Indole Flanked Pyrazolopyrimidine, a Novel Scaffold with Striking PAD-4 Inhibition Property: In-silico Designing, Synthesis & Pharmacological Evaluation
Description
Peptidyl Arginine Deiminase-4 (PAD-4) catalyzes the post-translational modification of peptidyl arginine to citrulline in histones of neutrophils resulting in release of neutrophil extracellular traps (NETs); which are up-regulated in inflammatory, neurodegeneration and cancerous conditions. We are reporting, in-silico designing, synthesis and pharmacological evaluation of novel indole linked pyrazolopyrimidine derivatives as PAD-4 inhibitors. The compounds were synthesized and have been unambiguously characterized through NMR and HRMS. The compounds were significantly inhibited PAD-4 and reduced the release of NETs from cultured neutrophils. The result also manifested decreased levels of ROS and nitrite in neutrophils with reduced expression of PAD-4 and other NETotic markers including neutrophil elastase, myeloperoxidase and citrullinated H3. Moreover, NETs isolated from neutrophils after novel PAD-4 inhibitors treatments, showed decreased cellular and mitochondrial oxidative stress and exhibited reduced migration upon exposure to fibroblasts. In addition, these fibroblasts showed decreased expression of markers of fibrogenesis. These results signify novel scaffold indole flanked pyrazolopyrimidines as PAD-4 binder and subsequent anti-NETotic NCEs
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Institutions
- National Institute of Pharmaceutical Education and ResearchTelangana, Hyderabad