A quantitative structure-activity study on artemisinine analogues
Abstract
Artemisinine is a natural constituent with antimalarial activity. Various ethers and esters were synthesized in our Institute. Their antimalarial activities were expressed in terms of SD90. Attempts were made to study the QSAR through Hansch analysis.
We determined the log P values of various compounds from 1-octanol/water system by HPLC. For compounds of higher log P values (3.0—5.0), 60% methanol was employed for elution, and for those of lower log P values (<3.0), 30% methanol was used. The values so determined were found to be consistent with those calculated based on the additive rule shown by Hansch. The molar refraction MR, aliphatic electronic parameters σ*, aromatic electronic parameters σp and σm, steric effects Es, field effect F, resonance effect R of the substituents were adopted from literature. Indicator variables Iα,β, were given the value of 1 for β-epimers, and O for α-epimers. A second indicator variable Io，p assumed the value 1 for o-substituted groups, and O for p- or m-substituents. The following equations were derived by the regression of such data.
log 1/C=1.120-0.198 (log P)2+1.155log P-0.612 Iα,β [1]
n=49; r =0.911; s =0.153；log P0= 2.91
1og 1/C = 3.112-0.142 1og P-0.599 Iα,β [2]
n=49; r = 0.830; s =0.205
Regression of the data of 14 ethereal compounds gave the following equation:
log l/C =0.968-0.223 (log P)2 + 1.162 log P-0.837σ*-0.145 Iα,β [3]
n = 14; r = 0.906；s = 0.168; log P0 = 2.60
From these equations, variations of anti-malarial activities are well explained by lipid-soluble properties. A comparison between eq(l) and (2) illustrates the superiority of eq(l) with a (log P)2 term. The ideal lipophilic character was calculated to be log P = 2.60-2.90. However, in the series of ethereal compounds, the electronic parameter of various substituents also have significant effect for the antimalarial activity of the compounds.
Keywords:
We determined the log P values of various compounds from 1-octanol/water system by HPLC. For compounds of higher log P values (3.0—5.0), 60% methanol was employed for elution, and for those of lower log P values (<3.0), 30% methanol was used. The values so determined were found to be consistent with those calculated based on the additive rule shown by Hansch. The molar refraction MR, aliphatic electronic parameters σ*, aromatic electronic parameters σp and σm, steric effects Es, field effect F, resonance effect R of the substituents were adopted from literature. Indicator variables Iα,β, were given the value of 1 for β-epimers, and O for α-epimers. A second indicator variable Io，p assumed the value 1 for o-substituted groups, and O for p- or m-substituents. The following equations were derived by the regression of such data.
log 1/C=1.120-0.198 (log P)2+1.155log P-0.612 Iα,β [1]
n=49; r =0.911; s =0.153；log P0= 2.91
1og 1/C = 3.112-0.142 1og P-0.599 Iα,β [2]
n=49; r = 0.830; s =0.205
Regression of the data of 14 ethereal compounds gave the following equation:
log l/C =0.968-0.223 (log P)2 + 1.162 log P-0.837σ*-0.145 Iα,β [3]
n = 14; r = 0.906；s = 0.168; log P0 = 2.60
From these equations, variations of anti-malarial activities are well explained by lipid-soluble properties. A comparison between eq(l) and (2) illustrates the superiority of eq(l) with a (log P)2 term. The ideal lipophilic character was calculated to be log P = 2.60-2.90. However, in the series of ethereal compounds, the electronic parameter of various substituents also have significant effect for the antimalarial activity of the compounds.