Relevance of the 1,2,4-trioxane ring in the leishmanicidal activity of artemisinin and derivatives: a computational study

Abstract

In this manuscript, one of the approaches that have been used in teaching Computational Chemistry to undergraduate chemistry  students is reported. The topic Neglected Tropical Diseases (NTDs) was used as a motivating element, a disturbing subject in several  regions of the world, including Brazil. Artemisinin (1) and derivatives (2 and 3) from the literature, with different degrees of leishmanicidal  activity, are computationally investigated to unravel the relevance of the 1,2,4-trioxane ring in its biological actions.  Initially, different theoretical approaches were investigated to establish the most adequate theory/atomic basis (B3LYP/6-31G**) for the  development of the study. Subsequently, molecular electrostatic potential (MEP) and molecular orbitals (MOs) approximations were used  in an assumption to identify key structural features of compounds necessary for their leishmanicidal activities, as well as to  investigate likely interactions with the receptor in a biological process. In addition, to discover the best geometry involving the studied  ligand-receptor complexes and to help in the investigation of the theme on screen, simulations of interactions between the endoperoxide  bridge region of the 1,2,4-trioxane ring of the compounds and the Fe2+ ion of the receptor (heme) were performed. The  investigation with MEP showed that the compounds (1 and 2), which have the 1,2,4-trioxane ring, can undergo electrophilic attack in this  region, mainly due to the existence of the endoperoxide bridge, unlike the compound (3) which missed this bridge. The scrutiny carried  out with the MOs, was anchored in information from the literature, indicating that the HOMO of the compounds (1 and 2) can interact  with the heme in the occurrence of a biological process. Besides that, the study of ligand-heme interaction, in addition to indicating  specific interactions between the endoperoxide bridge of the 1,2,4-trioxane ring and Fe²⁺ heme, corroborated the finding that the loss of  this bridge directly influences the loss of the leishmanicidal activity of one of the derivatives (3). The motivating topic NTDs, along with  the topics Methodology, Results and Discussion, as well as the Conclusions and References presented in this manuscript constitute a robust exercise that can help in the development of competence in Computational Chemistry in Chemical Education (undergraduate and  postgraduate).