| Artemisinin (Qinghaosu) was first isolated in 1972 from Artemisia annua L. by Chinese researchers. It is an effective antimalarial agent against chloroquine-resistant Plasmodium falciparum strains and cerebral malaria with low toxicity. In order to develop more potent, better water-soluble, less neurotoxic agents, a large mount of artemisinin analogs have been synthesized by the side chain changing or structure simplifying. However, the detailed mechanism of artemisinin derivatives is elusive. In attempts to understand the mechanism and the relationship of the antimalarial activity between their structures, the quantitative structure-activity relationships were studied in this thesis. 91 artemisinin derivatives' structure were calculated by HF/3-21G method and their quantum indices were calculated in theory.The main conclusions are as follows:1. The artemisinin's conformations comparison, which were optimized by series quantum chemistry methods respectively, and the comparison of chemical shifts, which were predicted based on 10-deoxoartemisinin's conformations, both showed that the HF/3-21 was a quite accurate method. Concerning the accuracy and the mount of CPU time, HF/3-21 G method was selected to optimize the artemisinin analogs for the building of QSAR model.2. The quantum indices were extracted basing on artemisinin analogues' electronic structure. The comparatively significant QSAR models were built by regression analysis. The models indicated that:a. The peroxo bridge is essential base group for the antimalarial activity,b. Supportting the mechanism that the creation of the free radical RO on O(l),c. Increasing the length of the substituent is conducive to antimalarial activity but the volume increasing is disadvantageous for the 10-O and 16-C substituted artemisinin analogs, so the forded chain of substituent should branches at the head group,d. The R or S isomer is conducive to antimalarial activity for the molecular area reducing,e. Substituting of electro withdrawing groups improves the antimalarial activity. |
