The primary role of medicinal chemist has become one of improving upon existing drugs by increasing their potency and duration of action and by decreasing toxic side effects as well as creating new drugs by molecular modifications. Very useful synthetic analogue with improved therapeutic properties can be obtained from a single lead compound by structural modification. The same applies to the group of natural lactone of plant origin, one of the diverse and important system of natural products with a broad spectrum biological activities. Physiological activity of natural lactone is known ever since santonine was used as anthelmintic and ascarisidal agent. The biological importance of unsaturated lactone is well known. The butenolide system is present in many cardiac glycosides shows strong cardiotonic activity. In particular, the ?-alkylidene butenolide skeleton is a useful entity that is present natural products such as fibrolides, dihydroxerulin and protoanemonin. Protoanemonin and its analogues possess antiviral, antibiotic and anticancer activities.