Non-reductive Homolytic Scission of Endoperoxide Bond for Activation of Artemisinin: The Bi-radical Perspectives

Artemisinin is the most successful antimalarial drug against malaria caused by Plasmodium falciparum. Despite its tremendous success and popularity in malaria therapeutics, the molecular mechanism of artemisinin’s activity is still elusive. The activation of artemisinin, i.e., cleavage of the endoperoxide bond at the infected cell that generates radical intermediates and the subsequent chemical rearrangements plays a key role in the antimalarial activities. In this work, applying state-of-the-art computational techniques based on the spin-constraint density functional theory (CDFT) along with ab initio thermodynamics, we have investigated various key steps of the molecular mechanism of artemisinin. The well-accepted artemisinin activation process is the reductive heterolytic scission of the endo-peroxide bond which is followed by subsequent chemical reactions that propagate via mono-radical intermediates. Adopting CDFT methodology, here we have investigated the possible alternative ‘biradical’ intermediates and their mechanistic pathways for the subsequent chemical reactions. The change in Gibbs free energy associated with the activation of artemisinin through homolytic-scissoring (biradical) intermediate is quite competitive and favorable compared to the reductive heterolytic-scissoring (monoradical) process. This indicates the alternative possibilities for the biradical activation process. The reported experimental EPR signals for the biradicals especially for similar anti-malarial drugs like G3-factor support our observations.

Non-reductive Homolytic Scission of Endoperoxide Bond for Activation of Artemisinin: The Bi-radical Perspectives

<p>Artemisinin is the most famous antimalarial drug against malaria caused by <i>Plasmodium falciparum</i>. Despite its tremendous success and popularity in malaria therapeutics, the molecular mechanism of artemisinin’s activity is still elusive. The activation of artemisinin, i.e., cleavage of the endoperoxide bond at the infected cell that generates radical intermediates and the subsequent chemical rearrangements plays a key role in the antimalarial activities. In this work, applying state-of-the-art computational techniques based on the spin constraint density functional theory (CDFT) along with <i>ab initio</i> thermodynamics, we have investigated various key steps of the molecular mechanism of artemisinin. The well-accepted artemisinin activation process is the reductive heterolytic scission of the endo-peroxide bond which is followed by subsequent chemical reactions that propagate via mono-radical intermediates. Here adopting the CDFT we have investigated the possible alternative ‘biradical’ intermediates and their mechanistic pathways for the subsequent chemical reactions. The change in Gibbs free energy associated with the activation of artemisinin through homolytic-scissoring (biradical) intermediate is quite competitive and favorable compared to the reductive heterolytic-scissoring (monoradical) process. This clearly indicates the alternative possibilities for the biradical activation process. The reported experimental EPR signals for the biradicals especially for similar anti-malarial drugs like G3-factor support our observations. </p>

Non-reductive Homolytic Scission of Endoperoxide Bond for Activation of Artemisinin: The Bi-radical Perspectives

<p>Artemisinin is the most famous antimalarial drug against malaria caused by <i>Plasmodium falciparum</i>. Despite its tremendous success and popularity in malaria therapeutics, the molecular mechanism of artemisinin’s activity is still elusive. The activation of artemisinin, i.e., cleavage of the endoperoxide bond at the infected cell that generates radical intermediates and the subsequent chemical rearrangements plays a key role in the antimalarial activities. In this work, applying state-of-the-art computational techniques based on the spin constraint density functional theory (CDFT) along with <i>ab initio</i> thermodynamics, we have investigated various key steps of the molecular mechanism of artemisinin. The well-accepted artemisinin activation process is the reductive heterolytic scission of the endo-peroxide bond which is followed by subsequent chemical reactions that propagate via mono-radical intermediates. Here adopting the CDFT we have investigated the possible alternative ‘biradical’ intermediates and their mechanistic pathways for the subsequent chemical reactions. The change in Gibbs free energy associated with the activation of artemisinin through homolytic-scissoring (biradical) intermediate is quite competitive and favorable compared to the reductive heterolytic-scissoring (monoradical) process. This clearly indicates the alternative possibilities for the biradical activation process. The reported experimental EPR signals for the biradicals especially for similar anti-malarial drugs like G3-factor support our observations. </p>

Study on Dust Turbulence-Chemical Agglomeration for Electrostatic Precipitation Technology

Due to the turbulent mixing between agglomeration agent and dust, the number of collisions per unit time between particles and droplets increases with the particle size in the process of chemical agglomeration, and the agglomeration efficiency increases accordingly. Turbulent agglomeration can promote the agglomeration effect of subsequent chemical agglomeration by strengthening the collision between particles and agglomerant droplets. The author used chemical agglomeration and turbulent mixing to cooperate in order to improve the efficiency of dust removal. Turbulent mixing can promote chemical agglomeration from agglomeration effect and dust removal efficiency, which can greatly improve electric dust removal technologyTurbulent mixing is the most intense at the inlet box position, and the agglomeration effect is the best. Turbulent mixing synergistic effect has an effect on dust removal efficiency. Compared with the three curves, it can be seen that the dust removal efficiency increases rapidly with the increase of agglomeration concentration, the curve trend changes obviously. The dust removal efficiency can reach 98.36 % and it is the highest in the middle section when the wind speed is greater than 11.2m/s. Through the experiment, the turbulent mixing and chemical coagulation method has a good application prospect in the electrostatic precipitators.

Introduction: Geology of Fractured Reservoirs

The characterisation of fractured reservoirs and fractured geothermal resources requires a thorough understanding of the geological processes that are involved during fracturing and the host rock rheological properties. The presence or absence of mechanical layering within the rock and the mode of failure substantially control the organization and scaling of the fracture system; subsequent chemical alteration and mineralization can both increase or decrease porosity and permeability. An integration of this understanding using information from outcrop analogues, together with static and dynamic subsurface data,can improve our ability to predict the behaviour of fractured reservoirs across a range of scales.Thematic collection: This article is part of the The Geology of Fractured Reservoirs collection available at: https://www.lyellcollection.org/cc/the-geology-of-fractured-reservoirs