Title:Macrolide Hybrid Compounds: Drug Discovery Opportunities in Anti- Infective and Anti-inflammatory Area
Volume: 17
Issue: 8
Author(s): Hana Cipcic Paljetak, Linda Tomaskovic, Mario Matijasic, Mirjana Bukvic, Andrea Fajdetic, Donatella Verbanac and Mihaela Peric
Affiliation:
Keywords:
Macrolide Hybrid, Azalide, Antibacterial, Antimalarial, Anti-inflammatory, Quinolone, Quinoline, Corticosteroid.
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.
