Tandem Synthesis of Furanaphthoquinones via Enamines and Evaluation of Their Antiparasitic Effects against Trypanosoma cruzi

Abstract

Furanaphthoquinones are well known in medicinal chemistry for exhibiting relevant structural heterogeneity and bioactivities. In this work, it was synthesized a series of furanaphthoquinones through a tandem reaction between lawsone (8) and cyclic ketones in the presence of morpholine. This strategy provides an efficient and general method for synthesizing furanaphthoquinones with activity against the epimastigote form of Trypanosoma cruzi (T. cruzi), the parasite that causes Chagas disease. Compound 9b was the better prototype, and it exhibited high potency for causing parasite death, showed reduced acute toxicity towards mammalian cells, and was capable of rupturing the epimastigote plasma membrane and acting on sterol 14α-demethylase (CYP51). Additionally, 9b reduced trypomastigote viability by 99% after 24 h. Candidate 9b demonstrated the best and most promising profile when bound to CYP51.

In Silico Antiprotozoal Evaluation of 1,4-Naphthoquinone Derivatives against Chagas and Leishmaniasis Diseases Using QSAR, Molecular Docking, and ADME Approaches

“…The steric interactions that stabilize ligand 68, also present in the two azoles mentioned [87], occur with residues Ala 291 (B), Ala 287 (B), Tyr 116 (B), and Phe 110 (B). Cardoso et al reported a hydrogen bond between their furan-naphthoquinones with the Tyr 116 residue in the binding site of this protein [88]; however, for molecules 66 and 68, the interactions with this residue are of the steric type. These same authors report cation-π interactions with the Fe of the Heme group, which were not observed in any 1,4-naphthoquinone derivative tested here.…”