title: Synthesis and evaluation of tricyclic dipyrido diazepinone derivatives as inhibitors of secretory phospholipase A2 with anti-inflammatory activity.
abstract: A series of tricyclic dipyrido diazepinone derivatives 6(a-f) bearing different substituents at the tenth position of diazepinone ring were designed and are characterized by 1H NMR, FTIR and X-Ray crystallography studies. The synthesised derivatives are tested in-vitro phospholipase A2 (PLA2) enzyme inhibitory activity and in-vivo anti-inflammatory activity against purified group I and group II PLA2 enzymes from the snake venom and human pleural fluid. Compounds bearing aromatic ring with different substituents at different positions shown varied specificity. The 6f derivative with strong electron withdrawing nitro (-NO2) and trifluoromethyl (-CF3) groups at ortho and para positions respectively shown greater inhibitory activity. Inhibitory effect of the compound appeared to be direct interaction with active site and likely competes with substrates as supported by substrate dependent and calcium independent assays. The IC50 value of potent PLA2 inhibitor 6f was 22.1 microM and showed similar potency in the neutralization of in vivo PLA2 induced mouse paw edema and hemolytic activity.
authors: Department of Studies in Chemistry, University of Mysore, Mysore-570 006, India.
authors: N R
authors: NR
authors: Thimmegowda
authors: K K
authors: KK
authors: Dharmappa
authors: C S Ananda
authors: CS
authors: Kumar
authors: M P
authors: MP
authors: Sadashiva
authors: A D
authors: AD
authors: Sathish
authors: B L
authors: BL
authors: Nanda
authors: B S
authors: BS
authors: Vishwanath
authors: K S
authors: KS
authors: Rangappa
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents; D001381:Azepines / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D004487:Edema / Q000188:drug therapy; D004791:Enzyme Inhibitors; D054501:Group II Phospholipases A2; D006461:Hemolysis / Q000187:drug effects; D020128:Inhibitory Concentration 50; D051379:Mice; D010741:Phospholipases A / Q000037:antagonists & inhibitors*; D054467:Phospholipases A2; D013329:Structure-Activity Relationship
chemical_list: D000893:Anti-Inflammatory Agents; D001381:Azepines; D004791:Enzyme Inhibitors; D010741:Phospholipases A; D054501:Group II Phospholipases A2; D054467:Phospholipases A2