Crystal structure of tebipenem pivoxil

The molecular structure of the first orally active carbapenem agent tebipenem pivoxil is described.


Chemical context
Carbapenem antibiotics, like all -lactam antibacterials that bind to and inhibit the peptidoglycan cross-linking transpeptidases, have attracted increasing attention recently because of their broader spectrum activities and stronger bactericidal actions compared to cephalosporins and penicillins. Since the first carbapenem structure thienamycin, a natural product derived from Streptomyces cattleya, was isolated in 1976 (Johnston et al., 1978), a handful of subsequent parenteral carbapenem agents, such as imipenem, panipenem, meropenem, biapenem, have been developed based on this parent compound and used clinically for the treatment of severe bacterial infections.
Tebipenem pivoxil (see scheme), as a novel oral carbapenem agent, was approved by the Pharmaceuticals and Medical Devices Agency of Japan (PMDA) on Apr 22, 2009. It was developed and marketed as Orapenem1 by Meiji Seika in Japan (as of 05/16/2016, the only approved country/area for its usage was Japan for treating children, as these oral antibiotics are often better tolerated than infusions) (Kijima et al., 2009). It is a prodrug that is quickly hydrolysed to the active antimicrobial agent LJC11,036 (5, reaction scheme) because the absorption rate of the pivaloyloxymethyl ester is higher than that of other prodrug-type -lactam antibiotics (Kato et al., 2010). The active metabolite 5 shows potent and well- ISSN 2056-9890 balanced antibacterial activity and also shows higher stability to human renal dehydropeptidase-I than meropenem (Isoda et al., 2006a;Kobayashi et al., 2005). Research has also revealed that the tebipenbem acyl--lactamase covalent complex remains very stable for longer than 90 min, partly explaining its resistance towards hydrolysis (Papp-Wallace et al., 2011).
Tebipenem pivoxil has a complex structure with four chiral centers and a 1-(1,3-thiazolin-2-yl)azetidin-3-ylthio side chain at the C-2 position. We hope the structural elucidation will facilitate future mechanistic studies of this molecule and of its interactions with enzymes that are responsible for bacterial resistance.

Supramolecular features
In the crystal, O-HÁ Á ÁN hydrogen bonds (Table 1) link the molecules into chains along [110]. C-HÁ Á ÁO hydrogen bonds are also observed. The packing viewed along the a axis is shown in Fig. 2.

Database survey
The tebipenem pivoxil we obtained was well characterized spectroscopically and carefully compared with reference values (Isoda et al., 2006a). To the best of our knowledge, including a search of the Cambridge Structural Database (CSD Version 5.39; Groom et al., 2016), no single crystal structure determination has previously been reported for this drug.

Synthesis and crystallization
As shown in the reaction scheme (also see Supporting Information), 3-mercapto-1-(1,3-thiazolin-2-yl)-azetidine hydrochloride (3) was first synthesized according to a method previously reported (Isoda et al., 2006b) with minor optimizations. The side chain 3 was then coupled with the commercially available carbapenem core (2), followed by hydrogenation/deprotection and SN 2 esterification to afford the desired tebipenem pivoxil 1 (Isoda et al., 2006a,b The crystal packing viewed along the crystallographic a axis showing the O-HÁ Á ÁN hydrogen bonds (Table 1) as dashed lines.

Figure 1
The molecular structure of the title compound, showing the atom labelling and 30% probability displacement ellipsoids. Table 1 Hydrogen-bond geometry (Å , ). structure has also been characterized with 1 H NMR, 13 C NMR, and IR spectroscopy. 1 H NMR, 13 C NMR, and IR spectra of tebipenem pivoxil 1 are included in the supporting information and compared with reference values, including the assignment of NMR chemical shifts and IR absorption bands (Isoda et al., 2006a).