Synthesis and anti-Trypanosoma cruzi activity of naphthoquinone-containing triazoles: Electrochemical studies on the effects of the quinoidal moiety

Abstract

In our continued search for novel trypanocidal compounds, twenty-six derivatives of para- and ortho-naphthoquinones coupled to 1,2,3-triazoles were synthesized. These compounds were evaluated against the infective bloodstream form of Trypanosoma cruzi, the etiological agent of Chagas disease. Compounds 17-24, 28-30 and 36-38 are described herein for the first time. Three of these novel compounds (28-30) were found to be more potent than the standard drug benznidazole, with IC50/24h values between 6.8 and 80.8μM. Analysis of the toxicity to heart muscle cells led to LC50/24h of <125, 63.1 and 281.6μM for 28, 29 and 30, respectively. Displaying a selectivity index of 34.3, compound 30 will be further evaluated in vivo. The electrochemical properties of selected compounds were evaluated in an attempt to find correlations with trypanocidal activity, and it was observed that more electrophilic quinones were generally more potent.

Synthesis of Amino Acid–Naphthoquinones and In Vitro Studies on Cervical and Breast Cell Lines

“…Thus, the redox reaction process is considered quasi-reversible. Furthermore, it is unclear if the reduction reaction of the quinone moiety occurs via a single-step two-electron process as compared to the two successive one-electron transfer steps producing semiquinone (Q − ) and quinone dianion (Q 2− ), as typically observed for well-behaved quinone derivatives (Q) in nonaqueous media [35,39,40,41,42,43].…”

“…These results are associated to the electron-accepting capacity of the chloride substituent, and possibly to some conformational effects which modify the electronic configuration of the naphthoquinone–amino acid derivatives, facilitating the reduction processes [41,50]. It is then expected that naphthoquinone compounds with amino acids and chloride substituents ( 4a – e ) present higher biological activity than derivatives ( 3a – e ), as estimated by their E 1/2 values, since reactive oxygen species (ROS) generation is facilitated at compounds with more positive E 1/2 [39,40,41,42,49,51]. However, additional factors such as solvents, nature of supporting electrolyte, protonation–deprotonation equilibrium, and intra- and intermolecular hydrogen bonding also play important roles in determining the half-wave potential of the redox reaction processes, probably affecting cellular biological processes.…”

Effects of a novel β–lapachone derivative on Trypanosoma cruzi : Parasite death involving apoptosis, autophagy and necrosis

“…Naphtoquinones such as β–lapachone are natural products isolated from different higher plant families and shown to present antimalarial (Carvalho et al., 1988, De Andrade-Neto et al., 2004, Pérez-Sacau et al., 2005), giardicidal (Corrêa et al., 2009), leishmanicidal (Guimarães et al., 2013) and trypanocidal activity against T. brucei (De Pahn et al., 1988) and Trypanosoma cruzi (Boveris et al., 1978, Docampo et al., 1978, Goijman and Stoppani, 1985, Pinto et al., 1997, Pinto et al., 2000, Menna-Barreto et al., 2005, Menna-Barreto et al., 2007, Menna-Barreto et al., 2009a, 2014). Furthermore, lapachone derivatives/analogues may display enhanced antiparasitic activity upon T. cruzi (Pinto et al., 1997; Ferreira et al., 2011, Diogo et al., 2013). …”

Optimization of 1,4-Naphthoquinone Hit Compound: A Computational, Phenotypic, and In Vivo Screening against Trypanosoma cruzi

“…Optimization of 1,4-naphthoquinones activity by the addition of triazole has generated either promising or completely inactive derivatives against T. cruzi [27], suggesting that the position of triazole insertion into quinones or its association with other substitutes modulates its biological activity. High trypanocidal potency has been proposed to be associated with orthoand para-quinoidal moieties of [1,2,3]-triazole-coupled naphthoquinones and their electrophilic properties, probably related to high ROS induction [42].…”