title: Effective discrimination of antimalarial potency of artemisinin compounds based on quantum chemical calculations of their reaction mechanism.
abstract: The reaction mechanism of 12 antimalarial artemisinin compounds with two competitive pathways was studied by means of quantum chemical calculations using the IMOMO(B3LYP/6-31(d,p):HF/3-21G) method. The oxygen-centered radicals, carbon-centered radicals, and transition states (TS) in both pathways were geometrically optimized. The obtained kinetic and thermodynamic energy profiles show that homolytic C-C cleavage reaction (pathway 2) is energetically more preferable than an intramolecular 1,5-hydrogen shift process (pathway 1), which is consistent with the docking calculations. However, compounds that can easily proceed along the pathway 1 have high activity. Therefore, both pathways are important for antimalarial activity. Moreover, effective discrimination between high and low activity compounds using EA1, deltaE1, and deltaE(1A-2A) was accomplished.
authors.affiliation: Department of Chemistry, Faculty of Science, Chulalongkorn University, Patumwan, Bangkok 10330, Thailand.
authors.forename: Somsak
authors.initials: S
authors.lastname: Tonmunphean
authors.forename: Vudhichai
authors.initials: V
authors.lastname: Parasuk
authors.forename: Sirirat
authors.initials: S
authors.lastname: Kokpol
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D037621:Artemisinins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D007700:Kinetics; D008968:Molecular Conformation; D010963:Plasmodium falciparum / Q000187:drug effects; D021281:Quantitative Structure-Activity Relationship; D011789:Quantum Theory; D013237:Stereoisomerism; D013816:Thermodynamics
chemical_list: D000962:Antimalarials; D037621:Artemisinins