Synthesis, Biological Evaluation, and Computational Analysis of Biaryl Side‐Chain Analogs of Solithromycin

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. We studied the impact of noncovalent interactions between the biaryl side‐chain of solithromycin and its bacterial ribosome target. Seven analogs were designed, and their biological activity was assessed by minimum inhibitory concentration and binding affinity assays. In addition, a computational model involving density functional theory was implemented to explain the stronger interactions observed for one of the analogs relative to solithromycin.