Antiparasitic Activity of Plumbago auriculata Extracts and Its Naphthoquinone Plumbagin against Trypanosoma cruzi

Abstract

Chagas disease (CD) caused by the protozoan Trypanosoma cruzi affects more than six million people worldwide. Treatment is restricted to benznidazole (Bz) and nifurtimox (Nf) that display low activity in the later chronic stage besides triggering toxic events that result in treatment abandonment. Therefore, new therapeutic options are necessary. In this scenario, natural products emerge as promising alternatives to treat CD. In the family Plumbaginaceae, Plumbago sp. exhibits a broad spectrum of biological and pharmacological activities. Thus, our main objective was to evaluate, in vitro and in silico, the biological effect of crude extracts of root and of aerial parts of P. auriculata, as well as its naphthoquinone Plumbagin (Pb) against T. cruzi. The phenotypic assays revealed potent activity of the root extract against different forms (trypomastigote and intracellular forms) and strains (Y and Tulahuen), with a compound concentration that reduced 50% of the number of the parasite (EC50) values ranging from 1.9 to 3.9 µg/mL. In silico analysis showed that Pb is predicted to have good oral absorption and permeability in Caco2 cells, besides excellent probability of absorption by human intestinal cells, without toxic or mutagenic potential effects, not being predicted as a substrate or inhibitor of P-glycoprotein. Pb was as potent as Bz against intracellular forms and displayed a superior trypanosomicidal effect (about 10-fold) in bloodstream forms (EC50 = 0.8 µM) as compared to the reference drug (8.5 µM). The cellular targets of Pb on T. cruzi were evaluated using electron microscopy assays and the findings on bloodstream trypomastigotes showed several cellular insults related to the autophagic process. Regarding toxicity in mammalian cells, the root extracts and the naphthoquinone present a moderate toxic profile on fibroblasts and cardiac cell lines. Then, aiming to reduce host toxicity, the root extract and Pb were tested in combination with Bz, and the data showed additive profiles with the sum of the fractional inhibitory concentration indexes (ΣFICIs) being 1.45 and 0.87, respectively. Thus, our work reveals the promising antiparasitic activity of Plumbago auriculata crude extracts and its purified naphthoquinone Plumbagin against different forms and strains of Trypanosoma cruzi in vitro.

Synthesis and evaluation of photophysical, electrochemical, and ROS generation properties of new chalcogen-naphthoquinones-1,2,3-triazole hybrids

“…Another prominent scaffold is the 1,2,3-triazole nucleus who have a wide range of applications, including explosives, agrochemicals, and mostly medicines. 19 Due to the biological activities associated with the 1,2,3-triazole ring, it is used as an important linker in new pharmacologically active molecules and showed properties such as anti-inflammatory, 20 anticonvulsant, 21 antioxidant, 22 antibacterial, 23 antiviral, 24 antifungal, 25 anti- T. cruzi ( Trypanosoma cruzi ), 26 antitubercular, 27 anticancer, 28 anti-HIV (Human Immunodeficiency Virus), 29 and anti-Alzheimer. 30 Moreover, the distinct electronic structure of this ring, along with its polydentate nature, allows it to effectively bind to metal ions and analytes, making it an ideal choice for chemosensors used in qualitative and quantitative studies.…”

Plumbagin: A Promising In Vivo Antiparasitic Candidate against Schistosoma mansoni and In Silico Pharmacokinetic Properties (ADMET)

“…Among naphthoquinones, plumbagin (PLUM) (5-hydroxy-2-methyl-1,4-naphthoquinone) is a polycyclic aromatic hydrocarbon ( Figure 1 B) that can be naturally isolated from various parts of plants of the families Plumbaginaceae, Ebenaceae, and Droseraceae, and has a broad spectrum of biological and pharmacological properties including activation of apoptosis, antioxidant, anti-inflammatory [ 51 ] anticancer [ 52 ], antibacterial [ 53 ], and antifungal [ 29 , 54 ]. Regarding the antiparasitic potential, extracts obtained from Plumbago auriculata , Plumbago zeylanica L., and Plumbago indica L., all rich in plumbagin, demonstrated action against Trypanosoma cruzi , Plasmodium falciparum , and Carmyerius spatiosus , respectively [ 55 , 56 , 57 ]. Furthermore, isolated plumbagin was able to induce programmed cell death (PCD) Leishmania promastigotes through elevation of reactive oxygen species (ROS), disruption of intracellular calcium homeostasis, and mitochondrial depolarization and by acting as an inhibitor of trypanothione redutase [ 42 , 58 ].…”