Design and synthesis of phenolic hydrazide hydrazones as potent poly(ADP-ribose) glycohydrolase (PARG) inhibitors |
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Affiliation: | 1. CSL Behring AG, Bern, Switzerland;2. Preclinical Research and Development, CSL Behring GmbH, Marburg, Germany;1. Department of Physics, SRM Valliammai Engineering College, Kattankulathur, Chengalpet Dt., Tamil Nadu, India;2. PG & Research Department of Physics, Presidency College, Chennai, Tamil Nadu, India;3. Biochemie Innovations Lab, Tindivanam, Tamil Nadu, India. |
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Abstract: | Poly(ADP-ribose) polymerase (PARP) and poly(ADP-ribose) glycohydrolase (PARG) are enzymes responsible for catalyzing the formation and degradation of poly(ADP-ribose) (PAR) polymers, respectively. Activation of PARP has been shown to be involved in cell death induced by genotoxic stimuli. On the other hand, genetic disruption of PARG also leads to increased level of cell death by accumulation of PAR. Unlike PARP, where significant medicinal effort has been expended to identify potent inhibitors, PARG has been insufficiently investigated as a molecular therapeutic target. In this study, we report the design, synthesis, and biological evaluation of phenolic hydrazide hydrazones as potent PARG inhibitors. Compounds 3d, 3e, 5d, 5e, 8a, 8b and 8c showed their ability to inhibit the catalytic activity of PARG in vitro with IC50 values of 1.0, 2.1, 3.1, 3.2, 3.1, 2.8 and 1.6 μM, respectively. |
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Keywords: | Synthesis Hydrazide-hydrazone PARG PARP Inhibitor Molecular docking |
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