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Discovery and Optimization of Phosphopantetheine Adenylyltransferase Inhibitors with Gram-Negative Antibacterial Activity

Appleton, Brent and Benton, Bret and De Vicente Fidalgo, Javier and Drumm Iii, Joseph and Feng, Brian and Geng, Mei and Lu, Yipin and Mamo, Mulugeta and Moreau, Bob and Mergo, Wosenu and Skepper, Colin and Steffek, Micah and Takeoka, Ken and Uehara, Kyoko and Wang, Lisha and Wei, Jun-Rong and Xie, Lili and Xu, Wenjian and Zhang, Qiong and Li, Cindy and Hu, Cheng (2018) Discovery and Optimization of Phosphopantetheine Adenylyltransferase Inhibitors with Gram-Negative Antibacterial Activity. Journal of Medicinal Chemistry, 61 (8). pp. 3325-3349. ISSN 15204804

Abstract

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.

Item Type: Article
Date Deposited: 17 Aug 2018 00:45
Last Modified: 17 Aug 2018 00:45
URI: https://oak.novartis.com/id/eprint/32523

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