Negishi cross-coupling enabled synthesis of novel NAD⁺-dependent DNA ligase inhibitors and SAR development

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• 作者：Kerry E. Murphy-Benenato^a ; Lakshmaiah Gingipalli^b ; ; P. Ann Boriack-Sjodin^a ; Gabriel Martinez-Botella^a ; Dan Carcanague^a ; Charles J. Eyermann^a ; Madhu Gowravaram^a ; Jenna Harang^a ; Michael R. Hale^b ; Georgine Ioannidis^a ; Harris Jahic^a ; Michele Johnstone^a ; Amy Kutschke^a ; Valerie A. Laganas^a ; James T. Loch III^a ; Matthew D. Miller^a ; Herbert Oguto^a ; Sahil Joe Patel^c
• 关键词：Cross-coupling ; Diaminonitrile ; Pyridopyrimidine ; NAD+-dependent ligase resistance ; Antibacterial
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2015
• 出版时间：15 November 2015
• 年：2015
• 卷：25
• 期：22
• 页码：5172-5177
• 全文大小：1226 K

文摘

Two novel compounds, pyridopyrimidines (trong class="boldFont">1trong>) and naphthyridines (trong class="boldFont">2trong>) were identified as potent inhibitors of bacterial NAD⁺-dependent DNA ligase (Lig) A in a fragment screening. SAR was guided by molecular modeling and X-ray crystallography. It was observed that the diaminonitrile pharmacophore made a key interaction with the ligase enzyme, specifically residues Glu114, Lys291, and Leu117. Synthetic challenges limited opportunities for diversification of the naphthyridine core, therefore most of the SAR was focused on a pyridopyrimidine scaffold. The initial diversification at R¹ improved both enzyme and cell potency. Further SAR developed at the R² position using the Negishi cross-coupling reaction provided several compounds, among these compounds trong class="boldFont">22gtrong> showed good enzyme potency and cellular potency.