X-ray structures of three penem antibiotics: Molecular mechanical and dynamic aspects

The structures of three beta-lactam penem antibiotics-i.e. the sodium[5R-[5 alpha,6 alpha(R*)]]-6-(1-hydroxyethyl)-7-oxo-3-[[(1-pyrrolidinylthioxometh yl)thio]methyl]4-thia-1-azabicyclo[3.2.0] hept-2-ene-2-carboxylate (compoun d 1), the [5R-[3(S*),5 alpha,6 alpha(R*)]]-3-[[2-(aminocarbonyl)-1-pyrrolid inyl]methyl]-6-(1 -hydroxyethyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene -2-carboxylic acid (compound 2), and the [5R-[5 alpha,6 alpha((R*)]]-3-[[(2 -amino-2-oxoethyl) methylamino]methyl]-6-(1-hydroxyethyl)-7-oxo-4-thia-1-az abicyclo[3.2.0]hept-2-ene-2-carboxylic acid (compound 3)-have been determin ed by X-ray analyses. In the crystal lattice two conformational isomers of 1 are present, which differ from each other in the spatial arrangement of t he dithiocarbamate chain. Compounds 2 and 3 are in zwitterionic form, being the hydrogen of the carboxylic acid moved to the amino nitrogen of the cha in at C2. This hydrogen atom, in both molecules, forms intramolecular hydro gen bonds with an oxygen atom of the carboxylate moiety and with the oxygen atom of the amido group of the side chain. The 3D structures of 1, 2, and 3 have been compared with those of previously reported beta-lactam penem an tibiotics. Particularly, the Woodward parameter and the Cohen distance, whi ch are considered important in determining the antibiotic activity, have be en discussed. Least-squares minimizations (RMS) of the distances between nu clei of selected pairs of atoms defining the pharmacological pattern have b een performed, comparing five common antibiotics (imipenem, ritipenem, ceph aloridine, amoxycillin, and benzylpenicillin) with our compounds. Finally, molecular dynamics calculations have been carried out on the three penem an tibiotics at different temperatures. The conformational behavior of the hyd roxyethyl chain, the carboxylate group, and the chain at C2 is discussed by considering the variation of some selected dihedral angles.