Abstract
Quinine is an alkaloid with powerful antimalarial activity, isolated from the bark of Peru’s cinchona trees. Quinidine is an erythro diastereoisomer of quinine also exhibiting antimalarial activity. Conformational studies performed so far had never identified conformers with intramolecular hydrogen bonds (IHB). The current study shows the possibility of conformers with an IHB between the quinuclidine and quinoline moieties of these molecules. The study was performed at different levels of theory: Hartree Fock (HF) with the 6-31G(d,p) basis set, Density Functional Theory (DFT) with the B3LYP functional and the 6-31+G(d,p) basis set and Møller–Plesset Perturbation Theory (MP2) with the 6-31+G(d,p) basis set, to confirm the results. The results suggest that the stabilising effect of this IHB is weaker or comparable with respect to the stabilising effect of the preferred mutual orientation of the two moieties. Although the IHB-containing conformers may not be the lowest energy ones, their relative energy is sufficiently low for them to be included among the possible ones responsible for the compounds’ antimalarial activity.
Highlights
Quinine (C20 H24 N2 H2, Figure 1) and quinidine are alkaloids isolated from the bark of cinchona trees found in Peru
Density Functional Theory (DFT) results are chosen with preference to Hartree Fock (HF) results because DFT takes into account part of the electronic correlation
They are closer to MP2 results, which take into account both electron correlation and dispersion energy
Summary
Quinine (C20 H24 N2 H2 , Figure 1) and quinidine are alkaloids isolated from the bark of cinchona trees found in Peru. C9–C10, corresponding to the C11–C10–C9–C8, C10–C9–C8–N1 and H22–O20–C9–C8 torsion angles Their rotations determine the mutual orientations of the two moieties, determining the possibility that the N atom and the OH group come close enough to form an intramolecular hydrogen bond (IHB). The results of a B3LYP/6-31+G(d,p) study of quinine and quinidine [15] were analysed terms of the C11–C10–C9–C8, C10–C9–C8–N1 and N1–C8–C9–O20 dihedral angles. The most stable conformer (78% population) corresponded with a cis open geometry with a −153◦ C10–C9–C8–N1 dihedral angle This motivated the current study, as we assumed that the opposite orientation of the OH might enable the formation of an IHB with the N atom of the quinuclidine moiety
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