In vitro antimalarial activity, β-haematin inhibition and structure-activity relationships in a series of quinoline triazoles.
A novel series of quinoline triazole amide analogues (38-51) has been synthesized. Analogues 38-44 had a Cl substituent at the 7-position of the quinoline ring, while 45-51 had a CN substituent at this position. Compounds 40, 45 and 49 were found to be the most active in the series against the Plasmodium falciparum chloroquine-sensitive D10 strain, with IC₅₀ values in the range of 349-1247 nM, with 40 and 45, but not 49 also exhibiting similar activity against the chloroquine-resistant K1 strain of parasite. Quinoline triazoles 40 and 44 were the most active β-haematin inhibitors, with 50% inhibitory concentrations of 14.7 and 8.9 μM respectively. In vitro antimalarial activity of the 7-Cl bearing analogues 38-44 exhibited a strong linear dependence of log(1/IC₅₀) on log P. Thus, the more lipophilic, the more active it was found be. The 7-CN series 45-51 showed no such dependence. The resistance index (IC₅₀ K1/IC₅₀ D10) also exhibited a linear dependence on log P, with a substantially steeper slope in the case of the 7-Cl series. The findings demonstrate the feasibility of producing hydrophilic analogues with strong activity and low cross-resistance with chloroquine.
Department of Chemistry, University of Cape Town, Private Bag, Rondebosch 7701, South Africa.
Mukesh C
MC
Joshi
Kathryn J
KJ
Wicht
Dale
D
Taylor
Roger
R
Hunter
Peter J
PJ
Smith
Timothy J
TJ
Egan
D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006420:Hemeproteins / Q000037:antagonists & inhibitors*; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects*; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D000962:Antimalarials; D006420:Hemeproteins; D011804:Quinolines; D014230:Triazoles; C020753:hemozoin
Antimalarial; Plasmodium falciparum; Resistance; Structure–activity relationships; β-Haematin