In this study, a series of twenty-five ring-substituted 4-arylamino-7-chloroquinolinium chlorides were prepared and characterized. The compounds were tested for their activity related to inhibition of photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts and also primary in vitro screening of the synthesized compounds was performed against mycobacterial species. 4-[(2-Bromophenyl)amino]-7-chloroquinolinium chloride showed high biological activity against M. marinum, M. kansasii, M. smegmatis and 7-chloro-4-[(2-methylphenyl)amino]quinolinium chloride demonstrated noteworthy biological activity against M. smegmatis and M. avium subsp. paratuberculosis. The most effective compounds demonstrated quite low toxicity (LD₅₀ > 20 μmol/L) against the human monocytic leukemia THP-1 cell line within preliminary in vitro cytotoxicity screening. The tested compounds were found to inhibit PET in photosystem II. The PET-inhibiting activity expressed by IC₅₀ value of the most active compound 7-chloro-4-[(3-trifluoromethylphenyl)amino]quinolinium chloride was 27 μmol/L and PET-inhibiting activity of ortho-substituted compounds was significantly lower than this of meta- and para-substituted ones. The structure-activity relationships are discussed for all compounds.

Department of Chemical Drugs Faculty of Pharmacy University of Veterinary and Pharmaceutical Sciences Palackeho 1 3 61242 Brno Czech Republic

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World Health Organization . Global Tuberculosis Report 2012. WHO Press; Geneva, Switzerland: 2012.

Wagner D., Young L.S. Nontuberculous mycobacterial infections: A clinical review. Infection. 2004;32:257–270. doi: 10.1007/s15010-004-4001-4. PubMed DOI

World Health Organization . WHO Global Strategy for Containment of Antimicrobial Resistance 2001. WHO Press; Geneva, Switzerland: 2001.

Koul A., Arnoult E., Lounis N., Guillemont J., Andries K. The challenge of new drug discovery for tuberculosis. Nature. 2011;469:483–490. doi: 10.1038/nature09657. PubMed DOI

Acharya N., Varshney U. Biochemical properties of single-stranded DNA-binding protein from Mycobacterium smegmatis, A fast-growing Mycobacterium and its physical and functional interaction with uracil DNA glycosylases. J. Mol. Biol. 2002;318:1251–1264. doi: 10.1016/S0022-2836(02)00053-0. PubMed DOI

Broussard G.W., Ennis D.G. Mycobacterium marinum produces long-term chronic infections in medaka: A new animal model for studying human tuberculosis. Comp. Biochem. Physiol. C Toxicol. Pharmacol. 2007;145:45–54. doi: 10.1016/j.cbpc.2006.07.012. PubMed DOI PMC

Valente W.J., Pienaar E., Fast A., Fluitt A., Whitney S.E., Fenton R.J., Barletta R.G., Chacon O., Viljoen H.J. A kinetic study of in vitro lysis of Mycobacterium smegmatis. Chem. Eng. Sci. 2009;64:1944–1952. doi: 10.1016/j.ces.2008.12.015. PubMed DOI PMC

Matveychuk A., Fuks L., Priess R., Hahim I., Shitrit D. Clinical and radiological features of Mycobacterium kansasii and other NTM infections. Resp. Med. 2012;106:1472–1477. doi: 10.1016/j.rmed.2012.06.023. PubMed DOI

Roth H.J., Fenner H. Arzneistoffe. 3rd ed. Deutscher Apotheker Verlag; Stuttgart, Germany: 2000.

