Thienamycin activity

Reactions. Although carbapenems are extremely sensitive to many reaction conditions, a wide variety of chemical modifications have been carried out. Many derivatives of the amino, hydroxy, and carboxy group of thienamycin (2) have been prepared primarily to study stmcture—activity relationships (24). The most interesting class of A/-derivatives are the amidines which are usually obtained in good yield by reaction of thienamycin with an imidate ester at pH 8.3. Introduction of this basic but less nucleophilic moiety maintains or improves the potency of the natural material while greatiy increasing the chemical stabiUty. Thus /V-formimidoyl thienamycin [64221-86-9] (MK 0787) (18), C 2H yN204S, (25) was chosen for clinical evaluation and... 

In common with the naturally occurring carbapenem thienamycin (2), the introduction of the /n j -6-[l-(R)-hydroxyethyi] group had a profound effect on the biological properties of the penems. This, together with an indication from an early study (93) that, as with other P-lactams, the 5(R)-enantiomer was solely responsible for antibacterial activity, provided impetus for the development of methods for the synthesis of chiral penems. 

Merck s thienamycin synthesis commences with mono (V-silylation of dibenzyl aspartate (13, Scheme 2), the bis(benzyl) ester of aspartic acid (12). Thus, treatment of a cooled (0°C) solution of 13 in ether with trimethylsilyl chloride and triethylamine, followed by filtration to remove the triethylamine hydrochloride by-product, provides 11. When 11 is exposed to the action of one equivalent of tm-butylmagnesium chloride, the active hydrogen attached to nitrogen is removed, and the resultant anion spontaneously condenses with the electrophilic ester carbonyl four atoms away. After hydrolysis of the reaction mixture with 2 n HC1 saturated with ammonium chloride, enantiomerically pure azetidinone ester 10 is formed in 65-70% yield from 13. Although it is conceivable that... 

For additional syntheses of thienamycin in both optically active and racemic forms, see (a) Ponsford,... 

Recently Ikegami used the thiol addition reaction in the preparation of optically pure 4-phenylthioazetidin-2-one, the starting material for an elegant ( + )-thienamycin synthesis (58). When 4-phenylsulfonylazetidin-2-one was treated with cinchonidine and thiophenol, the intermediate azetinone underwent a thiol addition reaction and the 4-phenylthioazetidin-2-one was obtained in 54% optical and 96% chemical yield (eq. [13]). Recrystallization of the optically active aze-tidinone allows isolation of the pure enantiomer from the mother liquor. The phenylthio group is eliminated later in the synthesis of thienamycin. 

The discovery of thienamycin created great excitement it is a structurally novel P-lactam antibiotic of outstanding potency and has a remarkable spectrum of activity. It was the broadest spectrum antibiotic of its day. There was, however, a major problem thienamycin is not a stable molecule. Merck scientists were faced with the touchy problem of modifying thienamycin chemically to create a stable molecule while maintaining all its remarkable properties. Following considerable effort, they... 

Pharmacology This product is a formulation of imipenem, a thienamycin antibiotic, and cilastatin sodium, the inhibitor of the renal dipeptidase, dehydropeptidase-1, which is responsible for the extensive metabolism of imipenem when it is administered alone. Cilastatin prevents the metabolism of imipenem, increasing urinary recovery and decreasing possible renal toxicity. The bactericidal activity of imipenem results from the inhibition of cell-wall synthesis, related to binding to penicillin-binding proteins (PBP). 

Other P-lactam antibiotics have revolutionized our understanding of the structure-activity relationships in this large group of antibiotics. Thienamycin (9.53), discovered in 1976, is a broad-spectrum antibiotic of high activity. It is lactamase resistant because of its hydroxyethyl side chain but is not absorbed orally as it is highly polar. Unfortunately,... 

Structure-activity correlations in the P-lactam antibiotic field have required drastic re-evaluation in view of the novel structures described above. Apparently, only the intact P-lactam ring is an absolute requirement for activity. The sulfur atom can be replaced (moxalactam) or omitted (thienamycin), and the entire ring itself is, in fact, unnecessary (nocardicin). The carboxyl group, previously deemed essential, can be replaced by a tetrazolyl ring (as a bioisostere), which results in increased activity and lactamase resistance. The amide side chain, so widely varied in the past, is also unnecessary, as shown in the example of thienamycin. There is a considerable literature analyzing the classical structure-activity relationships of the penicillin and cephalosporin groups. 

