Study On The Antimalarial Mechamism And Multi Dimension Quantitative Structure-activity Relationship Of QHS' Derivatives

QHS (C₁₅H₂₂O₅) is a novel antimalarial drug isolated from Chinese herb Artemisia annua L in 1972. Structural studies by chemical analysis, X-ray single-crystal diffraction and other spectroscopic methods showed that QHS is a sesquiterpene lactone with a peroxide group. QHS is very popular in treating malarial for high efficiency, rapid action and low toxicity. Great achievements have been acquired in search for the mechanism of action of QHS in the past a few decades, The most affirmative conclusion is that the endoperoxy bridge is a definitely striking feature for antimalarial activity. Endoperoxides are supposed to act on heme leading to the reduction of the peroxide bond and productin of radicals, which may be responsible for killing the parasite.The interactin of ferrous iron with artemisinin causes the peroxide bond to be broken and a cyclic product is produce between the peroxide bridge oxygen atoms and ferrous iron, and the cyclic product cleavaged for the shift of Fe( II) and o-centered free radical is produced. The mechanism is calculated at HF/STO-3G level for the first time to simulate the antimalarial mechanism of QHS and the mechanism is reasonably explained based on their electronic structures.To systemic study the three dimensional structure-activity relationship of QHS' derivatives, an efficient, steady model is built to carry out comparative molecular field analysis using proton probe, CH3 probe and Fe²⁺ probe. The quantum parameters of artemisinin derivatives were calculated at B3LYP/6-31G* level using Gaussian03 , the spatial and topological indices were calculated using Cerius² at SGI workstation.extracted based on artemisinin derivatives' electronic structure. The statistical methods genetic function approximation and genetic partial least squares are utilized and a comparatively significant QSAR models were built.