CONFORMATIONAL-ANALYSIS OF THE ANTIMALARIAL AGENT QUININE

Quinine, an active antimalarial compound, is one of the most abundant constituents extracted from the bark of Cinchona trees, The activity d ifferences among structurally related molecules appear to depend on th e absolute stereochemistry of some functional groups, a result that ha s stimulated a detailed conformational analysis of these molecules of biological interest. In the present study the potential energy surface (PES) for the antimalarial agent quinine (C20H24O2N2) has been compre hensively investigated using the molecular mechanics (MM) and quantum mechanical semiempirical AM1 and PM3 methods. Six distinct minimum-ene rgy structures are located on the multidimensional PES and also charac terized as true minima through harmonic frequency analysis. The relati ve stabilities and thermodynamic properties are reported. The coexiste nce of different conformers is discussed for the first time in the lit erature based on the calculated transition-state (TS) structures conne cting the six minima located on the PES for the quinine molecule. The theoretical results reported in the present study are in agreement wit h the experimental proposal, based on NMR data, that there are two pos sible forms for the quinine molecule in solution.