Monocyclic ß-Lactam: A Review on Synthesis and Potential Biological Activities of a Multitarget Core.

A monocyclic ring in their structure characterizes monobactams, a subclass of ß-lactam antibiotics. Many of these compounds have a bactericidal mechanism of action and acts as penicillin and cephalosporins, interfering with bacterial cell wall biosynthesis. The synthesis of novel ß-lactams is an emerging area of organic synthesis research due to the problem of increasing bacterial resistance to existing ß -lactam antibiotics, and, in this way, new compounds have been presented with several structural modifications, aiming to improve biological activities. Among the biological activities studied, the most outstanding are antibacterial, antitubercular, anticholesterolemic, anticancer, antiinflammatory, antiviral, and anti-enzymatic, among others. This review explores the vast number of works related to monocyclic ß-lactams, compounds of great importance in scientific research.

Monobactam formation in sulfazecin by a nonribosomal peptide synthetase thioesterase.

The N-sulfonated monocyclic ß-lactam ring characteristic of the monobactams confers resistance to zinc metallo-ß-lactamases and affords the most effective class to combat carbapenem-resistant enterobacteria (CRE). Here we report unprecedented nonribosomal peptide synthetase activities, wherein an assembled tripeptide is N-sulfonated in trans before direct synthesis of the ß-lactam ring in a noncanonical, cysteine-containing thioesterase domain. This means of azetidinone synthesis is distinct from the three others known in nature.

Active-Site Protonation States in an Acyl-Enzyme Intermediate of a Class A ß-Lactamase with a Monobactam Substrate.

The monobactam antibiotic aztreonam is used to treat cystic fibrosis patients with chronic pulmonary infections colonized by Pseudomonas aeruginosa strains expressing CTX-M extended-spectrum ß-lactamases. The protonation states of active-site residues that are responsible for hydrolysis have been determined previously for the apo form of a CTX-M ß-lactamase but not for a monobactam acyl-enzyme intermediate. Here we used neutron and high-resolution X-ray crystallography to probe the mechanism by which CTX-M extended-spectrum ß-lactamases hydrolyze monobactam antibiotics. In these first reported structures of a class A ß-lactamase in an acyl-enzyme complex with aztreonam, we directly observed most of the hydrogen atoms (as deuterium) within the active site. Although Lys 234 is fully protonated in the acyl intermediate, we found that Lys 73 is neutral. These findings are consistent with Lys 73 being able to serve as a general base during the acylation part of the catalytic mechanism, as previously proposed.

Monocyclic ß-lactams as antibacterial agents: facing antioxidant activity of N-methylthio-azetidinones.

A series of N-methylthio-ß-lactams with antibacterial activity were thoroughly evaluated as antioxidants. We found that only the presence of a polyphenolic moiety anchored to the ß-lactam ring ensured an adequate antioxidant potency. New compounds, efficiently combining in one structure antioxidant and antibacterial activity, may provide a promising basis for the development of new leads useful in adverse clinical conditions such as in cystic fibrosis patients, in whom colonization by MRSA and epithelial damage by chronic pulmonary oxidative stress take place.

Monocyclic ß-lactams: new structures for new biological activities.

The azetidinone core-structure offers a unique approach to the design and synthesis of new derivatives with unique biological properties. During the last two decades researches convincingly demonstrated that the prospect of structural modifications of monocyclic ß-lactams with specific substituents is an effective procedure for the detection and improvement of important pharmacological effects different from antibacterial activity. As a matter of fact, new ß-lactam compounds demonstrated biological activity as inhibitors of a wide range of enzymes. This review reports the latest developments on monocyclic ß-lactam compounds activity as anticancer, antitubercular, HFAAH inhibitors, HDAC inhibitors, anti-inflammatory drugs (tryptase inhibitors), Cathepsin K inhibitors, and vasopressin inhibitors. We attempted to highlight the intertwined relationships between structural features and biological activities, by analysing groups anchored on the three positions of the azetidinone ring as sources of molecular diversity.

Measurement of the degree of coupled isotopic enrichment of different positions in an antibiotic peptide by NMR.

An experimental strategy for determining the extent to which multiply isotopically labeled fragments are incorporated intact into relatively complicated compounds of interest is presented. The NMR methods employed are based on isotope-filtered one-dimensional spectra and difference HSQC spectra incorporating a spin echo designed to report on the presence of a second NMR active isotope at a coupled site. They supplement existing methods for determining the extent of isotopic incorporation at individual sites to reveal whether two coupled labeled sites in a precursor are incorporated as an intact unit into products. The methods described also circumvent 1H signal overlap and distinguish between the effects of different nitrogens coupled to individual carbons. The somewhat complicated case of valclavam illustrates the method's utility in measuring the J coupling constants between 13C and nearby sites that are only fractionally labeled with 15N, and measuring the fraction of molecules in which 13C is coupled to 15N, at each of several sites. The 15N of [2-13C, 15N]-labeled glycine is found to be incorporated into all three N positions of valclavam but most heavily into the N11 position. Specifically, 15N and 13C are incorporated into the N11 and C10 positions together as an 15N13C fragment approximately 8% of the time, whereas 15N is incorporated largely independently at the other positions.