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

## TL;DR

Researchers found that combining a new compound called Nitrile 2 with curcumin strongly inhibits a key enzyme in a deadly parasite, suggesting a promising new treatment approach.

## Contribution

The study introduces novel dipeptide nitriles and identifies a synergistic combination with curcumin for enhanced inhibition of rhodesain.

## Key findings

- Nitrile 2 combined with curcumin shows stronger synergistic inhibition of rhodesain than Nitrile 1 combined with curcumin.
- At high inhibition levels, Nitrile 2 + curcumin achieves a synergism with a combination index of 0.3843.
- The combination of Nitrile 2 and curcumin has greater therapeutic potential for treating trypanosomiasis.

## Abstract

Background/Objectives: Rhodesain is a cysteine protease crucial for the life cycle of Trypanosoma brucei rhodesiense, 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. Methods: In the present work, we carried out a combination study of two novel synthetic nitriles, Nitrile 1 and Nitrile 2, with curcumin, the golden multitarget nutraceutical obtained from Curcuma longa 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. Results: Comparing the CI values of the combinations Nitrile 1 + curcumin and Nitrile 2 + curcumin, we assessed that the inhibitory effect of the combination Nitrile 2 + curcumin against rhodesain was much more potent than that of the other combination. At the IC50 value, in the case of the combination Nitrile 1 + curcumin an additive effect occurred, while in the case of Nitrile 2 + curcumin, we observed a moderate synergism: at 99% of the effect, the synergism induced by the combination Nitrile 2 + curcumin was much stronger than the synergism promoted by the combination Nitrile 1 + curcumin (CI = 0.3843 vs 0.6622, respectively). Conclusions: The co-administration of dipeptide nitriles with curcumin enhances rhodesain inhibition through synergistic effects. Notably, Nitrile 2 + curcumin exhibits a stronger synergy at higher inhibition levels, indicating a greater therapeutic potential.