Metabolites isolated from inflorescences of Piper aduncum L. (Piperaceae) and structure-activity relationship study of chalcones derivatives with anti-Trypanosoma cruzi activity

Chagas disease is a neglected disease and affects over 1 million people worldwide. As benznidazole is the only available drug for treatment [1,2,3], searching for prototypes for therapeutical use is crucial. In our work with Brazilian plants, the hexane extract from inflorescences of Piper aduncum L. displayed anti-T. cruzi activity and after chromatographic procedures, afforded four compounds: dihydroflavokawin B-I, nerolidol-II, methyl 2,2-dimethyl-8-(3-methyl-2-butenyl)-2H-chromene-6-carboxilate-III and 2,2-dimethyl-8-(3-methyl-2-butenyl)-2H-chromene-6-carboxilic acid-IV. I and II showed activity against T. cruzi trypomastigotes (EC₅₀=56.1 and 22.9μM, respectively) and reduced cytotoxicity (CC₅₀ >200μM). Considering the activity of the dihydrochalcone, 26 related chalcones [Fig. 1] were synthesized for QSAR studies. The most active possessed phenyl and nitro groups at R³ (EC₅₀=3.3 and 13.9μM; CC₅₀ >200μM and CC₅₀=29.0μM, respectively).Compounds with highest SI were hydrogenated, and became inactive against T. cruzi. The implications of structural modifications on antitrypanosomal activity were studied by in silico models. The multivariate statistical analysis (MSA) identified promising subunits from the dataset and their statistical weights. The distribution of X variables suggests that substituents like R¹-propenyloxy (VIP=1.8, Coefficient=0.59 to Class A) and methoxyl at R⁴, R⁵ and R⁶ (VIPs=1.22, Coefficient=0.17 to Class A) are essential to antitrypanosomal activity. Furthermore, molecular features were investigated by machine learning techniques (MLT): One-R and J48, both suggesting that R¹-propenyloxy is the main feature for antitrypanosomal activity. In conclusion, chalcones and derivatives provided promising compounds as antitrypanosomal agents. Using MSA and MLT, essential molecular features were identified such as an α,β-unsaturated carbonyl system, methoxyl at R⁴, R⁵ and R⁶, and R¹-propenoxy that improved the antitrypanosomal activity.

Fig. 1 General Structure of Chalcone Derivatives

Aknowledgements

FAPESP, CAPES and CNPq for financial support.

• References

• 1 Chagas Disease – World Health Organization. https://www.who.int/en/news-room/fact-sheets/detail/chagas-disease-(american-trypanosomiasis)
• 2 Pinheiro E. et al. Chagas disease: review of needs, neglect, and obstacles to treatment access in Latin America. Rev Soc Bras Med Trop 2017; 50: 296-300
• 3 Vinuesa T. et al. Benznidazole Nanoformulates: A Chance to Improve Therapeutics for Chagas Disease. Am J Trop Med Hyg 2017; 97: 1469-1476