14- and 15-membered lactone macrolides and their analogues and hybrids: structure, molecular mechanism of action and biological activity.

Classical macrolides containing 14- or 15-membered aglycone lactone rings are basic and widely used antibacterial agents in clinical therapy. Macrolides exert antibacterial effects by blocking the exit peptide tunnel during translation at bacterial ribosomes. However, one macrolide occasionally manifests different docking modes or binding sites at ribosomes, which presents difficulties in designing macrolide modifications. In addition to their medical importance, lactone macrolides possess interesting chemistry driven by numerous intramolecular interactions or cascade transformations. Lactone macrolides are potent antibacterial/bactericidal agents, whereas derivatives of macrolactone antibiotics possess anti-malarial, anti-cancer, anti-inflammatory, and anti-leishmanial activity, and can regulate gastrointestinal motility. Hence, it is important to develop novel semi-synthetic and completely synthetic approaches for functionalising lactone cores of different macrolides and their structural analogues such as ketolides, fluoro-ketolides, acylides, and hybrids containing steroids, nucleosides, heterocycles, and peptides. Here, we discuss modifications that generate novel macrolides with enhanced biological potency and improved molecular mechanisms of action. The bibliography presented in this review contains references to articles and patents that were published and filed from 2009 to mid-2019.