Hydrolytic stability versus ring size in lactams: implications for the development of lactam antibiotics and other serine protease inhibitors.

beta-Lactam antibiotics act by acylating a serine hydroxyl group in the catalytic center of bacterial proteases. This requires, among other things, suitable reactivity of the lactam moiety. To evaluate the possible suitability of other lactam systems, kinetic studies were performed using the model reaction of lactams with hydroxide. Following the pace of the reaction by NMR, we found gamma-butyrolactam to be hydrolyzed considerably slower than beta-propiolactam. Surprisingly, delta-valerolactam and beta-propiolactam had the same reactivity. beta-Lactam antibiotics were more reactive than both by approximately a factor of 10(3). Medium-sized lactams were least susceptible to hydrolysis. The study highlights the as yet overlooked six-membered lactam ring as a promising vantage point for the development of new classes of antiinfectives and other serine protease inhibitors.