Natural and Synthetic Naphthoquinones Active Against Trypanosoma Cruzi: An Initial Step Towards New Drugs for Chagas Disease

Abstract

Chagas disease is one of the most important endemic diseases in Latin America, caused by Trypanosoma cruzi. The drugs used for the treatment of this disease, nifurtimox and benznidazole, are toxic and present severe side effects. The need of effective drugs, without adverse effects, has stimulated the search for new compounds with potential clinical utility. An overview of a number of natural naphthoquinones tested against T. cruzi parasites is provided. Among natural naphthoquinones, lapachol, β-lapachone and its α-isomer have demonstrated useful trypanocidal activities. In the search for new trypanocidal agents, this review outlines different structural modifications of natural quinones, as well as synthetic quinones, which have been subjected to trypanocidal studies. This review summarizes the mechanism of action and structure-activity relationships of the quinone derivatives, including some theoretical calculations that discuss the correlation of stereo electronic properties with the trypanocidal activity. In this context, this review will be useful for the development of new antichagasic drugs based mainly on structural modification of natural quinones.

In-silico Investigation of Antitrypanosomal Phytochemicals from Nigerian Medicinal Plants

“…Many naphthoquinones have been shown to be antitrypanosomal [100], and are suspected to interfere with redox thiol metabolism by inhibition of TbTR [101], [102]. There are docking poses, albeit not the lowest-energy poses, of isoplumbagin (docking pose energy = −9.9 kcal/mol) and lawsone (docking pose energy = −8.6 kcal/mol) with TbTR such that these quinone ligands are in the proximity of reduced trypanothione (Fig.…”

Synthesis and evaluation of (±)-dunnione and its ortho-quinone analogues as substrates for NAD(P)H:quinone oxidoreductase 1 (NQO1)

“…Claisen rearrangement of 10a (120°C, toluene) gave 3,3-dimethyl allyl lawsone (11a) (82%). 11a was cyclized to dunnione (2) mediated by Lewis acid NbCl 5 compounds 3-8 were prepared by analogous routes in similar yields. Most of these compounds were obtained with a mixture of stereoisomers, and compound 4 was mainly in its trans-isomer The steric configuration of structural formula was shown in the Supporting information (Fig.…”

Trypanosoma cruzi mitochondrial swelling and membrane potential collapse as primary evidence of the mode of action of naphthoquinone analogues

“…Quinone-containing plants have been used in diverse cultures as dyes, cosmetics, and food and, especially among Indian populations, for the treatment of different diseases [6,7]. Naphthoquinones are considered privileged structures in medicinal chemistry due to their structural properties and biological activities [8], especially against tumor cells and pathogenic protozoa [9,10]. Two major mechanisms of quinone cytotoxicity have been proposed: stimulation of oxidative stress and alkylation of cellular nucleophiles, which are the mechanisms of action common to a large range of biomolecules [11].…”