Étude De La Structure Moléculaire De L'oxacilline Et De L‚Acide Penicilloique Correspondant

Abstract

The crystal structures of (5-methyl-3-phenyl-4-isoxazolyl) penicillin monohydrate ( I ) and of the methyl diester of the corresponding penicilloic acid (11) were solved from X-Ray diffraction by direct methods and refined to R = 0.043 and 0.087 respectively. Bond distances and angles of I agree with those of other penicillin derivatives. The side-chains of molecules Iand I1 have the same conformation. INTRODUCTIONLa dQtermination des structures cristallines du sel sodique de l'oxacilline (I) et du diester mQthylique de l'acide p6nicilloique correspondant (11) s'inscrit dans le cadre d'une Qtude ggndrale des caractQristiques conformationnelles d'inhibiteurs de 8-lactamases ( ' '').I. Sel sodique de la (5-mdthyl-3-phdnyl-4-isoxazolyl) penicilline monohydrate 11. Diester mdthylique de l'acide (5-mdthyl-3-ph~nyl-4-isoxazolyl) piinicilloyque Les 5-lactamases catalysent l'hydrolyse des pdnicillines en acides penicilloiques biologiquement inactils; elles constituent le principal facteur de resistance des bactdries aux antibiotiques 6-lactamiques.-761 -L'oxacilline. comme d'autres penicillines semi-synchetiques possedant une chaine latlrale stbriquement encombree, a une bonne affinite pour le site actif de l'enzyme mais une vitesse d'hydrolyse trPs faible ('). DETERMINATION ET AFFINEMENT DES STRUCTURES CRISTALLINESLes cristaux du composd I ont 4t6 obtenus par lente evaporation d'une solution dans du n-butanol/mdthanol; ceux du composC 11, B partir d'une solution dans le methanol. Leurs densitis ont Bt.6 mesurges par la m6thode de flottation.Les structures moleculaires des deux composes ont Btd rtisolues par diffraction des rayons X. Les Les reflexions ont 6t6 enregistrees sur un diffractomstre automatique B quatre certles NONIUS CAD-4 avec balayage w / 2 0 utilisant la radiation C u 6 ( A -1.54178 1). La chaine latdrale de l'oxacilline adopte une geometric dtendue, diffdrente de celle de la cloxacilline et de la dicloxacilline qui apparaissent replides sur le noyau.L'analyse des angles digdres renseigngs ci-dessous montre que la chaine laterale de la mol6cule I1 conserve la m8me conformation que celle du compos6 I malgrd la modification du noyau 8-lactame.-769 -

β-Lactamases: Why and How

“…After ring opening, steric interaction between atoms b and e and their substituents forces the bcde dihedral angle to open up. A computational model of a penicilloate in vacuo, after molecular mechanics energy minimization and a molecular dynamics simulation, suggested a value of the bcde dihedral of −70 ± 10° at 300 K. This agrees well with the value of −74° from a crystal structure . In penicillin complexes of DD-peptidases, the average of this dihedral was −29 ± 12° (11 structures), and for all cases, including cephalosporins and carbapenems, the average was −33 ± 15°.…”

“…A computational model of a penicilloate in vacuo, after molecular mechanics energy minimization and a molecular dynamics simulation, suggested a value of the bcde dihedral of −70 ± 10°a t 300 K. This agrees well with the value of −74°from a crystal structure. 34 In penicillin complexes of DD-peptidases, the average of this dihedral was −29 ± 12°(11 structures), and for all cases, including cephalosporins and carbapenems, the average was −33 ± 15°. In all cases, therefore, the enzyme has a significant effect on the bcde angle after ring-opening.…”

Acyclic Twisted Amides

“…In general, the amide bond geometry of structurally characterized β-lactams presented in Figures and − can be characterized as N-pyramidalized (average χ N of 54.4°), while twist is less significant (average τ of 19.2°), as expected from the geometry of the fused four-membered ring system. There is only a very scattered correlation between N-pyramidalization and twist of the amide bond, with the general trend of higher twist with increased nitrogen pyramidalization ( R 2 = 0.30).…”

“…The most common are [ 2 .4.0] and [ 2 .3.0] ring systems with the six-membered ring such as 1,3-oxazinane (e.g., 4.30 ), and more common five-membered ring, such as thiazolidine 1,1-dioxide (e.g., 4.32 ), thiazolidine 1-oxide (e.g., 4.33 ), thiazolidine (e.g., 4.34 ), 1,3-selenazolidine (e.g., 4.36 ), pyrrolidine (e.g., 4.81 ), imidazolidine (e.g., 4.94 ), or oxazolidine (e.g., 4.101 ) . In general, more dense substitution of the fused ring, in particular at the α-positions to the nitrogen atom and the carbonyl group and ring unsaturation, result in higher N-pyramidalization. − These N-pyramidalized amides are well-known to be highly reactive as acylating reagents and are important pharmacophores in medicinal chemistry research.…”

Synthesis of charged cyclodextrins for encapsulation of antibiotics

“…The 1 H and 2D ROESY NMR data about the strength, stoichiometry and binding sites of the CD : penicillin complexes were combined in order to propose specific models for the supramolecular arrangement of each complex in solution. The drawings were obtained by combining the energy minimized structures of two CD-representatives -γCD (from Chem3D template) and GCYS (Chem3D, from GPSP crystal structure 61 ) -with an "open" conformation of AMX 127 and OXA 128 obtained after a 90° rotation of the aromatic side chain as found in the coordinates of the crystal forms (Figure 3.17). "Crystal"-like and "open" structures of the drugs are limiting cases, both of them likely to be present in solution 129 and participate in inclusion equilibria.…”