In vitro and in silico evaluations of new aryloxy-1,4-naphthoquinones as anti-Trypanosoma cruzi agents

González, Andrés; Becerra, Nohemí A.; Kashif, Muhammad; González, Mercedes; Cerecetto, Hugo; Aguilera, Elena; Nogueda‐Torres, Benjamín; Chacón-Vargas, Karla Fabiola; Zárate-Ramos, Juan J.; Castillo-Velázquez, Uziel; Salas, Cristian O.; Rivera, Gildardo; Vázquez, Karina

doi:10.1007/s00044-020-02512-9

Cited by 14 publications

(7 citation statements)

References 23 publications

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“…1), which was functionalized according to four criteria, to evaluate the effect of these modi cations on the trypanosomicidal effect on epimastigote and tripomastigote forms from Mexican strains of T. cruzi. These modi cations were: (a) the substitution of the hydrogen atom on C-3 by bromine or chlorine because it has been reported that this change modulates the trypanosomicidal activity on Tulahuén, NINOA, INC-5 and Y strains [14]. In the aryloxy moiety: (b) the substitutions of a nitro group in the aryloxy moiety at meta or para position; (c) as shown in VI, a methyl group at para position and meta position; (d) a substitution at para position by chlorine atom.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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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.

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Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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“…Moreover, the SI of IVM obtained for T. cruzi amastigotes was 12 in agreement with the drug selection criteria for infectious diseases that establish an SI value ≥10 as a promissory limit ( Katsuno et al., 2015 ). On the other hand, the SI of NFX and BZN reported in bibliography are very variable, with values ranging from 1.5 to over 200 according to the strain and the cell line used ( González et al., 2020 ). Reinforcing the idea of IVM as possible therapy against T. cruzi in humans, published pharmacokinetic data have shown a safety profile for the human use of the oral administration of IVM without adverse side effects, reaching plasmatic concentrations in the range of the EC50 values found in this work ( Guzzo et al., 2002 ).…”

Section: Discussionmentioning

confidence: 99%

Broadening the spectrum of ivermectin: Its effect on Trypanosoma cruzi and related trypanosomatids

Fraccaroli

Ruiz

Perdomo

et al. 2022

Front. Cell. Infect. Microbiol.

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Chagas disease is an endemic American parasitosis, caused by Trypanosoma cruzi. The current therapies, benznidazole (BZN) and nifurtimox (NFX), show limited efficacy and multiple side effects. Thus, there is a need to develop new trypanocidal strategies. Ivermectin (IVM) is a broad-spectrum antiparasitic drug with low human and veterinary toxicity with effects against T. brucei and Leishmania spp. Considering this and its relatively low cost, we evaluate IVM as a potential repurposed trypanocidal drug on T. cruzi and other trypanosomatids. We found that IVM affected, in a dose-dependent manner, the proliferation of T. cruzi epimastigotes as well as the amastigotes and trypomastigotes survival. The Selectivity Index for the amastigote stage with respect to Vero cells was 12. The IVM effect was also observed in Phytomonas jma 066 and Leishmania mexicana proliferation but not in Crithidia fasciculata. On the epimastigote stage, the IVM effect was trypanostatic at 50 μM but trypanocidal at 100 μM. The assays of the drug combinations of IVM with BNZ or NFX showed mainly additive effects among combinations. In silico studies showed that classical structures belonging to glutamate-gated Cl channels, the most common IVM target, are absent in kinetoplastids. However, we found in the studied trypanosomatid genomes one copy for putative IMPα and IMPβ, potential targets for IVM. The putative IMPα genes (with 76% similarity) showed conserved Armadillo domains but lacked the canonical IMPβ binding sequence. These results allowed us to propose a novel molecular target in T. cruzi and suggest IVM as a good candidate for drug repurposing in the Chagas disease context.

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“…Five mg of fraction 14 with the highest antioxidative activity were dissolved in 0.9 mL of methanol and analyzed in a UPLC coupled with an ACQUITY QDa mass detector (Waters, MA USA). The following conditions were used: ACQUITY UPLC ® CORTECS ® C 18 column (1.6 µm, 3.0 × 100 mm); mobile phase A (0.1% formic acid) and B (100% acetonitrile) in gradient run (0.5 min, 10.0% A, 90.0% B; 3.5 min, 50.0% A, 50.0% B; and 6 min, 10.0% A, 90.0% B), total time of execution: 6.0 min; caudal: 0.3 mL/min; injection volume: 2 µL; and column temperature: 40 • C. The identification of the main compounds was performed using a range of phenolic compounds, including kaempferol, quercetin, and apigenin (Sigma-Aldrich, St. Louis, MO, USA) [42].…”

Section: Flavonoid Detectionmentioning

confidence: 99%

Antioxidant and Antiproliferative Activity of the Ethanolic Extract of Equisetum myriochaetum and Molecular Docking of Its Main Metabolites (Apigenin, Kaempferol, and Quercetin) on β-Tubulin

et al. 2021

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Equisetum myriochaetum is a semi-aquatic plant found on riverbanks that is commonly used in traditional medicine as a diuretic agent. Additionally, the genus Equisetum stands out for its content of the flavonoid kaempferol, a well-known antiproliferative agent. Therefore, in this study, E. myriochaetum ethanolic extract was tested in vitro against a cervical cancer cell line (SiHa). Additionally, the antioxidative activity was evaluated through a 2,2-diphenyl-1-picrilhidrazil (DPPH) assay. Finally, a molecular docking analysis of apigenin, kaempferol, and quercetin on the active site of β-tubulin was performed to investigate their potential mechanism of action. All fractions of E. myriochaetum ethanolic extract showed antioxidative activity. Fraction 14 displayed an antiproliferative capacity with a half maximal inhibitory concentration (IC50) value of 6.78 μg/mL against SiHa cells.

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In vitro and in silico evaluations of new aryloxy-1,4-naphthoquinones as anti-Trypanosoma cruzi agents

Cited by 14 publications

References 23 publications

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

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

Broadening the spectrum of ivermectin: Its effect on Trypanosoma cruzi and related trypanosomatids

Antioxidant and Antiproliferative Activity of the Ethanolic Extract of Equisetum myriochaetum and Molecular Docking of Its Main Metabolites (Apigenin, Kaempferol, and Quercetin) on β-Tubulin

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