Abstract:The review reports a short biography of the Italian naturalized chemist Hugo Schiff and an outline on the synthesis and use of his most popular discovery: the imines, very well known and popular as Schiff Bases. Recent developments on their "metallo-imines" variants have been described. The applications of Schiff bases in organic synthesis as partner in Staudinger and hetero Diels-Alder reactions, as "privileged" ligands in the organometallic complexes and as biological active Schiff intermediates/targets have been reported as well.

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Since the 1940s β-lactam antibiotics have been used to treat bacterial infections. However, emergence and dissemination of β-lactam resistance has reached the point where many marketed β-lactams no longer are clinically effective. The increasing prevalence of multidrug-resistant bacteria and the progressive withdrawal of pharmaceutical companies from antibiotic research have evoked a strong reaction from health authorities, who have implemented initiatives to encourage the discovery of new antibacterials. Despite this gloomy scenario, several novel β-lactam antibiotics and β-lactamase inhibitors have recently progressed into clinical trials, and many more such compounds are being investigated. Here we seek to provide highlights of recent developments relating to the discovery of novel β-lactam antibiotics and β-lactamase inhibitors.

A new class of products in which the phenol group of salicylic acid is linked to alkanoyl moieties bearing nitrooxy functions has been synthesized and studied for their polyvalent actions. The products were stable in acid and neutral media, while they were hydrolyzed in human serum. Their half-lives were dependent upon the structure of alkanoyl moieties. The products showed anti-inflammatory activities similar to aspirin when tested in the carrageenan-induced paw edema assay in the rat. Interestingly, unlike aspirin, they showed reduced or no gastrotoxicity in a lesion model in rats at equimolar doses. A number of them were able to inhibit platelet aggregation induced by collagen in human platelet-rich plasma. All of the products were capable of relaxing rat aortic strips precontracted with phenylephrine in a concentration-dependent manner. Selected members of this new class of nonsteroidal anti-inflammatory drugs might represent possible safer alternatives to aspirin in different clinical settings.

A series of (nitrooxyacyloxy)methyl esters of aspirin were synthesized and evaluated as new NO-donor aspirins. Different amounts of aspirin were released in serum from these products according to the nature of nitrooxyacyloxy moiety present. In the aromatic series, there is a rather good linear correlation between the amount of aspirin released and the potencies of the products in inhibiting platelet aggregation induced by collagen. Both the native compounds and the related nitrooxy-substituted acid metabolites were able to relax rat aorta strips precontracted with phenylephrine, in keeping with a NO-induced activation of the sGC as a mechanism that underlies the vasodilator effect. The products here described are new improved examples of NO-donor aspirins containing nitrooxy groups. They could represent an alternative to the use of aspirin in a variety of clinical applications.

The introduction of antibiotics to treat bacterial infections either by killing or blocking their growth has been accompanied by the development of resistance mechanism that allows the bacteria to survive and proliferate. In particular the successive series of β-lactams have selected several generations of β-lactamases including ESBLs, AmpC β-lactamases, KPC carbapenamases in Enterobacteriaceae, the metallo β-lactamases VIMs and IMPs, and very recently the threatening NDM-1 that confers resistance to virtually any clinically used antibiotic. The increasing use of carbapenems due to the spread of resistance to other existing antibacterial agents has facilitated the spread of resistance, especially in Acinetobacter spp. due to OXA- and metallo-carbapenemases. The pharmaceutical industry, that abandoned this field at the end of the nineties, is now trying to recover by developing some novel β-lactam antibiotics and novel β-lactamase-inhibitors, the latter to be used in combination with new as well as seasoned β-lactam antibiotics. This article provides a survey of patent and scientific literature for β-lactamase inhibitors discovered in the period 2006-2010.

An efficient synthesis of α-amino-γ-lactone ketolide (3) was developed, which provided a versatile intermediate for the incorporation of a variety of aryl and heteroaryl groups onto the C-21 position of clarithromycin via HBTU-mediated amidation. The biological data for this important new class of macrolides revealed significantly potent activity against erythromycin-susceptible strains as well as efflux-resistant and erythromycin MLSB-resistant strains of S. pneumoniae and S. pyogenes. In addition, ketolide 11o showed excellent in vitro antibacterial activity against H. influenzae strain as compared to telithromycin. These results indicate that C-21 substituted γ-lactone ketolides have potential as a next generation macrolide antibiotics.