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 IC 50 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/IC 50 ) 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 (IC 50 K1/IC 50 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.