In Vivo Biological Evaluation of a Synthetic Royleanone Derivative as a Promising Fast-Acting Trypanocidal Agent by Inducing Mitochondrial-Dependent Necrosis

Abstract

The life-long and life-threatening Chagas disease is one of the most neglected tropical diseases caused by the protozoan parasite Trypanosoma cruzi. It is a major public health problem in Latin America, as six to seven million people are infected, being the principal cause of mortality in many endemic regions. Moreover, Chagas disease has become widespread due to migrant populations. Additionally, there are no vaccines nor effective treatments to fight the disease because of its long-term nature and complex pathology. Therefore, these facts emphasize how crucial the international effort for the development of new treatments against Chagas disease is. Here, we present the in vitro and in vivo trypanocidal activity of some oxygenated abietane diterpenoids and related compounds. The 1,4-benzoquinone 15, not yet reported, was identified as a fast-acting trypanocidal drug with efficacy against different strains in vitro and higher activity and lower toxicity than benznidazole in both phases of murine Chagas disease. The mode of action was also evaluated, suggesting that quinone 15 kills T. cruzi by inducing mitochondrion-dependent necrosis through a bioenergetics collapse caused by a mitochondrial membrane depolarization and iron-containing superoxide dismutase inhibition. Therefore, the abietane 1,4-benzoquinone 15 can be considered as a new candidate molecule for the development of an appropriate and commercially accessible anti-Chagas drug.

Unprecedented Elimination Reactions of Cyclic Aldols: A New Biosynthetic Pathway toward the Taiwaniaquinoid Skeleton

“…This rearrangement of seco-abietane dialdehydes has been employed in order to achieve the first enantiospecific synthesis of bioactive taxodal ( 28 ) and cupresol ( 30 ) from methyl ether 12 , which is easily obtained from (-)-abietic acid ( Scheme 7 ) [ 37 ].…”

“…The treatment of ketoaldehyde 27 , resulting from the ozonolysis of ether 12 , with ti-ophenol in basic media, gave bioactive taxodal ( 28 ) [ 37 ]. Alternatively, the oxidation of compound 27 with sodium chlorite produced a 1:1 mixture of epimers 29 .…”

“…Alternatively, the oxidation of compound 27 with sodium chlorite produced a 1:1 mixture of epimers 29 . The deprotection of methyl ether and further chromatography allowed us to obtain the enantiopure bioactive cupresol ( 30 ) [ 37 , 38 ].…”

Trypanosoma cruzi Arequipa: a tool for Chagas disease drug discovery

“…After 24 h of infection, nonphagocyted trypomastigotes were washed, and infected Vero cells were treated by adding BNZ at a concentration range from 100 to 0.4 μM (500 μL•well -1 volumes) at 37º C in humidified 95 % air, 5 % CO 2 atmosphere for 72 h. Untreated growth controls were also included. Counting of amastigotes and infected cells was performed in methanol-fixed and Giemsa-stained preparations by random analysis of 500 host cells (Martín-Escolano et al , 2020b). The infectivity index, defined as the average number of amastigote forms in infected cells multiplied by the percentage of infected cells, was also determined.…”

Biological characteristics of the Trypanosoma cruzi Arequipa strain make it a good model for Chagas disease drug discovery

“…We have determined the in vitro BNZ susceptibility profile of the different morphological forms of T. cruzi Arequipa, characterized acute-phase parasitaemia and chronic-phase tropism in BALB/c mice and analysed the in vitro BNZ susceptibility profile of T. cruzi Arequipa in both the acute and the chronic phases of CD. Some of the information related to the BNZ susceptibility profile has been compiled from previous published work (Martín-Escolano et al, 2019a, 2020b2020c, in which we studied this strain as a target for the discovery of new anti-Chagas compounds. The tropism of this strain makes it an interesting model for CD drug discovery.…”