PHOSPHODIESTERASE INHIBITORS DESIGN SYNTHESIS AND 3D QSAR STUDIES OF PDE4B INHIBITORY BENZAZOLES WITH ANTI INFLAMMATORY AND BRONCHODILATORY ACTIVITY

Abstract

quotOBJECTIVE: Some novel chemical entities bearing benzazole scaffold(s) were designed, synthesized and were evaluated by in vitro and in vivo protocols as selective PDE4B enzyme inhibitors. newlineMETHODS: The molecules were designed by in silico methods. The designed compounds were synthesized and characterized. All the compounds were evaluated for their potency to inhibit PDE4B and PDE4D enzymes using commercial assay kits. The molecules having two to four fold selectivity for PDE4B enzyme over PDE4D enzyme were subjected to pharmacological screening. Acute oral toxicity studies and anti-inflammatory activity testing screening were perfpormed. The compounds showing significant anti-inflammatory activity were evaluated for emetogenic potentialand bronchodilatory activity. newlineResults: A virtual library of 750 molecules was designed by fragment based drug designing and pharmacophore modeling, basing on the outcomes, novel molecules having selectivity for PDE4B over PDE4D in in silico were designed. The designed compounds were synthesised with moderate yields (58-72%) and characterized. PDE4B and PDE4D enzyme inhibition assays were performed for sixteen molecules and ten molecules were found to be selective for PDE4B over PDE4D. These molecules were found to be non-toxic in the acute oral toxicity studies performed as per OECD-423 guidelines. Significant anti-inflammatory activity was observed for compounds in some compounds when compared with the standard drug diclofenac. These molecules were also found to be less emetogenic than cisplatin. These compounds were evaluated for their bronchodilatory activity. One compound showed significant bronchodilatory activity, others showed moderate bronchodilatory activity. newlineConclusion: Benzazole scaffolds were designed and evaluated as selective PDE4B enzyme inhibitors. Compounds were found to be non-toxic, and were found possess significant anti-inflammatory activity, less emetogenic potential and moderate bronchodilatory activity. newlinequot newline