Abstract: “Since their discovery and subsequent proliferation in the 1920s, β-lactam antibiotics have contributed to the 50% increase in life expectance over the last century. However, antibiotic overuse and misuse, coupled with the rise in antibiotic resistant pathogens have caused the effectiveness of these drugs to decrease. Oxamazins are a class of heteroatom-activated β-lactam antibiotics that show good broad-spectrum antibiotic. The goal of our research is to progress through a traditional synthesis of simple oxamazins from readily available amino acids. We hope to explore the use of various synthetic strategies to make fully elaborated antibiotic compounds.”
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Hi Connor
Nice work! Well presented and interesting. I have a few questions. Have N-heteroatom substituted beta lactams been made before in the literature? If not, how did you and your advisor decide to make these your target? If yes, how do they change the activity, and if improved, is it understood why?
Are there any other procedures other than the Mitsunobu-like conditions for making the beta lactam linkage? This in light of the difficulties that the side products from DIAD give you?
Good luck completing your studies!
Wilfred van der Donk
Thank you for your comment!
N-heteroatom substituted beta-lactams have been reported in literature, however, the efficacy of the beta-lactam has not been expanded on. In addition to their use in antibiotics, they can also serve the function of being a beta-lactamase inhibitor. In terms of your second question, the Mitsunobu works most effectively but there other cyclization options, however, they do not yield as well.
Hi Connor,
Interesting poster—I definitely understand the pain of urea from DIAD coeluting with your products! A few questions for you—
1) What are your throughput like? What are the scales and yields for all your schemes? How are you troubleshooting to limit or remove the urea formation in your reactions?
2) In Scheme 2— is that a typo for lactam transformed into a ketone after hydrogenation?
3) What are your R groups/side chains— only Ser and Thr like you show in Figure 4? What are your target number of compounds before you do MIC? Do you have hypothesis on what modifications would be most efficacious, learning from the vast literature on b-lactam antibiotics?
Thanks!
Aya
Hello! Thank you for your comment!
In terms of your first question, we had to continually synthesize precursors throughout the scheme and we were only able to isolate the first beta-lactam product in 100 mg quantities. We have tried to selectively crystallize the reduced DIAD using ether to limited success. To answer your second question, there should be a nitrogen in the ring. Lastly, to answer your third question, we plan on testing all beta-lactam intermediates for their antibiotic activities but we anticipate the fully functionalized structure to be the most active. Based on the beta-lactam literature, we further anticipate adding an ATMO side chain which will improve broad-spectrum activity.