Researchers from various organizations led by Dave Spring at Cambridge University have recently communicated (Chem. Comm. 2008, 4962) their efforts at discovering new antibacterial agents. In particular they targeted agents that would display activity against strains of epidemic MRSA (EMRSA). Their strategy was to identify hits through phenotypic screening of diverse chemical libraries, followed by analog synthesis, SAR studies, and target identification. In other words, medicinal chemistry.
Previously, the same group reported the synthesis of a 223 member diversity oriented synthesis (DOS) library starting from a fluorous diazoacetate (Chem. Comm. 2006, 3296). As shown below by starting from the simple diazoacetate, a diverse set of compounds could be accessed by applying various transformations. The fluorous tag facilitated this work since it provided a general purification method for intermediates by FSPE. In addition, the inertness of the tag allows for a wide range of chemical reactions to be conducted increasing the attainable chemical space.
Once the library was produced, they screened the collection and found 64 compounds that inhibited the growth of EMRSA-15 and EMRSA-16 strains. Analog synthesis and SAR studies eventually identified a substituted dihydropyrimidine, named emmacin, as the most potent. They then compared the activity of emmacin versus other antimicrobials including erythromycin and oxacillin, both of which MRSA-16 is known to be resistant. Also included was another anti-EMRSA compound, gemmacin, that was derived from a different DOS library (Angew. Chem. Intl. Ed. 2008, 2808 ). That DOS library was produced using solid phase techniques. (Presumably, emmacin is named for one of the authors of this paper, Emma Wyatt, while gemmacin is named for one of the authors of the other paper, Gemma Thomas.) As seen in the table below, emmacin compared favorably to the other compounds tested. Please keep in mind also that racemic emmacin was examined, so it is possible that optically pure emmacin may be more active. The paper concludes by describing studies which determined that the target of emmacin as EMRSA-16 dihydrofolate reductase enzyme DfrB.
There seems to be a ways to go yet in terms of finding a new really active antibiotic for the treatment of MRSA, but the work presented in this paper is a great example of how fluorous techniques can be incorporated into a medicinal chemistry workflow for the discovery of novel therapeutic agents.