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