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Discovery and Optimization of Phosphopantetheine Adenylyltransferase Inhibitors with Gram-Negative Antibacterial Activity
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-03-18 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01861 Colin K. Skepper 1 , Robert J. Moreau 1 , Brent A. Appleton 1 , Bret M. Benton 1 , Joseph E. Drumm 1 , Brian Y. Feng 1 , Mei Geng 1 , Cheng Hu 1 , Cindy Li 1 , Andreas Lingel 1 , Yipin Lu 1 , Mulugeta Mamo 1 , Wosenu Mergo 1 , Mina Mostafavi 1 , Christopher M. Rath 1 , Micah Steffek 1 , Kenneth T. Takeoka 1 , Kyoko Uehara 1 , Lisha Wang 1 , Jun-Rong Wei 1 , Lili Xie 1 , Wenjian Xu 1 , Qiong Zhang 1 , Javier de Vicente 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-03-18 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01861 Colin K. Skepper 1 , Robert J. Moreau 1 , Brent A. Appleton 1 , Bret M. Benton 1 , Joseph E. Drumm 1 , Brian Y. Feng 1 , Mei Geng 1 , Cheng Hu 1 , Cindy Li 1 , Andreas Lingel 1 , Yipin Lu 1 , Mulugeta Mamo 1 , Wosenu Mergo 1 , Mina Mostafavi 1 , Christopher M. Rath 1 , Micah Steffek 1 , Kenneth T. Takeoka 1 , Kyoko Uehara 1 , Lisha Wang 1 , Jun-Rong Wei 1 , Lili Xie 1 , Wenjian Xu 1 , Qiong Zhang 1 , Javier de Vicente 1
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In the preceding manuscript [Moreau et al. 2018, 10.1021/acs.jmedchem.7b01691] we described a successful fragment-based lead discovery (FBLD) strategy for discovery of bacterial phosphopantetheine adenylyltransferase inhibitors (PPAT, CoaD). Following several rounds of optimization two promising lead compounds were identified: triazolopyrimidinone 3 and 4-azabenzimidazole 4. Here we disclose our efforts to further optimize these two leads for on-target potency and Gram-negative cellular activity. Enabled by a robust X-ray crystallography system, our structure-based inhibitor design approach delivered compounds with biochemical potencies 4–5 orders of magnitude greater than their respective fragment starting points. Additional optimization was guided by observations on bacterial permeability and physicochemical properties, which ultimately led to the identification of PPAT inhibitors with cellular activity against wild-type E. coli.
中文翻译：
具有革兰氏阴性抗菌活性的磷酸泛素腺苷酸转移酶抑制剂的发现和优化
在前面的手稿中[Moreau et al。2018，10.1021 / acs.jmedchem.7b01691]我们描述了一个成功的基于片段的铅发现（FBLD）策略用于细菌磷酸泛酰腺苷酰转移酶抑制剂（PPAT，COAD）的发现。经过几轮优化，确定了两个有前途的先导化合物：三唑并嘧啶酮3和4-氮杂苯并咪唑4。在这里，我们公开了我们的工作，以进一步优化针对靶点效力和革兰氏阴性细胞活性的这两种线索。借助强大的X射线晶体学系统，我们基于结构的抑制剂设计方法可提供具有比其各自片段起始点大4–5个数量级的生化潜能的化合物。通过对细菌渗透性和理化性质的观察指导其他优化，这最终导致鉴定出具有针对野生型大肠杆菌的细胞活性的PPAT抑制剂。
更新日期：2018-03-18
中文翻译：
具有革兰氏阴性抗菌活性的磷酸泛素腺苷酸转移酶抑制剂的发现和优化
在前面的手稿中[Moreau et al。2018，10.1021 / acs.jmedchem.7b01691]我们描述了一个成功的基于片段的铅发现（FBLD）策略用于细菌磷酸泛酰腺苷酰转移酶抑制剂（PPAT，COAD）的发现。经过几轮优化，确定了两个有前途的先导化合物：三唑并嘧啶酮3和4-氮杂苯并咪唑4。在这里，我们公开了我们的工作，以进一步优化针对靶点效力和革兰氏阴性细胞活性的这两种线索。借助强大的X射线晶体学系统，我们基于结构的抑制剂设计方法可提供具有比其各自片段起始点大4–5个数量级的生化潜能的化合物。通过对细菌渗透性和理化性质的观察指导其他优化，这最终导致鉴定出具有针对野生型大肠杆菌的细胞活性的PPAT抑制剂。
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