Reactions. Although carbapenems are extremely sensitive to many reaction conditions, a wide variety of chemical modifications have been carried out. Many derivatives of the amino, hydroxy, and carboxy group of thienamycin have been prepared primarily to study structure-activity relationships. 

Further, the discovery of 7-a-methoxy cephalosporins [5] from Streptomyces in 1971, carbapenems [6], thienamycin [7], clavulanic acid [8], sulbactum [9] as well as the totally synthetic oxapenems [10], oxacephams [11], and other bicyclic (3-lactams stimulated the search for novel antibiotics. More recent dedicated efforts to find new active molecules and modify the penicillin and cephalosporin structure have resulted in the discovery of simple monocyclic (3-lactams such as norcardicins and monobactams [12, 13]. Yet another dimension has been added to the (3-lactam research with the recent discovery of tricyclic (3-lactam antibiotics called trinems [14]. Thus, (3-lactam antibiotics in general can be classified into several groups based on their structures (Fig. 1). 

Vinyloxiranes are used for facile 7i-allyl complex formation [14], The -allylic ferralactone complex 41 was prepared by oxidative addition of Fe2(CO)9 to the functionalized vinyloxirane 40 and CO insertion. Treatment of the ferralactone complex 41 with optically active a-methylbenzylamine (42) in the presence of ZnCl2 gave the 7r-allylic ferralactam complex 45 via 44. In this case, as shown by 43, the amine attacks the terminal carbon of the allylic system and then the lactone carbonyl. Then, elimination of OH group generates the 7r-allylic ferralactam complex 45. Finally the /1-lactam 46 was obtained in 64% yield by oxidative decomplexation with Ce(TV) salt. The <5-lactam 47 was a minor product (24%). The precursor of the thienamycin 48 was prepared from 46 [15,16]. This mechanistic explanation is supported by the formation of both 7r-allyllactone and lactam complexes (49 and 51) from the allylic amino alcohol 50 [17]. 

Since the target enzymes of penicillins are membrane-bound proteins, an essential condition of antibacterial activity is that the antibiotic must be able to penetrate the outer spheres of the bacterial cell and reach its target in an active form. This problem is closely linked to the phenomenon of bacterial resistance (production of /3-lactamases), and justify the development of semisynthetic penicillins varying in the nature of the acylamino side chain at position C-6, and more recently the development of totally synthetic penems related to thienamycin (see Section 2.03.12.3). 

Although much of the work on the microbial hydroxylation of amides has been directed at active-site m ing of the enzyme responsible, the products themselves are valuable building blocks for further synthesis, for example, for various optically active sesquiteipenes or -lactams. In this latter context regioselective hydroxylation of unactivated positions is particularly attractive as several -lactam antibiotics, e.g. the carbapenem derivative thienamycin, have a free hydroxy group in their structure. 

It is quite interesting that despite the very high potency of thienamycin, it took over 25 years of worldwide screening before it was discovered. Today, we know that carbapenems are not rare. Many members of this family have been isolated in laboratories all over the world although none equals thienamycin in potency and spectrum of activity. The answer probably lies in its very low level of production by wild strains and its instability. Conventional screening procedures evidently missed this activity and only after the development of specific and sensitive modem assay procedures was it found. Thienamycin was discovered by a sensitive mode of action screen, the details of which have never been revealed. 

This method can be effectively applied to the preparation of /S-lactam compounds. The ester enolate-imine condensation approach to j8-lactam formation has been developed over the past decade. Thienamycin and related carbapenems have been the focus of particular attention because of their structural uniqueness and potent antibacterial activity. 

A synthetic penem-type -lactam (149) exhibited antibacterial activities similar to (+ )-thienamycin (77) (82JA6138). Sulbactam (ISO) showed fairly strong inhibitory activity against /3-Iactamase (78AAC414). Based on the background mentioned above, we developed a new convenient method for the synthesis of penam-type /3-lactams. 

The importance of j -lactams in the penicillins , cephalosporins , thienamycin and the recent discovery of antibiotic activity among monocyclic j -lactams such as norcardicins or the )5-lactamase inhibitor clavulanic acid have recently intensified research toward the synthesis of this system . Among the different procedures that have been developed for incorporating a 2-azetidinone unit , the ring expansion of cyclopropanol amines provides a simple and convenient route to these attractive small ring compounds. 

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