Browsing by Author "Van der Merwe, Johannes Dawid"

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    Synthesis and antiplasmodial structure-activity relationships for some novel 4-aminoquinolines and 5-chlorobenzimidazoles
    (2004) Van der Merwe, Johannes Dawid; Hunter, Roger; Egan, Timothy J
    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.