Stereochemistry of benzodiazepine receptor ligands. Possible role of C–H ⋯ X interactions in drug–receptor binding and crystal structures of CL218–872, Zopiclone and DMCM

Abstract

The crystal structures of three benzodiazepine (BDZ)-receptor ligands, i.e. CL218–872, Zopiclone and DMCM, are reported. CL218-872 crystallizes in the space group Pccn with a= 22.624(2), b= 13.073(2), c= 8.385(1)Å. 1160 reflections with I > 3σ(I) were used in the refinement. The structure was solved by direct methods and refined by weighted full-matrix least-squares with anisotropic non-H and isotropic H atoms to R= 0.038. Zopiclone crystallizes in the space group P2₁2₁2₁ with a= 5.567(3), b= 8.852(2), c= 35.677(17)Å. 915 reflections with I > 1.5σ(I) were used in the refinement. The structure was solved by direct methods and refined by weighted full-matrix least-squares with anisotropic non-H and calculated H atoms to R= 0.060. DMCM crystallizes in the space group P2₁/n with a= 13.801 (3), b= 10.980(2), c= 10.620(2)Å, β= 103.81(2)°. 1 857 reflections with I > 2σ(I) were used in the refinement. The structure was solved by direct methods and refined by weighted full-matrix least-squares with anisotropic non-H and isotropic H atoms to R= 0.044.

A detailed analysis of the hydrogen bonds (HB) which exist in the packing of the three crystals has been carried out in order to understand the role played by hydrogen-bond interactions in the mechanism of action in drug-receptor binding. The shortage of typical HB donor groups causes, in the structures examined, the occurrence of an unusual number of short C–H ⋯ X (X = O,N,F) interactions, where all hydrogens involved possess a partial positive charge, i.e. a somewhat acidic character. This fact can be an indication of the importance of such interactions, normally neglected. It is also shown, mainly by calculation of the electrostatic potential spanned by the single molecules, that the N–N group of the triazole ring in CL218–872 can play the role usually played by the strong acceptor CO group present in almost all BDZ-receptor ligands.