Structure and dynamics of theophylline derivatives by X-ray, NMR and molecular mechanics studies

The two theophylline derivatives 7-isobutyl-1,3-dimethylxanthine (1) and 7-butyl-1,3-dimethylxanthine (2) show antibronchospastic properties, the first one having a higher pharmacological activity together with a stronger solubility in aqueous solutions. Crystal structures, determined for both compounds, exhibit similar features at the molecular level, but a different crystal packing, i.e. compound 2 has a closer arrangement. Melting points and enthalpic data of the two compounds are in agreement with this closer arrangement of compound 2. NMR measurements show a remarkable mobility of the alkyl side chain of 2 and its very low solubility in aqueous solution. Systematic conformational searches, using the software package provided by Biosym Technologies, were carried out starting from the X-ray crystal structures with the atomic charges calculated with the AM1 routine. Results from these calculations, performed with the CFF91 force field in DISCOVER, underline the high conformational freedom of the side chain of compound 2. The collected results may be useful to understand the different pharmacological activity between compounds 1 and 2.