Cage hydrocarbons as linkers in dimeric drug design: Case studies with trimethoprim and tedizolid.

The looming threat of a "post-antibiotic era" has been caused by a rapid rise in antibacterial resistance and subsequent depletion of effective antibiotic agents in the clinic. An efficient strategy to address this shortfall lies in the reengineering of pre-existing and commercially available antibiotic drugs. This is exemplified by dimerization, a design concept in which two pharmacophores are covalently linked to form a new chemical entity. The cage hydrocarbons cubane (1), bicyclo[2.2.2]octane (BCO) (2), adamantane (3), and bicyclo[1.1.1]pentane (BCP) (4) present themselves as an attractive family of linkers in this regard. In this report, all four hydrocarbon cages were employed as linkers in a series of dimers based on the commercially available antibiotics trimethoprim and tedizolid. A detailed synthetic roadmap for the protection and deprotection of each pharmacophore is outlined. Several members of the trimethoprim series showed activity on par with that of their trimethoprim progenitor, although this was not the case for the tedizolid series. The design strategy outlined herein highlights the utility of the group as a platform for the rapid and modular construction of future novel antibiotics.

Lewis Base Catalyzed Synthesis of Sulfur Heterocycles via the C1-Pyridinium Enolate.

While the addition of C1-Lewis base enolates to carbonyls and related structures are well established, the related addition to thiocarbonyls compounds are unknown. Herein, we report a reaction cascade in which a C1-pyridinium enolate undergos addition to dithioesters, trithiocarbonates and xanthates. The reaction provides access to a range of dihydrothiophenes and dihydrothiopyrans (28-examples). Mechanistic investigations, including isolation of intermediates, electronic correlation, and kinetic isotope effect studies support the viability of an activated acid intermediate giving rise to the C1-pyridinium enolate which undergoes turnover limiting cyclization. Subsequent formation of a ß-thiolactone regenerates the catalyst with loss of carbon oxysulfide providing the observed products.