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Stroke is the 4th leading cause of death and disability in adults in the USA. However, in the majority of patients, the detrimental effects of an ischemic insult go untreated because of the lack of efficacious neuroprotective compounds. Using naturally occurring compounds as a building block to create efficacious neuroprotective compounds that cross the blood brain barrier may eventually benefit the stroke patients. However, historically, the development of novel compounds has been fraught with problems including lack of significant pleiotropic activity, inability to effectively cross the blood brain barrier and poor bioavailability. This article details, in a stepwise manner, the synthesis and in vitro screening steps used to produce new flavonoids that have increased neuroprotective activity compared to the parent compound fisetin. Moreover, as a preliminary de-risking step, select compounds have been screened in a transfected Madin Darby canine kidney cell assay as a measure of blood brain barrier penetration. Initial de-risking steps have allowed us to identify a series of BBB-penetrating neuroprotective candidates for further development.