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Medicinal Chemistry

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ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

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Research Article

Antiprotozoal Activities of Tetrazole-quinolines with Aminopiperidine Linker

Author(s): Patrick Hochegger, Johanna Faist, Werner Seebacher, Robert Saf, Pascal Mäser, Marcel Kaiser and Robert Weis*

Volume 15, Issue 4, 2019

Page: [409 - 416] Pages: 8

DOI: 10.2174/1573406414666181015115101

Price: $65

Abstract

Background: Human African Trypanosomiasis (HAT, sleeping sickness) and Malaria both are insect vectored tropical diseases. Only a couple of drugs is able to cure HAT, but all of them are toxic, prone to resistance and require parenteral administration. Malaria is responsible for high morbidity and mortality in humans. It is one of the global killers of children. Wide-spread drug resistance against traditional therapeutics which were once highly effective makes them almost useless. Therefore new drugs against both diseases are urgently needed.

Objective: Recently, we reported the synthesis and antiprotozoal activities of a number of new 2- substituted 4-carbamoyl- and 4-aminoquinolines. This study focussed on the synthesis of novel tetrazole derivatives which are linked to the quinoline core via a piperidine ring.

Methods: Novel compounds exhibiting a 7-chloroquinoline and a tetrazole ring were prepared via Ugi-azide reaction. Modifications were restricted to the orientation and the substitution of the linker. Compounds were tested for their activities against Trypanosoma brucei rhodesiense (STIB 900). Their antiplasmodial activities were determined against a sensitive (NF54) and a multiresistant strain (K1) of Plasmodium falciparum.

Results: Eighteen tetrazole derivatives were prepared. The results of the biological tests were compared with the activities of drugs in use and structure-activity relationships were discussed. Their antitrypanosomal activities were only moderate. In contrast some of the compounds showed promising activity against both strains of Plasmodium falciparum and good to excellent resistance indices.

Conclusion: The antiplasmodial activities depended on the orientation of the 4-aminopiperidine linker. Compounds with a tertiary amino group in position 4 of the quinoline ring exhibited equal activity against both strains, whereas those with a secondary amino group were mainly active against the sensitive strain.

Keywords: Amines, NMR spectroscopy, multicomponent reaction, Plasmodium falciparum, quinoline, antiprotozoal activities.