Janin Y.L. Antituberculosis drugs: Ten years of research. Bioorg. Med. Chem. 2007;15:2479–2513. doi: 10.1016/j.bmc.2007.01.030. PubMed DOI

Rivers E.C., Mancera R.L. New anti-tuberculosis drugs with novel mechanisms of action. Curr. Med. Chem. 2008;15:1956–1967. doi: 10.2174/092986708785132906. PubMed DOI

Vangapandu S., Jain M., Jain R., Kaurb S., Singh P.P. Ring-substituted quinolines as potential anti-tuberculosis agents. Bioorg. Med. Chem. 2004;12:2501–2508. doi: 10.1016/j.bmc.2004.03.045. PubMed DOI

Nayyar A., Monga V., Malde A., Coutinho E., Jain R. Synthesis, anti-tuberculosis activity, and 3D-QSAR study of 4-(adamantan-1-yl)-2-substituted quinolines. Bioorg. Med. Chem. 2007;15:626–640. doi: 10.1016/j.bmc.2006.10.064. PubMed DOI

Musiol R., Jampilek J., Buchta V., Silva L., Niedbala H., Podeszwa B., Palka A., Majerz-Maniecka K., Oleksyn B., Polanski J. Antifungal properties of new series of quinoline derivatives. Bioorg. Med. Chem. 2006;14:3592–3598. doi: 10.1016/j.bmc.2006.01.016. PubMed DOI

Musiol R., Jampilek J., Nycz J.E., Pesko M., Carroll J., Kralova K., Vejsova M., O’Mahony J., Coffey A., Mrozek A., Polanski J. Investigating the activity spectrum for ring-substituted 8-hydroxyquinolines. Molecules. 2010;15:288–304. doi: 10.3390/molecules15010288. PubMed DOI PMC

Gonec T., Bobal P., Sujan J., Pesko M., Guo J., Kralova K., Pavlacka L., Vesely L., Kreckova E., Kos J., et al. Investigating the spectrum of biological activity of substituted quinoline-2-carboxamides and their isosteres. Molecules. 2012;17:613–644. doi: 10.3390/molecules17010613. PubMed DOI PMC

Serda M., Mrozek-Wilczkiewicz A., Jampilek J., Pesko M., Kralova K., Vejsova M., Musiol R., Polanski J. Investigation of biological properties for (hetero)aromatic thiosemicarbazones. Molecules. 2012;17:13483–13502. doi: 10.3390/molecules171113483. PubMed DOI PMC

Cieslik W., Musiol R., Nycz J., Jampilek J., Vejsova M., Wolff M., Machura B., Polanski J. Contribution to investigation of antimicrobial activity of styrylquinolines. Bioorg. Med. Chem. 2012;20:6960–6968. doi: 10.1016/j.bmc.2012.10.027. PubMed DOI

Solomon V.R., Lee H. Quinoline as a privileged scaffold in cancer drug discovery. Curr. Med. Chem. 2011;18:1488–1508. doi: 10.2174/092986711795328382. PubMed DOI

Koul A., Choidas A., Treder M., Tyagi A.K., Drlica K., Singh Y., Ullrich A. Cloning and characterization of secretory tyrosine phosphatases of Mycobacterium tuberculosis. J. Bacteriol. 2000;182:5425–5432. PubMed PMC

Koul A., Herget T., Kleb B., Ullrich A. Interplay between mycobacteria and host signalling pathways. Nat. Rev. Microbiol. 2004;2:189–202. doi: 10.1038/nrmicro840. PubMed DOI

Manger M., Scheck M., Prinz H., von Kries J.P., Langer T., Saxena K., Schwalbe H., Furstner A., Rademann J., Waldmann H. Discovery of Mycobacterium tuberculosis protein tyrosine phosphatase A (MptpA) inhibitors based on natural products and a fragment-based approach. ChemBioChem. 2005;6:1749–1753. doi: 10.1002/cbic.200500171. PubMed DOI

Greenstein A.E., Grundner C., Echols N., Gay L.M., Lombana T.N., Miecskowski C.A., Pullen K.E., Sung P.Y., Alber T. Structure/function studies of Ser/Thr and Tyr protein phosphorylation in Mycobacterium tuberculosis. J. Mol. Microbiol. Biotechnol. 2005;9:167–181. doi: 10.1159/000089645. PubMed DOI

