Highly conformationally constrained halogenated 6-spiroepoxypenicillins as probes for the bioactive side-chain conformation of benzylpenicillin |
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Authors: | Richard E Shute David E Jackson Barrie W Bycroft |
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Institution: | (1) Department of Pharmaceutical Sciences, University of Nottingham, NG7 2RD Nottingham, UK;(2) Present address: ICI Pharmaceuticals, Mereside, Alderley Park, SK 10 4TG Macclesfield, Cheshire, UK |
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Abstract: | Summary The halogenated 6-spiroepoxypenicillins are a series of novel semisynthetic -lactam compounds with highly conformationally restricted side chains incorporating an epoxide. Their biological activity profiles depend crucially on the configuration at position C-3 of that epoxide. In derivatives with aromatic-containing side chains, e.g., anilide, the 3R-compounds possess notable Gram-positive antibacterial activity and potent -lactamase inhibitory properties. The comparable 3S-compounds are antibacterially inactive, but retain -lactamase inhibitory activity.Using the molecular simulation programs COSMIC and ASTRAL, we attempted to map a putative, lipophilic accessory binding site on the PBPs that must interact with the side-chain aromatic residue. Comparative computer-assisted modelling of the 3R, and 3S-anilides, along with benzylpenicillin, indicated that the available conformational space at room temperature for the side chains of the 3R and the 3S-anilides was mutually exclusive. The conformational space for the more flexible benzylpenicillin could accommodate the side chains ofboth the constrained penicillin derivatives. By a combination of van der Waals surface calculations and a pharmacophoric distance approach, closely coincident conformers of the 3R-anilide and benzylpenicillin were identified. These conformers must be related to the antibacterial, bioactive conformer for the classical -lactam antibiotics. From these proposed bioactive conformations, a model for the binding of benzylpenicillin to the PBPs relating the three-dimensional arrangement of a putative lipophilic S2-subsite, specific for the side-chain aromatic moiety, and the 3 -carboxylate functionality is presented.This work has been reported in preliminary form at the 4th Royal Society of Chemistry International Symposium on Recent Advances in the Chemistry of -lactam Antibiotics, Churchill College, Cambridge, U.K., 3–6 July 1988. |
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Keywords: | -Lactam antibiotics" target="_blank">gif" alt="beta" align="MIDDLE" BORDER="0">-Lactam antibiotics -Lactamase inhibitors" target="_blank">gif" alt="beta" align="MIDDLE" BORDER="0">-Lactamase inhibitors Penicillin binding proteins Accessory enzymic binding sites Pharmacophore |
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