title: Macrolide Hybrid Compounds: Drug Discovery Opportunities in Anti- Infective and Anti-inflammatory Area.
abstract: Macrolides, polyketide natural products, and their 15-membered semi-synthetic derivatives are composed of substituted macrocyclic lactone ring and used primarily as potent antibiotics. Recently their usefulness was extended to antimalarial and anti-inflammatory area. Hybrid macrolides presented in this article are the next generation semi-synthetic compounds that combine pharmacophores from antibacterial, antimalarial and anti-inflammatory area with 14- and 15-membered azalide scaffolds. Antibacterial azalide hybrids with sulphonamides showed improved activity against resistant streptococci while quinolone conjugates demonstrated full coverage of respiratory pathogens including macrolide resistant strains and their efficacy was confirmed in mouse pneumonia model. Antimalarial macrolide hybrids, mainly involving (chloro)quinoline pharmacophores, showed outstanding activity against chloroquine resistant strains, favourable pharmacokinetics, promising in vivo efficacy as well as encouraging developmental potential. Anti-inflammatory hybrids were obtained by combining macrolides with corticosteroid and non-steroidal anti-inflammatory drugs. They were found active in in vivo animal models of locally induced inflammation, asthma, inflammatory bowel disease and rheumatoid arthritis and demonstrated improved safety over parent steroid drugs. Overall, macrolide hybrids possess significant potential to be developed as potent novel medicines in therapeutic areas of utmost pharmaceutical interest.
authors.forename: Hana Cipcic
authors.initials: HC
authors.lastname: Paljetak
authors.forename: Linda
authors.initials: L
authors.lastname: Tomaskovic
authors.forename: Mario
authors.initials: M
authors.lastname: Matijasic
authors.forename: Mirjana
authors.initials: M
authors.lastname: Bukvic
authors.forename: Andrea
authors.initials: A
authors.lastname: Fajdetic
authors.forename: Donatella
authors.initials: D
authors.lastname: Verbanac
authors.affiliation: University of Zagreb School of Medicine, Center for Translational and Clinical Research, Salata 2, 10000 Zagreb, Croatia.
authors.forename: Mihaela
authors.initials: M
authors.lastname: Peric
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects; D055808:Drug Discovery; D006801:Humans; D007249:Inflammation / Q000188:drug therapy; D018942:Macrolides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008288:Malaria / Q000188:drug therapy
chemical_list: D000900:Anti-Bacterial Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000962:Antimalarials; D018942:Macrolides
keywords: Anti-inflammatory; Antibacterial; Antimalarial; Azalide; Corticosteroid; Macrolide Hybrid; Quinoline; Quinolone