Induced fit phenomena in clathrate structures of cephalosporins

Abstract

The antibiotics cephalexin, cephradine, cefaclor and cefadroxil form clathrate type inclusion compounds with naphthalene derivatives that readily crystallize from an aqueous solution. In these clathrates the antibiotic molecules form the hosting lattice and the naphthalene derivatives are the guest molecules, whereby water serves as “cement”. A list of potential guest molecules was drawn up using the concept of molecular similarity. This list was extended by a series of compounds which are not supposed to fit. It was shown that a large variety of naphthalene derivatives can be hosted in clathrates with cephalexin, cephradine and cefaclor. Cefadroxil, however, is much more selective in accommodating guest molecules. Although cephalexin, cephradine and cefaclor form the principal hosting lattice and govern the overall crystal structure of the clathrates, the guest molecules are capable of inducing deviations in the framework of the host molecules, i.e. induced fit. Cefadroxil, however, lacks this adaptability due to the rigid three-dimensional hydrogen bonded structure of its hosting framework, and an exact fit of a guest molecule in the hosting framework of cefadroxil is thus required, i.e. lock and key concept. All four antibiotics have a limited adaptability by varying the number of water molecules in the clathrates. Certain guest molecules replace water in order to obtain the required space for inclusion, whereas other guest molecules cause incorporation of extra water, which is apparently beneficial for the crystal packing. However, the adaptability due to varying the water content cannot account for the remarkable flexibility in accommodating guest molecules exhibited by cephalexin, cephradine and cefaclor. The concept of induced fit is relevant for the understanding and design of clathrate type structures.