Synthesis and antiplasmodial structure-activity relationships for some novel 4-aminoquinolines and 5-chlorobenzimidazoles

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dc.contributor.advisorHunter, Rogeren_ZA
dc.contributor.advisorEgan, Timothy Jen_ZA
dc.contributor.authorVan der Merwe, Johannes Dawiden_ZA
dc.date.accessioned2014-08-13T14:25:33Z
dc.date.available2014-08-13T14:25:33Z
dc.date.issued2004en_ZA
dc.descriptionIncludes bibliographical references.en_ZA
dc.description.abstractTwo novel 7-substituted 4-aminoalkylated quinolines, Nl,Nl-diethyl-N2-(7-trifuoromethylthio-4-quinolinyl)-1,2-ethanediamine 11 and Nt, Nl-diethyl-N2-(7-trifuoromethoxy-4-quinolinyl)-1,2-ethanediamine 12 were synthesized via a versatile 6-step route and their antiplasmodial activities against the chloroquine sensitive D10 strain of Plasmodium falciparum have been investigated in vitro. A quantitative structure activity analysis of these compounds showed an excellent correlation of log ICso, corrected for vacuolar accumulation, with log ß-haematin inhibitory activity when compared with known values for other analogues substituted at the 7 -position. The correlation showed a law accumulation-normalised ICso for 11, which suggests that it is the most potent antimalarial at the site of action of all of the analogues of this type. 11 and 12 however had relatively high observed IC50 values compared to the other analogues, which can be attributed to their low pKa1 values and subsequent low vacuolar accumulation in the parasite. In addition, the benzimidazole nucleus, which has similar dipolar character to 4-aminoquinoline nucleus, was investigated as alternative template for potential antimalarials. This involved the synthesis of the chloroquine-like analogues 2-(5-chlorobenzoimidazol-1-yl)-N-(2-diethylaminoethylethanamide 13, N-[2-(5-chlorobenzoimidazol-1-yl)ethyl]-2-( 4-methylpiperazin-1-yl)ethanamide 14 and N-[2-( 5-chlorobenzoimidazol-1-yl)ethyl]-N-[2-(4-methylpiperazin-1-yl)ethyl]amine 15. The latter two products were prepared by a regioselective route to 5-chlorobenzimidazoles. These compounds had poor activity against P. falciparum and none showed ß-haematin inhibitory activity although their precursor, 5-chloro-1 H-benzimidazole, had ß-haematin inhibitory activity. Their poor activity was ascribed to this lack of ß-haematin inhibitory activity as well as their low pKa which would result in poor vacuolar accumulation. Finally, the novel side chain N-(2-aminoethyl)-2-(4-methylpiperazin-1-yl)ethanamide 14b incorporated in 14 was coupled to a 7 -chloroquinoline nucleus in order to compare the 4-amino-7-chloroquinoline nucleus directly with the 5-chlorobenzimidazole nucleus. Thus, the analogous 4-aminoquinoline N-[2-(7-chloro- 4-quinolinyl)ethyl]-2-(4-methylpiperazin-1-yl)ethanamide 16 was synthesized. This compound retains anti-plasmodial activity, demonstrating that the lack of activity in 14 and 15 can be ascribed to the replacement of the quinoline nucleus with the benzimidazole nucleus and not to the side chain itself.en_ZA
dc.identifier.apacitationVan der Merwe, J. D. (2004). <i>Synthesis and antiplasmodial structure-activity relationships for some novel 4-aminoquinolines and 5-chlorobenzimidazoles</i>. (Thesis). University of Cape Town ,Faculty of Science ,Department of Chemistry. Retrieved from http://hdl.handle.net/11427/6285en_ZA
dc.identifier.chicagocitationVan der Merwe, Johannes Dawid. <i>"Synthesis and antiplasmodial structure-activity relationships for some novel 4-aminoquinolines and 5-chlorobenzimidazoles."</i> Thesis., University of Cape Town ,Faculty of Science ,Department of Chemistry, 2004. http://hdl.handle.net/11427/6285en_ZA
dc.identifier.citationVan der Merwe, J. 2004. Synthesis and antiplasmodial structure-activity relationships for some novel 4-aminoquinolines and 5-chlorobenzimidazoles. University of Cape Town.en_ZA
