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

Cristian      O. Salas; Mario      Faundez; Antonio      Morello; Juan      Diego Maya; Ricardo      A. Tapia

doi:10.2174/092986711793979779

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.

Keywords: Chagas disease, lapachol, lapachones, naphthoquinones, structure-activity relationships, Trypanosoma cruzi, trypanocidal effects, Trypanosomiasis, mammalian organisms, zoonotic infection, human migration, morbidity, asymptomatic period, serology, megacolon, megaesophagus, triatomid bugs, trypomastigote form, insect's midgut, pathology, nifurtimox, benznidazole, parasite, epimastigotes, pharmacokinetic properties, anorexia, psychic alterations, intestinal colic, diarrhea, skin manifestations, hypersensitivity, dermatitis, thrombocytopenic purpura, agranulocytosis, biotransformed, xanthine oxidoreductase, nitroheterocyclic, aromatic ring, cytotoxic effects, oxygensensitive, Sterol biosynthesis, purine metabolism, antioxidant, tryparedoxins, analgesic, anti-inflammatory, diospyrin, metabolite, tumor cells, drug development, oxygen radical production, heterocyclic compounds, oxazolic, imidazolic, naphthoimidazoles derivatives, toxicity, anti-chagasic drugs, trypanocidal activity, hybridization, lead compounds, nitrogen substitution, redox cycling, cellular respiration, electron affinity (EA), electronegativity, electrophilicity, norlapachones, quinones, indazolylquinones, sesquiterpene skeleton, lipophilicity, Quantitative Structure-Activity Relationships, carbonyl groups, complementary