Discovery of blood–brain barrier permeant amine-functionalized aurones as inhibitors of activated microglia

Sulfuretin, a naturally occurring aurone is reported to inhibit macrophage and microglia activation. A series of aurones incorporating basic amines and lipophilic functionalities at ring A and/or ring B were synthesized to improve upon present sulfuretin activity towards targeting brain microglia while overcoming the blood-brain barrier (BBB). Evaluation of the ability of the aurones to inhibit lipopolysaccharide (LPS)-stimulated nitric oxide (NO) secretion by murine BV-2 microglia has identified several inhibitors showing significant NO reduction at 1 to 10 µM. Potent inhibitors were represented by aurones with bulky, planar moieties at ring A (3f) or at ring B (1e and 1f) and having a pendant piperidine at ring B (1a, 2a, 2b, and 3f). The active aurones inhibited the BV-2 microglia polarizing towards the M1 state as indicated by attenuation of IL-1β and TNF-α secretions in LPS-activated microglia but did not induce the microglia towards the M2 state. The aurones 2a, 2b, and 1f showed high passive BBB permeability in the parallel artificial membrane permeability assay (PAMPA) owing to their optimal lipophilicities. 2a, being non-cell toxic, BBB permeant and potent, represents a new lead for the development of aurones as inhibitors of activated microglia.