Progress in the Understanding of the Key Pharmacophoric Features of the Antimalarial Drug Dihydroartemisinin: An Experimental and Theoretical Charge Density Study
Articolo
Data di Pubblicazione:
2013
Citazione:
Progress in the Understanding of the Key Pharmacophoric Features of the Antimalarial Drug Dihydroartemisinin: An Experimental and Theoretical Charge Density Study / G. Saleh, R. Soave, L. Lo Presti, R. Destro. - In: CHEMISTRY-A EUROPEAN JOURNAL. - ISSN 0947-6539. - 19:10(2013), pp. 3490-3503. [10.1002/chem.201202486]
Abstract:
The accurate, experimental charge density distribution, rho(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 1(r) scalar field, with the aim of classifying and quantifying the key real-space elements responsible for the known pharmacophoric features of DHA. From theconformational 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 alpha- and beta-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 nonlocal
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.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
charge densities; dihydroartemisinin; pharmacophores; quantum chemistry; X-ray diffraction
Elenco autori:
G. Saleh, R. Soave, L. Lo Presti, R. Destro
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