The Design and Synthesis of Coumarin- Yanglingmycin Hybrids as Potential Antibiotics
Antibacterial resistant microbes have been linked to over 2 million illnesses and 23,000 deaths per year in the US alone. In order to combat the spread of antibacterial resistance, new compounds that are active against resistant strains must be identified. Molecular hybridization is a drug design strategy that combines two active pharmacophores typically with unique mechanisms of action into a single molecule. Using this approach, it is anticipated that such compounds will display increased potency and the development of resistance will be slower. This study highlights efforts using molecular hybridization to design compounds with activity against resistant strains. Coumarin and Yanglingmycin are natural products that have each demonstrated antimicrobial activity and serve as the base molecular scaffolds for this study. In total, six fused hybrids were synthesized over three steps in yields ranging from 8-31%. Initial biological evaluation was hindered due to limited aqueous solubility. The addition of methyl-β-cyclodextrin improved solubility; however, antimicrobial assay results were inconsistent. To increase solubility without the need for methyl-β-cyclodextrin, hybrids employing a hydrophilic linker were designed and efforts towards their synthesis is discussed as well.
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