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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 (\u03c0\u2010stacking and H\u2010bonding) between from the biaryl side\u2010chain 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\u2010activity relationships (SAR) in tandem with new computational studies. The biological activity of each analog was evaluated in terms of ribosomal affinity (<jats:italic>K<\/jats:italic><jats:sub>d<\/jats:sub> determined by fluorescence polarization), as well as minimum inhibitory concentration assays (MICs). 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