Moxalactam

Fig. 10. Synthesis of moxalactam (48) from 6-amiaopeniciUanic acid (6-APA) where R is CH(CgH )2, DMSO is dimethyl sulfoxide and DBN is l,5-dia2abicyclo[4.3.0]non-5-ene. The overall yield of (63) is 26% from 6-APA in the 13 steps shown.

The antibacterial spectmm of moxalactam (Table 9) is similar in breadth and potency to that of cefotaxime (36). Hence, moxalactam (48) is classified with the third-generation cephalosporins. In general 1-oxacephalosporins are considerably more susceptible to P-lactamases than their sulfur counterparts... 

However, moxalactam is highly resistant to a broad spectrum of P-lactamases owiag to the effect of the 7a-methoxy group (194,195). 

Generally, nephrotoxicity is not a problem. Some cephalosporins, especially those with the 3-methylthiotetrazole side chain, such as moxalactam (48), show a tendency to promote bleeding. This appears to be due to a reduction in the synthesis of prothrombin and can be a problem especially in elderly patients, patients with renal insufficiency, or patients suffering from malnutrition (219). The same side chain seems to promote a disulfiramlike reaction in patients consuming alcohol following a cephalosporin dose (80,219). 

There are very few totally synthetic antibiotics presently on the market. One of these is the 1-oxacephem, moxalactam (96). One may speculate that the enhanced potency of moxa-1actam stems in part from the substitution of the smaller oxygen atom for the sulfur normally present in the six-membered ring of cephalosporins thereby enhancing the reactivity of the adjoining four-membered ring. It is also partly a measure of the present stage of development of chemical synthesis and of the relative economics of production of 7-aminocephalosporanic acid that such an involved synthesis apparently is economically competitive. 

Pieces of various routes to moxalactam have been published from which the following may be assembled as one of the plausible pathways. The benzhydrol ester of 6-aminopenici 11 anic acid ( ) is -chlorinated and treated with base whereupon the intermediate sulfenyl chloride fragments to ). Next, displacement with propargyl alcohol in the presence of zinc chloride gives predominantly the stereochemistry represented by dia-stereoisomer The side chain is protected as the phenyl-... 

Moxalactam is a synthetic antibiotic with good activity against Gram-negative bacteria including pseudomonads and has... 

Motretinide 12 Moxalactam 3, 218 Moxazocine T, 114 Moxisylyte U 116 Moxnidazole 246 Muzolimine 3, 137... 

Chloral hydrate Chloramphenicol Cimetidine Ciprofloxacin Clofibrate Danazol Disulfiram Doxycycline Erythromycin Fenofibrate Fluconazole Fluorouracil Fluoxetine Fluvoxamine Gemfibrozil Influenza vaccine Isoniazid Itraconazole Fovastatin Metronidazole Miconazole Moxalactam Neomycin Norfloxacin Ofloxacin Omeprazole Phenylbutazone Piroxicam Propafenone Propoyxphene Quinidine Sertraline Sulfamethoxazole Sulfinpyrazone Tamoxifen Testosterone Vitamin E Zafirlukast... 

Later in his career, Nagata s group made notable and useful synthetic contributions to the beta lactam field. This included developing an economically feasible synthetic method for the industrial manufacture of 1-oxacephems from penicillin G. These efforts led to the worldwide introduction in the 1980s of several clinically prominent and effective beta lactam antibiotics of the 1-oxacephem class including moxalactam. 

M. Narisada, T. Yoshida, M. Ohtani, K. Ezumi, M. Takasuka, Synthesis and Substituent Effects on Antibacterial Activity, Alkaline Hydrolysis Rates, and Infrared Absorption Frequencies of Some Cephem Analogues Related to Latamoxef (Moxalactam) , J. Med. Chem. 1983, 26, 1577-1582. 

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