Synthesis and Combination Studies of Novel Dipeptide Nitriles with Curcumin for a Potent Synergistic Action Against Rhodesain, Cysteine Protease of .

Rhodesain is a cysteine protease crucial for the life cycle of , a parasite that causes the lethal form of human African trypanosomiasis. For these reasons, rhodesain is considered an important target for the drug discovery process of novel antitrypanosomal agents. In the present work, we carried out a combination study of two novel synthetic nitriles, and , with curcumin, the golden multitarget nutraceutical obtained from L., which we demonstrated to inhibit rhodesain in a non-competitive manner. We calculated the combination index (CI) in both the combination studies by using the Chou and Talalay method. Comparing the CI values of the combinations + curcumin and + curcumin, we assessed that the inhibitory effect of the combination + curcumin against rhodesain was much more potent than that of the other combination. At the IC value, in the case of the combination + curcumin an additive effect occurred, while in the case of curcumin, we observed a moderate synergism: at 99% of the effect, the synergism induced by the combination curcumin was much stronger than the synergism promoted by the combination + curcumin (CI = 0.3843 0.6622, respectively). The co-administration of dipeptide nitriles with curcumin enhances rhodesain inhibition through synergistic effects. Notably, + curcumin exhibits a stronger synergy at higher inhibition levels, indicating a greater therapeutic potential.