title: Pharmacophore modeling of substituted 1,2,4-Trioxanes for quantitative prediction of their antimalarial activity.
abstract: A pharmacophore model has been developed for determining the essential structural requirements for antimalarial activity from the eight series of substituted 1,2,4-trioxanes. The best pharmacophore model possessing two aliphatic hydrophobic, one aromatic hydrophobic, one hydrogen-bond (H-bond) acceptor, and one H-bond acceptor (lipid) feature for antimalarial activity showed an excellent correlation coefficient for the training (r(2)(training) = 0.85) and a fair correlation coefficient for the test set (r(2)(test) = 0.51) molecules. The model predicts well to other known substituted 1,2,4-trioxanes including those which either are drugs or are undergoing clinical trials. In order to further validate this model, five substituted 1,2,4-trioxanes were synthesized from the generated focused library and screened for antimalarial activity. The observed activity of these molecules was consistent with the pharmacophore model, suggesting that the model may be useful in the design of potent antimalarial agents.
authors: Medicinal and Process Chemistry Division and Parasitology Division, Central Drug Research Institute, CSIR, Lucknow, 226001, India.
authors: Amit K
authors: AK
authors: Gupta
authors: S
authors: S
authors: Chakroborty
authors: Kumkum
authors: K
authors: Srivastava
authors: Sunil K
authors: SK
authors: Puri
authors: Anil K
authors: AK
authors: Saxena
mesh_terms: D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology*; D006571:Heterocyclic Compounds / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy; D008954:Models, Biological; D008958:Models, Molecular; D010963:Plasmodium falciparum / Q000187:drug effects*; D021281:Quantitative Structure-Activity Relationship
chemical_list: C503429:1,2,4-trioxane; D000962:Antimalarials; D006571:Heterocyclic Compounds