Synthesis and Evaluation of Tricyclic Dipyrido Diazepinone Derivatives as Inhibitors of Secretory Phospholipase A2 with Anti-Inflammatory Activity

N.   R.   Thimmegowda; K.   K.   Dharmappa; C.   S.   Ananda kumar; M.   P.   Sadashiva; A.   D.   Sathish; B.   L.   Nanda; B.   S.   Vishwanath; K.   S.   Rangappa

doi:10.2174/156802607780487650

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 antiinflammatory 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 μM and showed similar potency in the neutralization of in vivo PLA2 induced mouse paw edema and hemolytic activity.

Keywords: Tricyclic dipyrido diazepinone, phospholipase A2 inhibition, antiinflammatory

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