Orthogonal hydrogen and halogen bonding for 1,1-dimethylbiguanide-halogen stabilization: Synthesis, structural, and spectroscopic study

Abstract

Thyroid hormone inhibition by 1,1-dimethylbiguanide (metformin), a potent drug used to treat type-2 diabetes, has been recently reported. However, the mechanism of inhibition has not yet been explored. Orthogonal hydrogen bonds (HBs) and halogen bonds (XBs) extend the properties of the material for different applications, in addition to allowing the molecular recognition of biomolecules. In this study, the solvent effects on orthogonal HBs and XBs in metformin (MET) complexes with halogen molecules (X2 = I2, Br2, and Cl2) were investigated by experimental and theoretical (DFT) studies. The molecular adducts were investigated using spectroscopic techniques, such as UV–Vis, FT-IR, TGA, and SEM imaging. DFT (rwb97xd and MP2) and experimental (FT-IR of solid complexes) results revealed the presence of cis and trans imine groups (CNH). Upon complexation with X2, two conformations were formed: METX2-I and METX2-II, in which the imine groups were trans and cis, respectively. Orthogonal HBs and XBs were directly involved with the stabilization of METX2-II over METX2-I by ~5.0 kcal/mol. The effect of the solvent on the stability of the complexes was investigated experimentally (using acetonitrile, ethanol, methanol, and dichloromethane) and theoretically (using the polarized continuum model (PCM) at MP2/aug-cc-pvdz. The results demonstrate that the formed complexes were stabilized by orthogonal XBs and HBs in polar solvents. The formation constants measured in different solvents correlate with the stability constants of the complexes (R = 0.95).