Muller D., Krick A., Kehraus S., Mehner C., Hart M., Kupper F.C., Saxena K., Prinz H., Schwalbe H., Janning P., et al. Sponge-related cyanobacterial peptides with Mycobacterium tuberculosis protein tyrosine phosphatase inhibitory activity. J. Med. Chem. 2006;49:4871–4878. doi: 10.1021/jm060327w. PubMed DOI

Malhotra V., Arteaga-Cortes L.T., Clay G., Clark-Curtiss J.E. Mycobacterium tuberculosis protein kinase K confers survival advantage during early infection in mice and regulates growth in culture and during persistent infection: Implications for immune modulation. Microbiology. 2010;156:2829–2841. doi: 10.1099/mic.0.040675-0. PubMed DOI PMC

Malhotra V., Okon B.P., Clark-Curtiss J.E. Mycobacterium tuberculosis protein kinase K enables growth adaptation through translation control. J. Bacteriol. 2012;194:4184–4196. PubMed PMC

Strong H.L. Substituted quinoline herbicide intermediates and process. 5625068 A. U.S. Patent. 1997 Apr 29;

Grossmann K. Quinclorac belongs to a new class of highly selective auxin herbicides. Weed Sci. 1998;46:707–716.

Grossmann K., Kwiatkowski J., Tresch S. Auxin herbicides induce H2O2 overproduction and tissue damage in cleavers (Galium. aparine L.) J. Exp. Bot. 2001;362:1811–1816. doi: 10.1093/jexbot/52.362.1811. PubMed DOI

Tan S., Evans R.R., Dahmer M.L., Singh B.K., Shaner D.L. Imidazolinone-tolerant crops: History, current status and future. Pest. Manag. Sci. 2005;61:246–257. doi: 10.1002/ps.993. PubMed DOI

Gollut J.J.R., Gayet A.J.A. Process for the preparation of a quinoline carboxylic acid. WO2013072376 A1. 2013 May 23;

Musiol R., Jampilek J., Kralova K., Richardson D.R., Kalinowski D., Podeszwa B., Finster J., Niedbala H., Palka A., Polanski J. Investigating biological activity spectrum for novel quinoline analogues. Bioorg. Med. Chem. 2007;15:1280–1288. doi: 10.1016/j.bmc.2006.11.020. PubMed DOI

Musiol R., Tabak D., Niedbala H., Podeszwa B., Jampilek J., Kralova K., Dohnal J., Finster J., Mencel A., Polanski J. Investigating biological activity spectrum for novel quinoline analogues 2: Hydroxyquinolinecarboxamides with photosynthesis inhibiting activity. Bioorg. Med. Chem. 2008;16:4490–4499. doi: 10.1016/j.bmc.2008.02.065. PubMed DOI

Draber W., Tietjen K., Kluth J.F., Trebst A. Herbicides in photosynthesis research. Angew. Chem. 1991;3:1621–1633.

Tischer W., Strotmann H. Relationship between inhibitor binding by chloroplasts and inhibition of photosynthetic electron-transport. Biochim. Biophys. Acta. 1977;460:113–125. doi: 10.1016/0005-2728(77)90157-8. PubMed DOI

Trebst A., Draber W. Structure activity correlations of recent herbicides in photosynthetic reactions. In: Greissbuehler H., editor. Advances in Pesticide Science. Pergamon Press; Oxford, UK: 1979. pp. 223–234.

Bowyer J.R., Camilleri P., Vermaas W.F.J. Photosystem II and its interaction with herbicides. In: Baker N.R., Percival M.P., editors. Herbicides, Topics in Photosynthesis. Volume 10. Elsevier; Amsterdam, The Netherlands: 1991. pp. 27–85.

