Development of Potent and Selective Inhibitors for Group VIA Calcium-Independent Phospholipase A₂ Guided by Molecular Dynamics and Structure–Activity Relationships

The development of inhibitors for phospholipase A₂ (PLA₂) is important in elucidating the enzymes implication in various biological pathways. PLA₂ enzymes are an important pharmacological target implicated in various inflammatory diseases. Computational chemistry, organic synthesis, and in vitro assays were employed to develop potent and selective inhibitors for group VIA calcium-independent PLA₂. A set of fluoroketone inhibitors was studied for their binding mode with two human cytosolic PLA₂ enzymes: group IVA cPLA₂ and group VIA iPLA₂. New compounds were synthesized and assayed toward three major PLA₂s. This study led to the development of four potent and selective thioether fluoroketone inhibitors as well as a thioether keto-1,2,4-oxadiazole inhibitor for GVIA iPLA₂, which will serve as lead compounds for future development and studies. The keto-1,2,4-oxadiazole functionality with a thioether is a novel structure, and it will be used as a lead to develop inhibitors with higher potency and selectivity toward GVIA iPLA₂.