The Synthesis and Biological Examination of 5-Membered Nitrogen-Based Heterocycles.

摘要

Nitrogen-based heterocycles represent a large percentage of pharmaceutical drugs comprising over half of the FDA approved drugs. Taking inspiration from nitrogen-rich marine natural products, bromoageliferin and oroidin, we have identified the 5-membered nitrogen-based 2-aminoimidazole heterocycle as a key pharmacophore toward many bioactive properties. Herein is reported the synthesis and biological examination of a library of 1, 4- disubstituted 2-aminoimidazoles. Initial examination showed the 1, 4-disubstituted 2- aminoimidazoles as potent biofilms modulators, both towards biofilm inhibition and biofilm dispersion. Additionally, we also report their ability to attenuate antibiotic resistance in methicillin-resistant Staphylococcus aureus (MRSA). These initial screens prompted us to develop novel synthetic routes towards structurally analogous 5-membered nitrogen based heterocycles including: 2-aminothiazoles, a 2-aminooxazole derivative, and imidazole-2-one and imidazole-2-thione derivatives. These compounds were tested for their ability to break antibiotic resistance in MRSA, with the lead compound being observed to cause an 8-fold drop in the MIC of oxacillin against MRSA when co-dosed at sub-MIC levels. Finally we report the ability of functionalized 2-aminoimidazoles, bis-2-aminimidazoles, and amino acid inspired 2-aminoimidazoles to inhibit the formation of advanced glycation end-products (AGEs) as well as possess the ability to break preformed AGEs.