title: Conformational analysis of r207910, a new drug candidate for the treatment of tuberculosis, by a combined NMR and molecular modeling approach.
abstract: R207910 is an enantiomeric compound from a new class of antimycobacterial agents, the diarylquinolines [Science; 307:223 (2005)]. As enantiospecific interaction is required for biologic activity, we have undertaken a combined nuclear magnetic resonance and molecular modeling study to gain new insights into its conformation in solution and its absolute configuration. A conformational analysis using a Monte-Carlo method has been performed on each of the four possible stereomers of this compound leading to the identification of their most stable conformation. Additional ab initio calculation was performed with emphasis on the strength of the observed intramolecular hydrogen bond. Simultaneously, a complete structural identification has been carried out by a set of monodimensional and bidimensional (1)H-(13)C-NMR experiments. Determination of inter-proton distances has been achieved by a series of (1)H-(1)H ROESY NMR experiments with different mixing times followed by a volume quantification of the correlations peaks. These experimental data were compared with the theoretical distances obtained from the conformational analysis. The remarkable match shows that R207910 adopts one of the low-energy conformations predicted by molecular modeling and belongs to the (RS, SR) couple of diastereoisomers. A posteriori validation of our approach has been performed by X-ray structure determination that concluded for the RS configuration.
authors.affiliation: Johnson & Johnson Pharmaceutical Research & Development, Campus de Maigremont-BP615, 27106 Val de Reuil Cedex, France. sgaurran@prdfr.jnj.com
authors.forename: Sandrine
authors.initials: S
authors.lastname: Gaurrand
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Desjardins
authors.forename: Christophe
authors.initials: C
authors.lastname: Meyer
authors.forename: Pascal
authors.initials: P
authors.lastname: Bonnet
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Argoullon
authors.forename: Hassan
authors.initials: H
authors.lastname: Oulyadi
authors.forename: Jérôme
authors.initials: J
authors.lastname: Guillemont
mesh_terms: D000995:Antitubercular Agents / Q000737:chemistry*; D018360:Crystallography, X-Ray; D064687:Diarylquinolines; D006860:Hydrogen Bonding; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008958:Models, Molecular; D008968:Molecular Conformation; D011804:Quinolines / Q000737:chemistry*
chemical_list: D000995:Antitubercular Agents; D064687:Diarylquinolines; D011804:Quinolines; C493870:bedaquiline