Delaney J., Clarke E., Hughes D., Rice M. Modern agrochemical research: A missed opportunity for drug discovery? Drug Discov. Today. 2006;11:839–845. doi: 10.1016/j.drudis.2006.07.002. PubMed DOI

Duke S.O. Herbicide and pharmaceutical relationships. Weed Sci. 2010;58:334–339. doi: 10.1614/WS-09-102.1. DOI

Swanton C.J., Mashhadi H.R., Solomon K.R., Afifi M.M., Duke S.O. Similarities between the discovery and regulation of pharmaceuticals and pesticides: In support of a better understanding of the risks and benefits of each. Pest. Manag. Sci. 2011;67:790–797. doi: 10.1002/ps.2179. PubMed DOI

Otevrel J., Mandelova Z., Pesko M., Guo J., Kralova K., Sersen F., Vejsova M., Kalinowski D., Kovacevic Z., Coffey A., et al. Investigating the spectrum of biological activity of ring-substituted salicylanilides and carbamoylphenylcarbamates. Molecules. 2010;15:8122–8142. doi: 10.3390/molecules15118122. PubMed DOI PMC

Imramovsky A., Pesko M., Kralova K., Vejsova M., Stolarikova J., Vinsova J., Jampilek J. Investigating spectrum of biological activity of 4- and 5-chloro-2-hydroxy-N-[2-(arylamino)-1-alkyl-2-oxoethyl]benzamides. Molecules. 2011;16:2414–2430. PubMed PMC

Imramovsky A., Pesko M., Monreal-Ferriz J., Kralova K., Vinsova J., Jampilek J. Photosynthesis-Inhibiting efficiency of 4-chloro-2-(chlorophenylcarbamoyl)phenyl alkylcarbamates. Bioorg. Med. Chem. Lett. 2011;21:4564–4567. doi: 10.1016/j.bmcl.2011.05.118. PubMed DOI

Fajkusova D., Pesko M., Keltosova S., Guo J., Oktabec Z., Vejsova M., Kollar P., Coffey A., Csollei J., Kralova K., et al. Anti-infective and herbicidal activity of N-substituted 2-aminobenzothiazoles. Bioorg. Med. Chem. 2012;20:7059–7068. doi: 10.1016/j.bmc.2012.10.007. PubMed DOI

Kos J., Zadrazilova I., Pesko M., Keltosova S., Tengler J., Gonec T., Bobal P., Kauerova T., Oravec M., Kollar P., et al. Antibacterial and herbicidal activity of ring-substituted 3-hydroxynaphthalene-2-carboxanilides. Molecules. 2013;18:7977–7997. doi: 10.3390/molecules18077977. PubMed DOI PMC

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

Garuti L., Roberti M., Bottegoni G. Irreversible protein kinases inhibitors. Curr. Med. Chem. 2011;18:2981–2994. doi: 10.2174/092986711796391705. PubMed DOI

Schenone S., Brullo C., Musumeci F., Radi M., Castagnolo D. Curr. Med. Chem. 2011;18:5061–5078. doi: 10.2174/092986711797636135. PubMed DOI

Lawrence R.M., Dennis K.C., O’Neill P.M., Hahn D.U., Roeder M., Struppe C. Development of a scalable synthetic route to GSK369796 (N-tert-butyl isoquine), a novel 4-aminoquinoline antimalarial drug. Org. Process. Res. Dev. 2008;12:294–297. doi: 10.1021/op7002776. DOI

Kralova K., Sersen F., Pesko M., Klimesova V., Waisser K. Photosynthesis-inhibiting effects of 2-benzylsulphanylbenzimidazoles in spinach chloroplasts. Chem. Pap. 2012;66:795–799. doi: 10.2478/s11696-012-0192-9. DOI

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

Kralova K., Sersen F., Sidoova E. Effect of 2-alkylthio-6-aminobenzothiazoles and their 6-N-substituted derivatives on photosynthesis inhibition in spinach chloroplasts. Gen. Phys. Biophys. 1993;12:421–427. PubMed

Kralova K., Sersen F., Miletin M., Hartl J. Inhibition of photosynthetic electron transport by some anilides of 2-alkylpyridine-4-carboxylic acids in spinach chloroplasts. Chem. Pap. 1998;52:52–55.

