplasts (Spinacia oleracea L.) chloroplasts (IC50 = 43.0 μmol/L). For all the compounds, the relationships between the lipophilicity and the chemical structure of the studied compounds as well as their structure–activity relationships are discussed.

Highlights

Compounds possessing a -CONH- moiety simulating a peptide bond in their molecule show a broad range of biological effects
All studied compounds were prepared according to Scheme 1
A series of sixteen ring-substituted N-phenylpyrazine-2-carboxamides were prepared by condensation of the corresponding chlorides of some substituted pyrazinecarboxylic acids with ring-substituted anilines

Summary

Introduction

Compounds possessing a -CONH- moiety simulating a peptide bond in their molecule show a broad range of biological effects. Pyrazinamide, with its simple structure, provides a good opportunity for further modification with a view to increasing its antimycobacterial activity. We have prepared and studied several series of the pyrazinamide analogues with the -CONH- linker connecting the pyrazine and benzene rings. All compounds were assayed in vitro against major Mycobacterium and various fungal species [1,2,3,4,5,6]. Some compounds were found to exhibit photosynthesis-inhibiting activity [2,5,7,8]. Introducing of halogens (-Cl, -F, -CF3) was the most successful structural modification. N-(3-Trifluoromethylphenyl)pyrazine-2-carboxamide, 5-tert-butyl-6-chloro-N(3-trifluoromethylphenyl)pyrazine-2-carboxamide, and N-(3-iodo-4-methylphenyl)pyrazine-2-carboxamide have shown the highest activity against M. tuberculosis H37Rv (MIC = 3.13-6.25 μg/mL) [5]

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Results

Conclusion