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 -

The presence and configuration (syn or anti) of an oxyimino group in the 7 (beta)-acyl side chain of 3-cephems do not modify the intrinsic reactivity of the beta-lactam ring, but have highly enzyme-specific effects. When compared with the corresponding desoxyimino beta-lactam compound: (i) with the plasmid-mediated Escherichia coli RTEM-2 serine beta-lactamase, the substrate activity of the anti isomer is increased and that of the syn isomer is decreased; (ii) with the Streptomyces R61 serine D-alanyl-D-alanine cleaving peptidase (a highly penicillin-sensitive enzyme), the rate of enzyme acylation is not or only little affected when the oxyimino group is in the syn configuration, but is decreased when the oxyimino group is in the anti configuration; (iii) with the Actinomadura R39 serine D-alanyl-D-alanine-cleaving peptidase (an exceedingly highly penicillin-sensitive enzyme), the rate of enzyme acylation is unaffected whatever the configuration of the substituent. The oxidation of the sulphur atom of the dihydrothiazine ring on the beta-face of the molecule makes it both a poorer inactivator of the DD-peptidases and a poorer substrate of the beta-lactamase. The Streptomyces albus G Zn2+-containing D-alanyl-D-alanine-cleaving peptidase (a highly penicillin-resistant enzyme) remains highly resistant to all compounds tested.

Cefotaxime (figure 1) belongs to the third-generation cephalosporins('). This molecule combines high antibacterial power and resistance to the most of &lactamases @). Its C7 side chain is characterized by a syn oxyimino moiety conjugated to an aminothiaznlyl group.From NMR experiments, Ochiai et al (3) suggested the. presence of an hydrogen bond between the nitrogen atom of the exocyclic amide function and the oxyimino oxygen atom. But this intramolecular bond has not bem observed in the crystal structures of RU25159 (4) and cefmenoxime (5), two analogs of cefotaxime , nor in the 2 -( 2-amino-4 -thiazolyl ) 2 -2 -mehxyimino methylacetamide (6) , the isolated C, side-cbain of cefotaxime.We report here the X-ray, molecular smcturc of the 242-amino-4-thiazolyl) 2 2 -methoxyimino methylacetamide Crystal were obtained by evaporation of a HCI / methanol solution. The molecule cocrystallizes with HCI and H20. The main crystallographic data and the conditions of the structure determination are reported in table 1. Atomic coordinates and thermal parameters are given in table 2. The H(41). H(31). H(32)and H(131) atom were revealed by A-Fourier. Figure 4 shows the comparison between the title molecule and the non-hydrochloride one, after superposition of their amide functio~. The conformations are similar; the oxyimino group and the thiazolyl ring lie in the same plane (diedral angle of 3. 49 with $e C(5)4(6) and C(7)-N(8) double bonds in trans position. This plane is nearly perpendicular to the exocyclic amide moiety (angle between thiazolyl and amidc mean planes : 83.8". between oxyimino and amide mean planes : 83.7 ").The crystal packing is assumed by differenr intermolecular H bonds between the chloride ion, the water molecule and the title compound, as it can be seen in figure 5 and table 3.In conclusion, the N( 13)-O(9) H bridge suggested by Ochiai and the lanar conformation expected are no more observed; the N(4) protonation does not induce any conformation change of 5, syn sidechain.

Mr = 248.70, dx = 1.53 Mgm−3, C2/c, Z = 8, a = 15.704(1), b = 7.623(1), c = 18.659(4) Å, β = 104.83(1)°, V = 2159.3 Å3, λ CuKα = 1.54178 Å, μ = 46.91 cm−1, F(000) = 1024, T = 293 K, final R value = 0.043, 2190 independent reflections, 1971 considered as observed (I ≥ 2.5 σ (I)) collected on a Enraf‐ Nonius CAD‐4 diffractometer. The chlorine substitution on the aminothiazol nucleus does not induce any conformational change by comparison with the unsubstituted analogue. This could explain the identical biochemical activity of cefotaxime, a third generation cephalosporin, and its chloro analogue.

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