Structure-activity relationships of some indolo[3,2-c]quinolines with antimalarial activity.
The synthesis, physicochemical characterization and in vitro antimalarial activity of a series of indolo[3,2-c]quinolines (9a-f) are described. There is only a poor correlation between the activity and hydrophobicity. In contrast, 33% of the observed variation in antimalarial activity can be attributed to the size of the side chain attached to position 9 of the indoloquinoline ring. An increase in the size of this dibasic side chain generally results in a reduction in activity, suggesting that it is accommodated in a site/cavity of limited size on the receptor. More significantly, the charge on the distal nitrogen (N3) on the side chain, located 10-11 A from the quinoline N, could account for 75% of the observed variation. Since a large charge on N3 is associated with improved antimalarial activity, it is suggested that N3 is protonated and functions as a H bond donor in the drug-receptor interaction.
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Department of Pharmacy, National University of Singapore, 10, Kent Ridge Crescent, Singapore, Republic of Singapore 119260.
Ngiam
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Tan
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Kuaha
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Wilairat
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D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002626:Chemistry, Pharmaceutical / Q000379:methods; D057927:Hydrophobic and Hydrophilic Interactions; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests / Q000379:methods; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000962:Antimalarials; D007211:Indoles; D011804:Quinolines