Moro Whitney Beysselance, Yang Zhengrong, Kane Tasha A, Zhou Qingxian, Harville Steve, Brouillette Christie G, Brouillette Wayne J
Department of Chemistry, University of Alabama at Birmingham, 901 14th Street South, Birmingham, AL 35294, USA.
J Comb Chem. 2009 Jul-Aug;11(4):617-25. doi: 10.1021/cc9000357.
A new lead class of antibacterial drug-like NAD synthetase (NADs) inhibitors was previously identified from a virtual screening study. Here a solution-phase synthetic library of 76 compounds, analogs of the urea-sulfonamide 5838, was synthesized in parallel to explore SAR on the sulfonamide aryl group. All library members were tested for enzyme inhibition against NADs and nicotinic acid mononucleotide adenylyltransferase (NaMNAT), the last two enzymes in the biosynthesis of NAD, and for growth inhibition in a Bacillus anthracis antibacterial assay. Most compounds that inhibited bacterial growth also showed inhibition against one of the enzymes tested. While only modest enhancements in the enzyme inhibition potency against NADs were observed, of significance was the observation that the antibacterial urea-sulfonamides more consistently inhibited NaMNAT.
先前通过虚拟筛选研究鉴定出一类新型的类抗菌药物烟酰胺腺嘌呤二核苷酸合成酶（NADs）抑制剂。在此，平行合成了一个包含76种化合物的溶液相合成文库，这些化合物是脲-磺酰胺5838的类似物，以探索磺酰胺芳基上的构效关系。对文库中的所有成员进行了针对NADs和烟酸单核苷酸腺苷酸转移酶（NaMNAT）（NAD生物合成中的最后两种酶）的酶抑制测试，以及炭疽芽孢杆菌抗菌试验中的生长抑制测试。大多数抑制细菌生长的化合物也显示出对所测试的一种酶的抑制作用。虽然仅观察到针对NADs的酶抑制效力有适度增强，但值得注意的是，抗菌脲-磺酰胺更一致地抑制NaMNAT。