dc.identifier.ris TY - Thesis / Dissertation AU - Van der Merwe, Johannes Dawid AB - Two novel 7-substituted 4-aminoalkylated quinolines, Nl,Nl-diethyl-N2-(7-trifuoromethylthio-4-quinolinyl)-1,2-ethanediamine 11 and Nt, Nl-diethyl-N2-(7-trifuoromethoxy-4-quinolinyl)-1,2-ethanediamine 12 were synthesized via a versatile 6-step route and their antiplasmodial activities against the chloroquine sensitive D10 strain of Plasmodium falciparum have been investigated in vitro. A quantitative structure activity analysis of these compounds showed an excellent correlation of log ICso, corrected for vacuolar accumulation, with log ß-haematin inhibitory activity when compared with known values for other analogues substituted at the 7 -position. The correlation showed a law accumulation-normalised ICso for 11, which suggests that it is the most potent antimalarial at the site of action of all of the analogues of this type. 11 and 12 however had relatively high observed IC50 values compared to the other analogues, which can be attributed to their low pKa1 values and subsequent low vacuolar accumulation in the parasite. In addition, the benzimidazole nucleus, which has similar dipolar character to 4-aminoquinoline nucleus, was investigated as alternative template for potential antimalarials. This involved the synthesis of the chloroquine-like analogues 2-(5-chlorobenzoimidazol-1-yl)-N-(2-diethylaminoethylethanamide 13, N-[2-(5-chlorobenzoimidazol-1-yl)ethyl]-2-( 4-methylpiperazin-1-yl)ethanamide 14 and N-[2-( 5-chlorobenzoimidazol-1-yl)ethyl]-N-[2-(4-methylpiperazin-1-yl)ethyl]amine 15. The latter two products were prepared by a regioselective route to 5-chlorobenzimidazoles. These compounds had poor activity against P. falciparum and none showed ß-haematin inhibitory activity although their precursor, 5-chloro-1 H-benzimidazole, had ß-haematin inhibitory activity. Their poor activity was ascribed to this lack of ß-haematin inhibitory activity as well as their low pKa which would result in poor vacuolar accumulation. Finally, the novel side chain N-(2-aminoethyl)-2-(4-methylpiperazin-1-yl)ethanamide 14b incorporated in 14 was coupled to a 7 -chloroquinoline nucleus in order to compare the 4-amino-7-chloroquinoline nucleus directly with the 5-chlorobenzimidazole nucleus. Thus, the analogous 4-aminoquinoline N-[2-(7-chloro- 4-quinolinyl)ethyl]-2-(4-methylpiperazin-1-yl)ethanamide 16 was synthesized. This compound retains anti-plasmodial activity, demonstrating that the lack of activity in 14 and 15 can be ascribed to the replacement of the quinoline nucleus with the benzimidazole nucleus and not to the side chain itself. DA - 2004 DB - OpenUCT DP - University of Cape Town LK - https://open.uct.ac.za PB - University of Cape Town PY - 2004 T1 - Synthesis and antiplasmodial structure-activity relationships for some novel 4-aminoquinolines and 5-chlorobenzimidazoles TI - Synthesis and antiplasmodial structure-activity relationships for some novel 4-aminoquinolines and 5-chlorobenzimidazoles UR - http://hdl.handle.net/11427/6285 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/6285
dc.identifier.vancouvercitationVan der Merwe JD. Synthesis and antiplasmodial structure-activity relationships for some novel 4-aminoquinolines and 5-chlorobenzimidazoles. [Thesis]. University of Cape Town ,Faculty of Science ,Department of Chemistry, 2004 [cited yyyy month dd]. Available from: http://hdl.handle.net/11427/6285en_ZA
dc.language.isoengen_ZA
dc.publisher.departmentDepartment of Chemistryen_ZA
dc.publisher.facultyFaculty of Scienceen_ZA
dc.publisher.institutionUniversity of Cape Town
dc.subject.otherChemistryen_ZA
dc.titleSynthesis and antiplasmodial structure-activity relationships for some novel 4-aminoquinolines and 5-chlorobenzimidazolesen_ZA
dc.typeMaster Thesis
dc.type.qualificationlevelMasters
dc.type.qualificationnameMScen_ZA
uct.type.filetypeText
uct.type.filetypeImage
uct.type.publicationResearchen_ZA
uct.type.resourceThesisen_ZA
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