Novel 3-lactam antibiotics

Although penicillins and cephalosporins are the best known and most researched 0-lactams, there are other 0-lactam structures which are of great interest in the antibacterial field. 

Clavulanic acid (Fig. 10.53) was isolated from Streptomyces clavuligerus by Beechams (1976). It has weak and unimportant antibiotic activity. However, it is a powerful and irreversible inhibitor of most 0-lactamases1 and as such is now used in combination 

1 It must be realized that there are various types of p-lactamases. Clavulanic acid is effective against most but not all. 

The structure of clavulanic acid proved quite a surprise once it was determined, since it was the first example of a naturally occurring (3-lactam ring which was not fused to a sulfur-containing ring. It is instead fused to an oxazolidine ring structure. 

It is also unusual in that it does not have an acylamino side-chain. 

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Esters are commonly regarded as unreactive toward addition of alkyl radicals [120]. Recently, two studies have demonstrated that this may not be true. In the first, somewhat special, example, the addition of a benzylic radical to the carbonyl group of butenolides was observed during the preparation of potential novel /3-lactam antibiotics (Scheme 29) [118]. 

The formal total synthesis of the novel /3-lactam antibiotic thienamycin has been accomplished from an isoxazoline derivative generated by [3 + 2] dipolar cycloaddition <79H(l2)l 183). Reaction of the nitrile oxide derived from 3-nitropropanal dimethyl acetal with methyl crotonate gave the isoxazoline (477) regio- and stereo-selectively. The isoxazoline was converted to amino ester (478) by hydrogenation and then to /3-lactam (479) by ester saponification and ring closure with DCC. Treatment of (479) with p-nitrobenzyl chloroformate and reaction of the derived acetal (480) with excess N-p-nitrobenzyloxycar-bonylcysteamine gave thioacetal (481), a compound which has previously been converted into ( )-(8S )-thienamycin (Scheme 106). 

A family of novel (3-lactam antibiotics based on /V-methyltio substituted 2-azetidinones have also shown the apoptosis-inducing properties against human solid tumor cell lines such as breast, prostate, and head-and-neck [44]. 

An early report that showcased the power of C-H activation approaches in steroid synthesis can be found in the work of Yoshikoshi (Equation 26) [87]. Irradiation of diazoketone 148 in the presence of CuO led to the generation of a putative carbene intermediate that underwent chemoselective insertion at the proximal, suitably positioned, methine C-H to give tetracycle 149. Another noteworthy example can be found in the synthesis of thienamycin (152), a novel / -lactam antibiotic, reported by workers at Beecham (Scheme 15.15) [16]. This transformation may constitute the first use of a rhodium catalyst to effect a C-H insertion. In the experiment, treatment of 150 with Rh2(OAc)4 furnished the key trans- -lactam 151 in 25% yield. Curiously, the investigators noted that conducting the C-H insertion process under irradiation furnished product in higher yields. Both of these early examples clearly illustrate the power of C-H insertion as a strategy for rapid introduction of molecular complexity onto a scaffold. 

Also the novel antifungal antibiotic (-)-PF1163B (211), isolated from Strep-tomyces sp., which features a 13-membered macrocycle incorporating both a lactone and a lactam unit, was synthesized by an RCM route (Scheme 42) [101]. While only poor results were obtained by treatment of diene 210 (containing 8% of an unidentified epimer) with catalyst A, the use of NHC catalyst C led, under the conditions outlined in the scheme, to the corresponding cyclization product in 60% yield along with 10% of a diastereomer resulting from epimer-ization in a previous step. 

Many peptide antibiotics have novel structural motifs, such as cyclic structures and are often further modified, (such as in jS-lactamic antibiotics) and conjugated with sugars, lipids, and other molecules. 

The nocardicins (A to G) have been isolated from a strain ofNocardia and comprise a novel group of /3-lactam antibiotics (Fig. 5.6A). Nocardicin A is the most active member, and possesses significant activity against Gram-negative but not Gram-positive bacteria. 

In search of novel and more effective antibacterial agents, numerous /1-lactam antibiotics bearing a pyridazine core have been synthesized mainly in Japan. Thus, the penicillin derivative (125) characterized by a 3-hydroxypyridazine-4-carboxamido subunit has been patented as a broad-spectrum bactericide [342-345] likewise, the corresponding cephalosporin analogue has been claimed in a patent [346]. 

Seto and coworkers47 reported a study on viridenomycin (77), a novel 24-membered macrocyclic polyene lactam antibiotic. A new antitumor antibiotic, designated AL081,... 

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... 

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. 

As a result of the intense interest in exploitation of the biological properties of the /3-lactam antibiotics a large number of nuclear analogs of the various naturally occurring structures have been synthesized. In addition to the carbapenems and oxapenams already described (Sections 5.12.3.4.2 and 5.12.3.4.3) a number of other novel bicyclic azetidinones have been reported. Examples of many of these are listed in Table 6. The methods used to synthesize these compounds are too varied to list in any systematic way. 

S, Hanessian, S. P. Sahoo, C. Couture, and H. Wyss, Novel synthetic approaches to monocyclic [3-lactam antibiotics, Bull Soc. Chim. Belg. 93 571 (1984). 

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). 

Gallop et al. [80] reported the preparation of p-lactams via a [2+2] cycloaddition reaction of ketenes with resin-bound imines derived from amino acids (Scheme 9). This is another solid-phase adaptation of the Staudinger reaction, which could lead to the synthesis of structurally diverse 3,4-bis-substituted 2-azetidinones [81]. In addition, a novel approach to the synthesis of A-unsubstituted-p-lactams, important building blocks for the preparation of p-lactam antibiotics, and useful precursors of chiral p-amino acids was described [82]. 

It must be underlined that, for the development of a successful FILA based on the use of non-related tracers, the latter should also show sufficient affinity for the specific binding sites of the imprinted polymer otherwise the assay will not be selective. For instance, in order to facilitate the competition between the labeled derivative and the analyte, Moreno-Bondi et al. have developed a FILA for the analysis of penicillins [34, 36] using novel fluorescently labeled [5-lactam antibiotics with a close resemblance to the analyte (Fig. 12) [95]. 

Benito-Pena, E., M.C. Moreno-Bondi, G. Orellana, et al. 2005. Development of a novel and automated fluorescent immunoassay for the analysis of P-lactam antibiotics. J. Agric. Food Chem. 53 6635-6642. 

More recent studies have shown that a novel hepta-acylated lipid A (m/z 1855, Fig. 11.2c) is present in a subset of clinical isolates from patients with severe CF pulmonary disease. Formation of hepta-acylated lipid A results from loss of an enzymatic activity (PogL) that ordinarily deacylates the 3-position of the diglucosamine backbone. Retention of this fatty acid at this position is associated with enhanced resistance to i-lactam antibiotics but not to aminoglycosides. 

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