A diversity-oriented synthesis approach of the neuroleptic drug halopemide, reported to be a phospholipase D2 (PLD2) inhibitor (but later shown to be a dual PLD1/2 inhibitor) afforded ML298 (CID 53393915), a potent, >53-fold PLD2 selective allosteric inhibitor (cellular PLD1, IC50 >20,000 nM, cellular PLD2, IC50 = 355 nM). ML298 displays no inhibition of PLD1, and therefore is an improvement over our first generation PLD2 selective inhibitor, VU0364739 (cellular PLD1, IC50 = 1,500 nM, cellular PLD2, IC50 = 20 nM), as at standard in vitro doses, and in vivo exposure levels, both PLD1 and PLD2 are inhibited. ML298 possesses favorable physiochemical and dystrophia myotonica protein kinase (DMPK) properties, making it a useful tool to probe selective PLD2 function in vitro and in vivo. Data here shows therapeutic relevance in virology and oncology.