A library of 15 novel and heretofore uncharacterized adamantyl and oradamantyl phthalimidines was synthesized and evaluated for neuroprotective and anti-angiogenic properties. Phthalimidine treatment in LPS-challenged cells effected reductions in levels of secreted TNF-α and nitrite relative to basal amounts. The primary SAR suggests nitration of adamantyl phthalimidines has marginal effect on TNF- α activity but promotes anti-nitrite activity; thioamide congeners retain anti-nitrite activity but are less effective reducing TNF-α. Site-specific nitration and thioamidation provided phthalimidine 24, effecting an 88.5% drop in nitrite concurrent with only a 4% drop in TNF-α. Notable anti-angiogenesis activity was observed for 20, 21 and 22.
Luo, W., Tweedie, D., Beedie, S-L., Vargesson, N., Figg, W. D., Greig, N. H., & Scerba, M. T. (2018). Design, synthesis and biological assessment of N-adamantyl, substituted adamantyl and noradamantyl phthalimidines for nitrite, TNF-α and angiogenesis inhibitory activities. Bioorganic & Medicinal Chemistry, 26(8), 1547-1559. https://doi.org/10.1016/j.bmc.2018.01.032