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 lowenergy 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.

ATP Synthase and the Actions of Inhibitors Utilized To Study Its Roles in Human Health, Disease, and Other Scientific Areas

“…R207910 is an enantiomeric compound with two chiral centers. It adopts the lowest-energy conformation with the carbon alpha relative to the quinoline moiety R and the carbon beta S (135). The binding of the inhibitor to the binding site in ATP synthase is stereoselective, and its (S,R) stereoisomer is 2 orders of magnitude less inhibitory than R207910 (215).…”

Conformational isomerization of N-(naphthalen-1-yl)-N-(phenyl(quinolin-3-yl)methyl)amide derivatives

“…Full 1 H NMR spectroscopy of compound 1 is shown in Figure 1 and two interesting phenomena were found. The first one is that no proton resonance was found at around 6.16 ppm, where the proton signal of CH should appear in that range according to 1 H NMR predicting formula [6] . We ascribed it to shield effect of five aromatic rings, which brought the signal to a lower field and was overlapped with aromatic protons.…”

Asymmetric Synthesis and Absolute Configuration Assignment of a New Type of Bedaquiline Analogue

“…Because the structural difference between bedaquiline and our final compounds is so small and according to the overlay results of the crystal structure of bedaquiline from the PDB database (ID: 4V1F) and the optimized conformer of (1R, 2S) isomer of TM-05 ( Figure S9), it is reasonable to assume that they will have similar characteristic correlation peaks in their 2D NOESY or ROESY spectra. Specifically, in the spectra of the (1R, 2S)/(1S, 2R) group of TM-05, the Ph(o)/E and A/Ha 1 correlations should be observed, and the Ph(o)/Ha 1 and A/E correlations should be absent; conversely, regarding the (1R, 2R)/(1S, 2S) group of TM-05, the Ph(o)/Ha 1 and A/E correlations should appear, while Ph(o)/E and A/Ha 1 should disappear [33]. However, in the 2D NOESY spectrum ( Figure S5 …”