Kralova K., Sersen F., Pesko M., Waisser K., Kubicova L. 5-Bromo- and 3,5-dibromo-2-hydroxy-N-phenylbenzamides–inhibitors of photosynthesis. Chem. Pap. 2013 doi: 10.2478/s11696-013-0416-7. DOI

Kralova K., Sersen F., Klimesova V., Waisser K. 2-Alkylsulphanyl-4-pyridine-carbothioamides - Inhibitors of oxygen evolution in freshwater alga Chlorella vulgaris. Chem. Pap. 2011;65:909–912. doi: 10.2478/s11696-011-0082-6. DOI

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

Atal N., Saradhi P.P., Mohanty P. Inhibition of the chloroplast photochemical reactions by treatment of wheat seedlings with low concentrations of cadmium: Analysis of electron transport activities and changes in fluorescence yields. Plant. Cell. Physiol. 1995;32:943–951.

Kralova K., Sersen F., Kubicova L., Waisser K. Inhibitory effects of substituted benzanilides on photosynthetic electron transport in spinach chloroplasts. Chem. Pap. 1999;53:328–331.

Rath T., Roderfeld M., Blocher S., Rhode A., Basler T., Akineden O., Abdulmawjood A., Halwe J.M., Goethe R., Bulte M., et al. Presence of intestinal Mycobacterium avium subspecies paratuberculosis (MAP) DNA is not associated with altered MMP expression in ulcerative colitis. BMC Gastroenterology. 2011;11:34–54. doi: 10.1186/1471-230X-11-34. PubMed DOI PMC

Barlin G.B., Ireland S.J., Nguyen T.M.T., Kotecka B., Rieckmann K.H. Potential antimalarials. XX. Mannich base derivatives of 2-[7-(chloroquinolin-4-ylamino and 7-bromo(and 7-trifluoromethyl)-1,5-naphthyridin-4-ylamino]-4-chloro(or 4- or 6-t-butyl or 4- or 5-fluoro)-phenols and 4(or 6)-t-butyl-2-(7-trifluoromethylquinolin-4-ylamino)phenol. Aust. J. Chem. 1997;47:1143–1154.

Burckhalter J.H., DeWald H.A., Tendick F.H. An alternate synthesis of camoquin. J. Am. Chem. Soc. 1950;72:1024–1025. doi: 10.1021/ja01158a504. DOI

Francois B. N-(4-Quinolinyl)glycine derivatives, antiinflammatory and pain killing agents. DE 1965638 A. 1970 Sep 3;

Price C.C., Leonard N.J., Peel E.W., Reitsema R.H. Some 4-amino-7-chloroquinoline derivatives. J. Am. Chem. Soc. 1946;68:1807–1808. doi: 10.1021/ja01213a039. PubMed DOI

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.

Schwalbe R., Steele-Moore L., Goodwin A.C. Antimicrobial Susceptibility Testing Protocols. CRC Press; Boca Raton, FL, USA: 2007.

Pauk K., Zadrazilova I., Imramovsky A., Vinsova J., Pokorna M., Masarikova M., Cizek A., Jampilek J. New derivatives of salicylamides: Preparation and antimicrobial activity against various bacterial species. Bioorg. Med. Chem. in press. PubMed

Gonec T., Kos J., Zadrazilova I., Pesko M., Keltosova S., Tengler J., Bobal P., Kollar P., Cizek A., Kralova K., et al. Antimycobacterial and herbicidal activity of ring-substituted 1-hydroxynaphthalene-2-carboxanilides. Bioorg. Med. Chem. 2013 in press. PubMed

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