Methicillin resistant <i>Staphylococcus aureus</i>, MRSA is a serious public health concern worldwide, in the United States alone, 11,000 deaths were attributed to complication from MRSA infections in 2012.  MRSA gains resistance to β-lactam antibiotics by producing modified penicillin binding proteins and β-lactamase enzymes.  The production of these resistance factors is regulated based on β-lactam challenge.  We previously discovered a tricyclic indoline, Of1, from diversity-oriented synthesis that re-sensitizes MRSA to β-lactam antibiotics. To elaborate on this activity and bring these compounds closer to clinical trials, we turned to property-guided synthesis and designed a series of aza-tricyclic indolines (ATIs) to optimize physiochemical properties for in vivo studies.  In order to access ATIs, a novel and highly efficient gold-catalyzed tandem cyclization was developed. Compared with Of1,  several ATIs showed not only enhanced aqueous solubility and metabolic stability, but also improved activity in MRSA.

Property-guided synthesis of β-lactam adjuvants for methicillin resistant <i>Staphylococcus aureus</i>

251st National Meeting (2016)

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Property-guided synthesis of β-lactam adjuvants for methicillin resistant Staphylococcus aureus