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.

Department of Environmental Ecology Faculty of Natural Sciences Comenius University Mlynska Dolina CH 2 Bratislava 84215 Slovakia

Faculty of Pharmacy Charles University Prague Heyrovskeho 1203 Hradec Kralove 50005 Czech Republic

Institute of Chemistry Faculty of Natural Sciences Comenius University Mlynska Dolina CH 2 Bratislava 84215 Slovakia

Laboratory of Virology and Chemotherapy Rega Institute KU Leuven Minderbroedersstraat 10 Leuven B 3000 Belgium

See more in PubMed

Ukrainets I.V., Bereznyakova N.L. Heterocyclic diuretics. Chem. Heterocycl. Compd. 2012;48:155–165. doi: 10.1007/s10593-012-0979-1. PubMed DOI PMC

Miniyar P.B., Murumkar P.R., Patil P.S., Barmade M.A., Bothara K.G. Unequivocal role of pyrazine ring in medicinally important compounds: A review. Mini Rev. Med. Chem. 2013;13:1607–1625. PubMed

Mueller R., Rappert S. Pyrazines: Occurrence, formation and biodegradation. Appl. Microbiol. Biot. 2010;85:1315–1320. doi: 10.1007/s00253-009-2362-4. PubMed DOI

Dolezal M., Zitko J. Pyrazine derivatives: A patent review (June 2012-present) Expert Opin. Ther. Pat. 2014;25:33–47. PubMed

Kucerova-Chlupacova M., Kunes J., Buchta V., Vejsova M., Opletalova V. Novel pyrazine analogs of chalcones: Synthesis and evaluation of their antifungal and antimycobacterial activity. Molecules. 2015;20:1104–1117. doi: 10.3390/molecules20011104. PubMed DOI PMC

Zhang D.F., Liu Y., Zhang C.L., Zhang H., Wang B., Xu J., Fu L., Yin D.L., Cooper C.B., Ma Z.K., et al. Synthesis and biological evaluation of novel 2-methoxypyridylamino-substituted riminophenazine derivatives as antituberculosis agents. Molecules. 2014;19:4380–4394. doi: 10.3390/molecules19044380. PubMed DOI PMC

Rychtarcikova Z., Kratky M., Gazvoda M., Komloova M., Polanc S., Kocevar M., Stolarikova J., Vinsova J. N-Substituted 2-isonicotinoylhydrazinecarboxamides—New antimycobacterial active molecules. Molecules. 2014;19:3851–3868. doi: 10.3390/molecules19043851. PubMed DOI PMC

Singh P., Mishra A.K., Malonia S.K., Chauhan D.S., Sharma V.D., Venkatesan K., Katoch V.M. The paradox of pyrazinamide: An update on the molecular mechanisms of pyrazinamide resistance in Mycobacteria. J. Commun. Dis. 2006;38:288–298. PubMed

Carel C., Nukdee K., Cantaloube S., Bonne M., Diagne C.T., Laval F., Daffe M., Zerbib D. Mycobacterium tuberculosis proteins involved in mycolic acid synthesis and transport localize dynamically to the old growing pole and septum. PLoS ONE. 2014;9:e97148. doi: 10.1371/journal.pone.0097148. PubMed DOI PMC

Sayahi H., Pugliese K.M., Zimhony O., Jacobs W.R., Jr., Shekhtman A., Welch J.T. Analogs of the antituberculous agent pyrazinamide are competitive inhibitors of NADPH binding to M. tuberculosis fatty acid synthase I. Chem. Biodivers. 2012;9:2582–2596. doi: 10.1002/cbdv.201200291. PubMed DOI

Servusova B., Paterova P., Mandikova J., Kubicek V., Kucera R., Kunes J., Dolezal M., Zitko J. Alkylamino derivatives of pyrazinamide: Synthesis and antimycobacterial evaluation. Bioorg. Med. Chem. Lett. 2014;24:450–453. doi: 10.1016/j.bmcl.2013.12.054. PubMed DOI

Good N.E. Inhibitors of Hill reaction. Plant Physiol. 1961;36:788–803. doi: 10.1104/pp.36.6.788. PubMed DOI PMC

Kralova K., Sersen F., Cizmarik J. Inhibitory effect of piperidinoethylesters of alkoxyphenylcarbamic acids on photosynthesis. Gen. Physiol. Biophys. 1992;11:261–267. PubMed

Dolezal M., Miletin M., Kunes J., Kralova K. Substituted amides of pyrazine-2-carboxylic acids: Synthesis and biological activity. Molecules. 2002;7:363–373. doi: 10.3390/70300363. DOI

Draber W., Tietjen K., Kluth J.F., Trebst A. Herbicides in photosynthesis research. Angew. Chem. Int. Ed. 1991;30:1621–1633. doi: 10.1002/anie.199116211. DOI

Barber J., Marder J.B. Photosynthesis and the application of molecular genetics. Biotechnol. Genet. Eng. Rev. 1986;4:355–404. doi: 10.1080/02648725.1986.10647832. DOI

Shipman L.L. Theoretical-study of the binding-site and mode of action for photosystem-ii herbicides. J. Theor. Biol. 1981;90:123–148. doi: 10.1016/0022-5193(81)90126-0. DOI

Kral’ova K., Sersen F., Kubicova L., Waisser K. Inhibition of photosynthetic electron transport in spinach chloroplasts by 3-and 4-halogeno substituted benzanilides and thiobenzanilides. J. Trace Microprobe Tech. 2000;18:251–256.

