Expanding the chemical space of aryloxy-naphthoquinones as potential anti-Chagasic agents: synthesis and trypanosomicidal activity

Abstract

In continuation our effort to research the chemical space of aryloxy-naphthoquinones as potential anti-Chagas agents, we synthesized nine derivatives and these compounds were evaluated in vitro against the epimastigote and trypomastigote forms of Mexican strains of Trypanosoma cruzi (T. cruzi). Most of these derivatives are highly active against epimastigote forms (IC 50 < 1.0 µM) compared to the reference drug benznidazole (Bzn). Then these were evaluated on trypomastigotes, which is showing better potency results than Bzn for compounds 3b and 3g. In addition, the cytotoxicity of these compounds was determined on the murine macrophage cell line J774. 3b and 3i were the most selective compounds against NINOA trypomastigote and INC-5 epimastigote forms, respectively. Further these compounds also have good oral bioavailability according to theoretical predictions. Finally, we were able to determine optimal substitution patterns using pharmacophoric models. All these results are provided very useful structural information to continue our designing of naphthoquinone derivatives against T. cruzi.

New Amino Naphthoquinone Derivatives as Anti-Trypanosoma cruzi Agents Targeting Trypanothione Reductase

“…Likewise, regarding the effect of the halogen atom at C-2 on the naphthoquinone core, a chlorine atom and bromine atom increases the parasiticidal activity on the NINOA strain and INC-5 strains, respectively. This evidence confirms our previous results regarding the importance of a halogen atom in this position [27]. Most of the Series II compounds were more potent than the Series I compounds.…”

“…Mobile trypomastigotes were counted in 15 microscope fields at 40× magnification. Quantification of the degree of lysis for each case was expressed as a percentage considering the number of viable trypomastigotes with respect to the negative control [27]. The half-maximal lytic concentration (LC 50 ) was determined by linear regression.…”

“…The synthesis of derivatives from Series I (2a-i) was conducted according to a previ ously reported procedure [12,27,30], and as shown in Scheme 1, using mono-or dihalo naphthoquinones 1a-c as starting material. The nucleophilic substitution of 1a-c with 2 morpholinoethanamine, 1-cyclopentylpiperazine, or 4-(piperidin-4-yl)morpholine in basic medium, with acetonitrile as a solvent at room temperature, yielded the quinone derivatives 2a-i (18-86%).…”

Ligand-Based Virtual Screening and Molecular Docking of Benzimidazoles as Potential Inhibitors of Triosephosphate Isomerase Identified New Trypanocidal Agents

“…Motile protozoa were counted in 15 fields at 40× using an optical microscope. The lysis percentage of each treatment was calculated by comparing the viable trypomastigotes with the negative control [ 64 ]. The half-maximum lytic concentration (LC 50 ) was determined for each compound using the Probit statistical tool.…”

In Silico Antiprotozoal Evaluation of 1,4-Naphthoquinone Derivatives against Chagas and Leishmaniasis Diseases Using QSAR, Molecular Docking, and ADME Approaches

“…Treatment with DPNQ in infected female mice promoted a halving of the parasite load, and ensured a 60% survival rate of the animal [15]. In 2021, Becerra et al used pharmacophoric models based on different studies to design and subsequently synthesize nine phenolic derivatives, which were tested against T. cruzi strains, most of which showed good activity compared to BNZ, and the best prospects showed low toxicity [16]. Plumbagin is a plant-derived naphthoquinone metabolite (5-hydroxy-2-methyl-1,4-naphthaquinone) that inhibits trypanothione reductase, and has been validated as a drug which is responsible for promoting oxidative stress in Leishmania [9].…”