DFT study of the reductive decomposition of artemisinin.
Artemisinin is a sesquiterpene lactone with an endoperoxide function that is essential for its antimalarial activity. The DFT B3LYP method, together with the 6-31G(d) and 6-31+G(d,p) basis set, is employed to calculate a set of radical anions and neutral species supposed to be formed during the rearrangement of artemisinin from the two radicals (C-centered and O-centered) that are supposed to play a relevant role in the mechanism of action. The B3LYP results show that the primary and the secondary radicals centered on C(4), generated by homolytic break of the C(3)-C(4) bond and by 1,5 hydrogen shift, respectively, are more stable than radicals centered on oxygen. The calculations show that the activation barriers for rearrangements are low, leading to a thermodynamically favorable process. These results reinforce our previous conclusions based on semi-empirical calculations but also give additional information on the reductive decomposition of artemisinin.
Taranto
Alex Gutterres
AG
Departamento de Saúde, Universidade Estadual de Feira de Santana, BA, Brazil.
de Mesquita Carneiro
José Walkimar
JW
de Araujo
Martha Teixeira
MT
D000962:Antimalarials / Q000378:metabolism* / Q000494:pharmacology; D037621:Artemisinins / Q000378:metabolism* / Q000494:pharmacology; D003198:Computer Simulation; D006859:Hydrogen / Q000737:chemistry; D006860:Hydrogen Bonding; D008433:Mathematics; D008956:Models, Chemical; D010084:Oxidation-Reduction; D010100:Oxygen / Q000737:chemistry; D012717:Sesquiterpenes / Q000378:metabolism* / Q000494:pharmacology; D013816:Thermodynamics
D000962:Antimalarials; D037621:Artemisinins; D012717:Sesquiterpenes; D006859:Hydrogen; C031327:artemisinin; D010100:Oxygen