Synthesis and Testing of Novel Bisbenzimidazole Inhibitors of Bacterial MTN
In the U.S. at least 2 million people become infected with antibiotic resistant bacteria and at least 23,000 people die each year of these infections. With very few new FDA approved drugs, there is a need for new antibiotics in the market. The enzyme Methylthioadenosine nucleosidase (MTN) is a very important enzyme for metabolism and cell signaling found in microbes, but absent in humans, and is a potential target for new antibiotics. A drug termed “15A” was identified as a MTN inhibitor based on computer aided screening of the NCI diversity set II chemical database and MTN enzyme assays. In our study, a series of 8 analogs of 15A have been synthesized in order to study the chemical features required for good enzyme inhibition. The 15A analogs were structurally characterized using proton nuclear magnetic resonance (1H NMR), infrared (IR) spectroscopy, and gas chromatography-mass spectrometry (GC-MS). The analogs were further tested for MTN inhibitory activity using a UV-spectrophotometric assay, and yielded inhibitory constants in the low micromolar range. Current studies aim to determine the specificity and discriminatory activity for these compounds that will allow us to assemble a structure-activity relationship (SAR) that should help guide future design of MTN inhibitors that may be useful as a new class of antibiotics.
Lee, Christina and Mukuna, Romaric, "Synthesis and Testing of Novel Bisbenzimidazole Inhibitors of Bacterial MTN" (2017). 2017 Undergraduate Research and Scholarship Conference.