A series of 2-cinnamyliden-1,3-diones related to the natural product coruscanone A was prepared from simple commercially available precursors via Knoevenagel condensation, and evaluated for antifungal, antibacterial and antiparasitic activities. Most of the compounds tested displayed antifungal effects against opportunistic pathogen C. neoformans comparable to coruscanone A and its derivatives suggesting that the mechanism of action of this class of compounds would involve Michael addition of a nucleophilic site of the biological target on the styryl side chain instead of the previously proposed reaction at the cyclopentenedione ring. In addition, some showed good in vitro antileishmanial activity (L. donovani), one of the compounds being superior to pentamidine and comparable to amphotericin B.