has already been shown. The activity of rotenone on mitochondrial complex I was found to be dependent on the bent form of the rotenoid at the B/C ring junction, E ring substitution, and 2,3 dimethoxy substitution . Evaluation of the activity of a series of rotenone and deguelin analogs on the NADH:ubiquinone oxidoreductase also demonstrated important differences in activity . It is evident from the various examples presented that the activities of rotenoids on mitochondrial complex I can vary significantly, even with minor structural changes. The variation in activity observed on our rapidly generated series of structural analogs points in the same direction. As shown in Figure and Table , the cyclic and bent form of the rotenoid at the B/C ring junction is essential for activity, since compounds 40 and 41 were not active. The lack of activity of compounds 33 to 36 highlights the central role of an aliphatic substitution on the E ring for bioactivity.