Crystal Structure and 1H NMR Experimental and Theoretical Study of Conformers of 5-Methyl-1-(4’-methylphenylsulfonylamino)-1H-[1,2,3]-triazole-4-carboxylic Acid Ethyl Ester and 5-Methyl-1-(phenylsulfonylamino)-1H-[1,2,3]-triazole-4-carboxylic Acid Ethyl Ester

Abstract

We reported experimental and theoretical investigation of conformers of 1,2,3-triazole derivatives, substances of exclusively synthetic origin, subject of extensive studies, because of several biological properties, such as antiviral, antimicrobial and antileishmaniasis. We reported molecular/supramolecular X-ray structures of antiophidian compounds I and II. For I and II there are two crystallographic different molecules in the unit cell (A and B). To explore the causes of the similarities in the compound's crystal structures, intermolecular interactions were explored using the Hirshfeld surface as the fingerprint plots. In addition, density functional theory (DFT) calculations were carried out at the ωB97x-D/6-31G(d,p)-PCM-CHCl 3 level aiming to contribute to the interpretation of the experimental data and complement the experimental findings. Two structures named 2A and 5B were found in good agreement with the respective X-ray solid state ones (A and B). Theoretical 1 H nuclear magnetic resonance (NMR) spectra calculated for 5B rotated structure (torsion angles deviation around 40° to 90°) was in fine agreement with experimental results (in CDCl 3) indicating that the solution molecular structure is considerably different from optimized equilibrium geometries and solid-state structure. Therefore, care is needed when using X-ray structures or DFT geometries to model interaction of drugs with biological targets since significant conformational changes may take place in solution.

Unveiling the Molecular Structure of Antimalarial Drugs Chloroquine and Hydroxychloroquine in Solution through Analysis of 1H NMR Chemical Shifts

“…In addition, the binding modes of chloroquine and hydroxychloroquine to a macromolecule may not be strictly related to the preferred molecular structure in water solution. Different crystal structures of proteins co-complexed with chloroquine are on the Protein Data Bank; however, using the solid-state structure as a model to investigate the interactions in biological media may not be so accurate since significant changes in the crystal structure can take place when dissolved in solvent (see for example, ref ). We believe that the knowledge of the statistically predominant drug molecular structure in aqueous media is of relevance for performing efficient molecular modeling studies.…”