Progress in the Understanding of the Key Pharmacophoric Features of the Antimalarial Drug Dihydroartemisinin: An Experimental and Theoretical Charge Density Study

• Published in: Chemistry : a European journal 2013-03, Vol.19 (10), p.3490-3503
• Main Authors: Saleh, Gabriele, Soave, Raffaella, Lo Presti, Leonardo, Destro, Riccardo
• Format: Article
• Language: English
• Subjects: Antimalarials - chemistry; Antimalarials - pharmacology; Artemisinins - chemistry; Artemisinins - pharmacology; Backbone; Bonding; Chains; charge densities; Charge density; Chemistry; Diffraction; dihydroartemisinin; Drugs; Minerals; Models, Theoretical; Molecular Conformation; Molecular Structure; pharmacophores; Polyethers; quantum chemistry; Reduction; Three dimensional; X-Ray Diffraction; X-rays
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201202486

The accurate, experimental charge density distribution, ρ(r), of the potent antimalarial drug dihydroartemisinin (DHA) has been derived for the first time from single‐crystal X‐ray diffraction data at T=100(2) K. Gas‐phase and solid‐state DFT simulations have also been performed to provide a firm basis of comparison with experimental results. The quantum theory of atoms in molecules (QTAIM) has been employed to analyse the ρ(r) scalar field, with the aim of classifying and quantifying the key real‐space elements responsible for the known pharmacophoric features of DHA. From the conformational perspective, the bicyclo[3.2.2]nonane system fixes the three‐dimensional arrangement of the 1,2,4‐trioxane bearing the active OO redox centre. This is the most nucleophilic function in DHA and acts as an important CH⋅⋅⋅O acceptor. On the contrary, the rest of the molecular backbone is almost neutral, in accordance with the lipophilic character of the compound. Another remarkable feature is the CO bond length alternation along the O‐C‐O‐C polyether chain, due to correlations between pairs of adjacent CO bonds. These bonding features have been related with possible reactivity routes of the α‐ and β‐DHA epimers, namely 1) the base‐catalysed hemiacetal breakdown and 2) the peroxide reduction. As a general conclusion, the base‐driven proton transfer has significant non‐local effects on the whole polyether chain, whereas DHA reduction is thermodynamically favourable and invariably leads to a significant weakening (or even breaking) of the OO bond. The influence of the hemiacetal stereochemistry on the electronic properties of the system has also been considered. Such findings are discussed in the context of the known chemical reactivity of this class of important antimalarial drugs. Disclosing an antimalarial pharmacophore: The pharmacophoric ability of the potent antimalarial drug dihydroartemisinin (DHA) resides on the interplay among the chemical features within the molecular backbone. These have been quantitatively rationalised at the molecular and sub‐molecular level through an experimental and theoretical study of the DHA charge density and the electrostatic potential in real space (see figure).