Kral’ova K., Sersen F., Miletin M., Dolezal M. Inhibition of photosynthetic electron transport in spinach chloroplasts by 2,6-disubstituted pyridine-4-thiocarboxamides. Chem. Pap. Chem. Zvesti. 2002;56:214–217.

Servusova B., Eibinova D., Dolezal M., Kubicek V., Paterova P., Pesko M., Kral’ova K. Substituted N-benzylpyrazine-2-carboxamides: Synthesis and biological evaluation. Molecules. 2012;17:13183–13198. doi: 10.3390/molecules171113183. PubMed DOI PMC

Allen J.R., Andrews K.L., Frohn M.J., Harrington P.E., Pickrell A.J., Rzasa R.M. Nitrogen-Heterocyclic Compounds as Phosphodiesterase 10 Inhibitors. WO 2,011,143,129. U.S. Patent. 2011 Nov 17;

Zhu J.L., Wong H., Zhang Z.X., Yin Z.W., Kadow J., Meanwell N.A., Wang T. Malononitrile as a carbonyl synthon: A one-pot preparation of heteroaryl amide via a SNAr-oxidation-displacement strategy. Tetrahedron Lett. 2004;45:5909–5911. doi: 10.1016/j.tetlet.2004.05.154. DOI

Albert A., Brown D.J., Wood H.C.S. Pteridine studies. Part VIII. The degradation of pteridine. Methylation of the hydroxypteridines and degradation of the products. J. Chem. Soc. 1956:2066–2075. doi: 10.1039/jr9560002066. DOI

Jandourek O., Dolezal M., Kunes J., Kubicek V., Paterova P., Pesko M., Buchta V., Kralova K., Zitko J. New potentially active pyrazinamide derivatives synthesized under microwave conditions. Molecules. 2014;19:9318–9338. doi: 10.3390/molecules19079318. PubMed DOI PMC

Devinsky F., Kopecka-Leitmanova A., Sersen F., Balgavy P. Interaction of surfactants with model and biological-membranes. 8. Amine oxides. 24. Cutoff effect in antimicrobial activity and in membrane perturbation efficiency of the homologous series of N,N-dimethylalkylamine oxides. J. Pharm. Pharmacol. 1990;42:790–794. doi: 10.1111/j.2042-7158.1990.tb07022.x. PubMed DOI

Balgavy P., Devinsky F. Cut-off effects in biological activities of surfactants. Adv. Colloid Interface. 1996;66:23–63. doi: 10.1016/0001-8686(96)00295-3. PubMed DOI

Przestalski S., Sarapuk J., Kleszczynska H., Gabrielska J., Hladyszowski J., Trela Z., Kuczera J. Influence of amphiphilic compounds on membranes. Acta Biochim. Pol. 2000;47:627–638. PubMed

Sarapuk J., Kubica K. Cut-off phenomenon. Cell. Mol. Biol. Lett. 1998;5:261–269.

Moreland D.E. Research on biochemistry of herbicides—An historical overview. Z. Naturforsch. C. 1993;48:121–131.

Kral’ova K., Sersen F., Devinsky F., Lacko I. Photosynthesis-inhibiting effects of cationic biodegradable gemini surfactants. Tenside Surf. Deterg. 2010;47:288–293. doi: 10.3139/113.110079. DOI

Gonec T., Kos J., Zadrazilova I., Pesko M., Govender R., Keltosova S., Chambel B., Pereira D., Kollar P., Imramovsky A., et al. Antibacterial and herbicidal activity of ring-substituted 2-hydroxynaphthalene-1-carboxanilides. Molecules. 2013;18:9397–9419. doi: 10.3390/molecules18089397. PubMed DOI PMC

Kralova K., Sersen F., Cizmarik J. Dimethylaminoethyl alkoxyphenylcarbamates as photosynthesis inhibitors. Chem. Pap. Chem. Zvesti. 1992;46:266–268.

Kralova K., Bujdakova H., Cizmarik J. Antifungal and antialgal activity of piperidonopropyl esters of alkoxy-substituted phenylcarbamic acids. Pharmazie. 1995;50:440–441. PubMed

Sersen F., Kralova K. Concentration-dependent inhibitory and stimulating effects of amphiphilic ammonium salts upon photosynthetic activity of spinach chloroplasts. Gen. Physiol. Biophys. 1996;15:27–36. PubMed

Izawa S. Acceptors and donors for chloroplast electron transport. In: Colowick P., Kaplan N.O., editors. Methods in Enzymology. Volume 69. Academic Press; New York, NY, USA; London, UK: 1980. pp. 413–434. Part C.

