Design, Synthesis, and Structure–Activity Relationship Studies of Novel Thioether Pleuromutilin Derivatives as Potent Antibacterial Agents

Abstract

A series of novel thioether pleuromutilin derivatives incorporating various heteroaromatic substituents into the C14 side chain have been reported. Structure–activity relationship (SAR) studies resulted in compounds <b>52</b> and <b>55</b> with the most potent in vitro antibacterial activity among the series (MIC = 0.031–0.063 μg/mL). Further optimization to overcome the poor water solubility of compound <b>55</b> resulted in compounds <b>87</b>, <b>91</b>, <b>109</b>, and <b>110</b> possessing good in vitro antibacterial activity with increased hydrophilicity. Compound <b>114</b>, the water-soluble phosphate prodrug of compound <b>52</b>, was also prepared and evaluated. Among the derivatives, compound <b>110</b> showed moderate pharmacokinetic profiles and good in vivo efficacy in both MSSA and MRSA systemic infection models. Compound <b>110</b> was further evaluated in CYP450 inhibition assay and displayed intermediate in vitro inhibition of CYP3A4