Synthesis,Biological Evaluation,and Computational Analysis of Biaryl Side-Chain Analogs of Solithromycin |
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| Authors: | Dr. Samer S. Daher Dr. Miseon Lee Dr. Xiao Jin Dr. Christiana N. Teijaro Prof. Steven E. Wheeler Dr. Marlene A. Jacobson Dr. Bettina Buttaro Prof. Rodrigo B. Andrade |
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| Affiliation: | 1. Department of Chemistry, Temple University, 1901 N. 13th Street, Philadelphia, PA 19122 USA;2. Department of Chemistry, University of Georgia, 140 Cedar Street, Athens, GA 30602 USA;3. Moulder Center for Drug Discovery Research, School of Pharmacy, Temple University, 3307 N. Broad Street, Philadelphia, PA 19140 USA;4. Department of Microbiology and Immunology, School of Medicine, Temple University, 3500 N. Broad Street, Philadelphia, PA 19140 USA |
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| Abstract: | There is an urgent need for new antibiotics to mitigate the existential threat posed by antibiotic resistance. Within the ketolide class, solithromycin has emerged as one of the most promising candidates for further development. Crystallographic studies of bacterial ribosomes and ribosomal subunits complexed with solithromycin have shed light on the nature of molecular interactions (π-stacking and H-bonding) between from the biaryl side-chain of the drug and key residues in the 50S ribosomal subunit. We have designed and synthesized a library of solithromycin analogs to study their structure-activity relationships (SAR) in tandem with new computational studies. The biological activity of each analog was evaluated in terms of ribosomal affinity (Kd determined by fluorescence polarization), as well as minimum inhibitory concentration assays (MICs). Density functional theory (DFT) studies of a simple binding site model identify key H-bonding interactions that modulate the potency of solithromycin analogs. |
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| Keywords: | click chemistry density functional theory macrolide solithromycin π-stacking |
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