1. Synthesis and biological evaluation of isoindoloisoquinolinone, pyroloisoquinolinone and benzoquinazolinone derivatives as poly(ADP-ribose) polymerase-1 inhibitors.
- Author
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Suyavaran A, Ramamurthy C, Mareeswaran R, Shanthi YV, Selvakumar J, Mangalaraj S, Kumar MS, Ramanathan CR, and Thirunavukkarasu C
- Subjects
- Animals, Chickens, Drug Design, Enzyme Inhibitors chemistry, Indoles chemical synthesis, Indoles chemistry, Indoles pharmacology, Isoquinolines chemical synthesis, Isoquinolines chemistry, Isoquinolines pharmacology, Poly(ADP-ribose) Polymerases chemistry, Protein Binding, Protein Conformation, Quinazolinones chemistry, Structure-Activity Relationship, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors pharmacology, Oxidative Stress drug effects, Poly(ADP-ribose) Polymerase Inhibitors, Quinazolinones chemical synthesis, Quinazolinones pharmacology
- Abstract
A series of novel fused isoquinolinones with isoindoloisoquinolinone, pyroloisoquinolinone, and benzoquinalizinone skeletons were synthesized from corresponding phenethylimides. The isoquinolinone derivatives were evaluated for their protective effect on chicken erythrocytes subjected to oxidative damage. The effect of isoquinolinone derivatives were analysed by estimation of cell viability, antioxidant enzyme activities, DNA damage (comet assay), PARP-1 inhibition assay and molecular docking of the compounds with PARP-1 active site. The compounds CRR-271, CRR-288 and CRR-224+225 showed significant protective effect at 100 μM concentration. The PARP-1 inhibition assay revealed the IC50 values of CRR-271, CRR-288 and CRR-224+225 as <200 nM, further molecular docking studies shows higher binding energies with PARP-1 active site. Interesting findings in this study suggest that the novel isoquinolinone derivatives inhibit PARP-1 activity and protect cells against oxidative DNA damage, which could be implemented in the treatment of inflammatory diseases., (Copyright © 2014 Elsevier Ltd. All rights reserved.)
- Published
- 2015
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