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[1]
World Health Organization 2017, Human African trypanosomiasis; Available from:. http://www.who.int/trypanosomiasis_african/ news/HAT_elimination_on_track/en/
[2]
World Health Organization, Human African Trypanosomiasis, Fact sheet N°259, updated January. 2017.
[3]
World Health Organization, Human African trypanosomiasis; Symptoms, diagnosis & treatment. Available from:. http://www.who.int/trypanosomiasis_african/diagnosis/en/index.html
[4]
Huber, D.; Barrett, M.P. Uptake and mode of action of drugs used against sleeping sickness. Biochem. Pharmacol., 2001, 61, 1-5.
[5]
Kennedy, P.G.E. Human African trypanosomiasis of the CNS: Current issues and challenges. J. Clin. Invest., 2004, 113, 496-504.
[6]
Bhambra, A.S.; Edgar, M.; Elsegood, M.R.J.; Li, Y.; Weaver, G.W.; Arroo, R.R.J.; Yardley, V.; Burrell-Saward, H.; Krystof, V. Design, synthesis and antitrypanosomal activities of 2,6-disubstituted-4,5,7-trifluorobenzothiophenes. Eur. J. Med. Chem., 2016, 108, 347-353.
[7]
World Health Organization, Malaria, Fact sheet N°094, updated April. 2017.
[8]
Tun, K.M.; Imwong, M.; Lwin, K.M.; Win, A.A.; Hlaing, T.M.; Hlaing, T.; Lin, K.; Kyaw, M.P.; Plewes, K.; Faiz, M.A.; Dhorda, M.; Yeong, C.P.; Pukrittayakamee, S.; Ashley, E.A.; Anderson, T.J.C.; Nair, S.; McDew-White, M.; Flegg, J.A.; Grist, E.P.M.; Guerin, P.; Maude, R.J.; Smithuis, F.; Dondorp, A.M.; Day, N.P.J.; Nosten, F.; White, N.J.; Woodrow, C.J. Spread of artemisinin-resistant Plasmodium falciparum in Myanmar: A cross-sectional survey of the K13 molecular marker. Lancet Infect. Dis., 2015, 15, 415-421.
[9]
Lu, F.; Culleton, R.; Zhang, M.; Ramaprasad, A.; von Seidlein, L.; Zhou, H.; Zhu, G.; Tang, J.; Liu, Y.; Wang, W.; Cao, Y.; Xu, S.; Gu, Y.; Li, J.; Zhang, C.; Gao, Q.; Menard, D.; Pain, A.; Yang, H.; Zhang, Q.; Cao, J. emergence of indigenous artemisinin-resistant plasmodium falciparum in Africa. N. Engl. J. Med., 2017, 376, 991-993.
[10]
Faist, J.; Hinteregger, C.; Seebacher, W.; Saf, R.; Mäser, P.; Kaiser, M.; Weis, R. New derivatives of 7-chloroquinolin-4-amine with antiprotozoal activity. Bioorg. Med. Chem., 2017, 25, 941-948.
[11]
Hochegger, P.; Faist, J.; Seebacher, W.; Saf, R.; Mäser, P.; Kaiser, M.; Weis, R. New derivatives of quinoline-4-carboxylic acid with antiplasmodial activity. Bioorg. Med. Chem., 2017, 25, 2251-2259.
[12]
Pandey, S.; Agarwal, P.; Srivastava, K.; Kumar, S.R.; Puri, S.K.; Verma, P.; Saxena, J.K.; Sharma, A.; Lal, J.; Chauhan, P.M.S. Synthesis and bioevaluation of novel 4-aminoquinoline-tetrazole derivatives as potent antimalarial agents. Eur. J. Med. Chem., 2013, 66, 69-81.
[13]
Ostrovskii, V.A. Medicinal chemistry of tetrazoles. Russ. Chem. Bull., 2012, 61, 768-780.
[14]
Nava-Zuazo, C.; Estrada-Soto, S.; Guerrero-Alvarez, J.; León-Rivera, I.; Molina-Salinas, G.M.; Said-Fernández, S.; Chan-Bacab, M.J.; Cedillo-Rivera, R.; Moo-Puc, R.; Mirón-López, G.; Navarrete-Vazquez, G. Design, synthesis, and in vitro antiprotozoal, antimycobacterial activities of N-2-[(7-chloroquinolin-4-yl)amino] ethylureas. Bioorg. Med. Chem., 2010, 18, 6398-6403.
[15]
Martin, R.E.; Green, L.G.; Guba, W.; Kratochwil, N.; Christ, A. Discovery of the first nonpeptidic, small-molecule, highly selective somatostatin receptor subtype 5 antagonists: A chemogenomics approach. J. Med. Chem., 2007, 50, 6291-6294.
[16]
Madrid, P.B.; Liou, A.P.; DeRisi, J.L.; Guy, R.K. Incorporation of an intramolecular hydrogen-bonding motif in the side chain of 4-aminoquinolines enhances activity against drug-resistant P. Falciparum. J. Med. Chem., 2006, 49, 4535-4543.
[17]
Baltz, T.; Baltz, D.; Giroud, C.; Crockett, J. Cultivation in a semi-defined medium of animal infective forms of Trypanosoma brucei, T. equiperdum, T. evansi, T. rhodesiense and T. gambiense. EMBO J., 1985, 4, 1273-1277.
[18]
Räz, B.; Iten, M.; Grether-Bühler, Y.; Kaminsky, R.; Brun, R. The Alamar blue assay to determine drug sensitivity of African trypanosomes (T.b. rhodesiense and T.b. gambiense) in vitro. Acta Trop., 1997, 68, 139.
[19]
Huber, W.; Koella, J.C. A comparison of three methods of estimating EC50 in studies of drug resistance of malaria parasites. Acta Trop., 1993, 55, 257-261.
[20]
Desjardins, R.E.; Canfield, C.J.; Haynes, J.D.; Chulay, J.D. Quantitative assessment of antimalarial activity in vitro by a semiautomated microdilution technique. Antimicrob. Agents Chemother., 1979, 16, 710-718.
[21]
Matile, H.; Pink, J.R.L. In: Immunological Methods; Lefkovits, I.; Pernis, B., Eds.; Academic Press: San Diego, 1990; pp. 221-234.
[22]
Ponnudurai, T.; Leeuwenberg, A.D.; Meuwissen, J.H. Chloroquine sensitivity of isolates of Plasmodium falciparum adapted to in vitro culture. Trop. Geogr. Med., 1981, 33, 50-54.
[23]
Thaithong, S.; Beale, G.H.; Chutmongkonkul, M. Susceptibility of Plasmodium falciparum to five drugs: An in vitro study of isolates mainly from Thailand. Trans. R. Soc. Trop. Med. Hyg., 1983, 77, 228-231.
[24]
Page, B.; Page, M.; Noel, C. A new fluorometric assay for cytotoxicity measurements in-vitro. Int. J. Oncol., 1993, 3, 473-476.
[25]
Ahmed, S.A.; Gogal, R.M.; Walsh, J.E. A new rapid and simple non-radioactive assay to monitor and determine the proliferation of lymphocytes: an alternative to [3H]thymidine incorporation assay. J. Immunol. Methods, 1994, 170, 211-224.

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