Article pubs.acs.org/JACS
Nonracemic Antifolates Stereoselectively Recruit Alternate Cofactors and Overcome Resistance in S. aureus Santosh Keshipeddy,‡ Stephanie M. Reeve,‡ Amy C. Anderson,* and Dennis L. Wright* Department of Pharmaceutical Sciences, University of Connecticut, 69 North Eagleville Road, Storrs, Connecticut 06269, United States S Supporting Information *
ABSTRACT: While antifolates such as Bactrim (trimethoprimsulfamethoxazole; TMP-SMX) continue to play an important role in treating community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA), resistance-conferring mutations, specifically F98Y of dihydrofolate reductase (DHFR), have arisen and compromise continued use. In an attempt to extend the lifetime of this important class, we have developed a class of propargyllinked antifolates (PLAs) that exhibit potent inhibition of the enzyme and bacterial strains. Probing the role of the configuration at the single propargylic stereocenter in these inhibitors required us to develop a new approach to nonracemic 3-aryl-1-butyne building blocks by the pairwise use of asymmetric conjugate addition and aldehyde dehydration protocols. Using this new route, a series of nonracemic PLA inhibitors was prepared and shown to possess potent enzyme inhibition (IC50 values
