4UFZ

Synthesis of Novel NAD Dependant DNA Ligase Inhibitors via Negishi Cross-Coupling: Development of SAR and Resistance Studies

Summary for 4UFZ

• Entry DOI: 10.2210/pdb4ufz/pdb
• Descriptor: DNA LIGASE, 5,7-bis(azanyl)-2-tert-butyl-4-(1,3-thiazol-2-yl)pyrido[2,3-d]pyrimidine-6-carbonitrile, 1-(2,4-dimethylbenzyl)-6-oxo-1,6-dihydropyridine-3-carboxamide, ... (4 entities in total)
• Functional Keywords: ligase
• Biological source: HAEMOPHILUS INFLUENZAE
• Total number of polymer chains: 1
• Total formula weight: 37095.04

Authors

Murphy-Benenato, K.E.,Boriack-Sjodin, P.A.,Martinez-Botella, G.,Carcanague, D.,Gingipali, L.,Gowravaram, M.,Harang, J.,Hale, M.,Ioannidis, G.,Jahic, H.,Johnstone, M.,Kutschke, A.,Laganas, V.A.,Loch, J.,Oguto, H.,Patel, S.J. (deposition date: 2015-03-20, release date: 2015-10-28, Last modification date: 2024-05-08)

Primary citation

Murphy-Benenato, K.E.,Gingipalli, L.,Boriack-Sjodin, P.A.,Martinez-Botella, G.,Carcanague, D.,Eyermann, C.J.,Gowravaram, M.,Harang, J.,Hale, M.R.,Ioannidis, G.,Jahic, H.,Johnstone, M.,Kutschke, A.,Laganas, V.A.,Loch, J.T.,Miller, M.D.,Oguto, H.,Patel, S.J.
Negishi Cross-Coupling Enabled Synthesis of Novel Nad(+)-Dependent DNA Ligase Inhibitors and Sar Development.
Bioorg.Med.Chem.Lett., 25:5172-, 2015

PubMed Abstract: Two novel compounds, pyridopyrimidines (1) and naphthyridines (2) 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 R(1) improved both enzyme and cell potency. Further SAR developed at the R(2) position using the Negishi cross-coupling reaction provided several compounds, among these compounds 22g showed good enzyme potency and cellular potency.

PubMed: 26463129
DOI: 10.1016/J.BMCL.2015.09.075

Experimental method

X-RAY DIFFRACTION (2.33 Å)