Purcell M., Leroux G., Carpentier R. Interaction of the electron donor diphenylcarbazide with the herbicide-binding niche of photosystem II. Biochim. Biophys. Acta Int. J. Biochem. Biophys. 1991;1058:374–378. doi: 10.1016/S0005-2728(05)80133-1. DOI

Borse T.H., Maheshwari V.L., Baviskar M.P. Effect of diphenyl carbazide on the metribuzin induced inhibition of photosystem-II photochemistry. J. Plant Biochem. Biotechnol. 2000;9:119–121. doi: 10.1007/BF03263097. DOI

Kamachi H., Tamura N., Inoue H. Putative second binding site of DCMU on the oxidizing side of photosystem II in photosystem II membranes depleted of functional Mn. Plant Cell Physiol. 1992;33:437–443.

Renger G. The action of 3-(3,4-dichlorophenyl)-l,l-dimethylurea on the water-splitting enzyme system Y of photosynthesis. Biochim. Biophys. Acta. 1973;314:113–116. doi: 10.1016/0005-2728(73)90070-4. PubMed DOI

Carpentier R., Fuerst E.P., Nakatani H.Y., Arntzen C.J. A second site for herbicide action in photosystem II. Biochim. Biophys. Acta. 1985;808:293–299. doi: 10.1016/0005-2728(85)90012-X. DOI

Callis P.R. Binding phenomena and fluorescence quenching. II: Photophysics of aromatic residues and dependence of fluorescence spectra on protein conformation. J. Mol. Struct. 2014;1077:22–29. doi: 10.1016/j.molstruc.2014.04.051. DOI

Kral’ova K., Sersen F., Pesko M., Waisser K., Kubicova L. 5-Bromo- and 3,5-dibromo-2-hydroxy-N-phenylbenzamides—Inhibitors of photosynthesis. Chem. Pap. 2014;68:46–52.

Zitko J., Servusova B., Paterova P., Mandikova J., Kubicek V., Kucera R., Hrabcova V., Kunes J., Soukup O., Dolezal M. Synthesis, Antimycobacterial activity and in vitro cytotoxicity of 5-chloro-N-phenylpyrazine-2-carboxamides. Molecules. 2013;18:14807–14825. doi: 10.3390/molecules181214807. PubMed DOI PMC

Jones R.N., Barry A.L. Optimal dilution susceptibility testing conditions, recommendations for MIC interpretation, and quality-control guidelines for the ampicillin-sulbactam combination. J. Clin. Microbiol. 1987;25:1920–1925. PubMed PMC

National Committee for Clinical Laboratory Standards . Method for Antifungal Disc Diffusion Susceptibility Testing of Yeasts: Approved Guideline M44-A. NCCLS; Wayne, PA, USA: 2004.

Naesens L., Stephens C.E., Andrei G., Loregian A., De Bolle L., Snoeck R., Sowell J.W., De Clercq E. Antiviral properties of new arylsulfone derivatives with activity against human betaherpesviruses. Antivir. Res. 2006;72:60–67. doi: 10.1016/j.antiviral.2006.03.013. PubMed DOI

Naesens L., Vanderlinden E., Roth E., Jeko J., Andrei G., Snoeck R., Pannecouque C., Illyes E., Batta G., Herczegh P., et al. Anti-influenza virus activity and structure-activity relationship of aglycoristocetin derivatives with cyclobutenedione carrying hydrophobic chains. Antivir. Res. 2009;82:89–94. doi: 10.1016/j.antiviral.2009.01.003. PubMed DOI PMC

Vanderlinden E., Goktas F., Cesur Z., Froeyen M., Reed M.L., Russell C.J., Cesur N., Naesens L. Novel inhibitors of influenza virus fusion: Structure-activity relationship and interaction with the viral hemagglutinin. J. Virol. 2010;84:4277–4288. doi: 10.1128/JVI.02325-09. PubMed DOI PMC

Masarovicova E., Kralova K. Approaches to measuring plant photosynthesis activity. In: Pessarakli M., editor. Handbook of Photosynthesis. 2nd ed. Taylor & Francis Group; Boca Raton, FL, USA: 2005. pp. 617–656.

Kralova K., Sersen F., Sidoova E. Photosynthesis inhibition produced by 2-alkylthio-6-R-benzothiazoles. Chem. Pap. 1992;46:348–350.

Derivatives of 3-Aminopyrazine-2-carboxamides: Synthesis, Antimicrobial Evaluation, and in Vitro Cytotoxicity

Ureidopyrazine Derivatives: Synthesis and Biological Evaluation as Anti-Infectives and Abiotic Elicitors

3-Substituted N-Benzylpyrazine-2-carboxamide Derivatives: Synthesis, Antimycobacterial and Antibacterial Evaluation

Synthesis and Antifungal Screening of 2-{[1-(5-Alkyl/arylalkylpyrazin-2-yl)ethylidene]hydrazono}-1,3-thiazolidin-4-ones