Structure-activity relationship studies of c-di-AMP synthase inhibitor, bromophenol-thiohydantoin

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• 作者：Yue Zheng ; Jie Zhou ; Stefan M. Cooper Jr. ; Clement Opoku-Temeng ; Amanda Moreira De Brito ; Herman O. Sintim ; ^{hsintim@umd.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：c-di-AMP ; DisA ; Inhibitor ; Bromophenol-TH ; SAR
• 刊名：Tetrahedron
• 出版年：2016
• 出版时间：23 June 2016
• 年：2016
• 卷：72
• 期：25
• 页码：3554-3558
• 全文大小：437 K

文摘

C-di-AMP, a bacterial second messenger, regulates various processes in Gram-positive bacteria and mycobacteria. Small molecule inhibitors of c-di-AMP metabolic enzymes could affect bacterial growth and viability. A medium throughput screening identified bromophenol-thiohydantoin (BTH) as the first inhibitor of c-di-AMP synthase, DisA. Herein, we performed SAR studies of bromophenol-thiohydantoin to identify the salient features on BTH that are important for DisA inhibition. Seemingly minor substitution changes (e.g., aromatic bromo to chloro substitutions) resulted in dramatic changes in ligand potency. Bromophenol TH is specific for c-di-AMP synthase and did not inhibit RocR (c-di-GMP PDE), YybT (c-di-AMP PDE) or WspR (c-di-GMP synthase).