Phenylbenzothiazole derivatives: effects against a Trypanosoma cruzi infection and toxicological profiles

Martínez-Cerón, Sarai; Gutiérrez-Nágera, Nora Andrea; Mirzaeicheshmeh, Elaheh; Cuevas‐Hernández, Roberto I.; Trujillo‐Ferrara, José G.

doi:10.1007/s00436-021-07137-4

Cited by 7 publications

(6 citation statements)

References 54 publications

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“…The compound benzothiazole derivative 2-methoxy-4-[5-(trifluoromethyl)-1,3-benzothiazol-2-yl] phenol (BT10) was evaluated for Trypanosoma cruzi . It was found to inhibit the proliferation of epimastigote (IC 50 (Epi) = 23.1 ± 1.75 μM) and trypomastigote (IC 50 (Tryp) = 8.5 ± 2.9 μM) [ 28 , 29 , 30 ]. In another study, the effect of benzothiazole derivatives on Giardia lamblia and Trichomonas vaginalis was investigated, the benzothiazoles exhibited good giardicidal activity (IC 50 = 4.627 ± 1.67 μM) and antitrichomonal activity (7.68 ± 3.059 μM) at 48 h of incubation [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

“…Among the beneficial biological and pharmacological properties of benzothiazole derivatives are their anticancer [ 14 ], antimicrobial [ 15 ], antidiabetic [ 16 ], anticonvulsant [ 17 ], anti-inflammatory [ 18 ], antiviral [ 19 ], and antitubercular activities [ 20 ]. In relation to their antiparasitic activities, they have been described as [ 21 , 22 , 23 ] leishmanicidal [ 24 , 25 ], anthelmintic [ 26 ], antimalarial [ 27 ], and trypanocidal [ 28 , 29 , 30 ].…”

Section: Introductionmentioning

confidence: 99%

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Riluzole, a Derivative of Benzothiazole as a Potential Anti-Amoebic Agent against Entamoeba histolytica

et al. 2023

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Amoebiasis is produced by the parasite Entamoeba histolytica; this disease affects millions of people throughout the world who may suffer from amoebic colitis or amoebic liver abscess. Metronidazole is used to treat this protozoan, but it causes important adverse effects that limit its use. Studies have shown that riluzole has demonstrated activity against some parasites. Thus, the present study aimed, for the first time, to demonstrate the in vitro and in silico anti-amoebic activity of riluzole. In vitro, the results of Entamoeba histolytica trophozoites treated with IC50 (319.5 μM) of riluzole for 5 h showed (i) a decrease of 48.1% in amoeba viability, (ii) ultrastructural changes such as a loss of plasma membrane continuity and alterations in the nuclei followed by lysis, (iii) apoptosis-like cell death, (iv) the triggering of the production of reactive oxygen species and nitric oxide, and (v) the downregulation of amoebic antioxidant enzyme gene expression. Interestingly, docking studies have indicated that riluzole presented a higher affinity than metronidazole for the antioxidant enzymes thioredoxin, thioredoxin reductase, rubrerythrin, and peroxiredoxin of Entamoeba histolytica, which are considered as possible candidates of molecular targets. Our results suggest that riluzole could be an alternative treatment against Entamoeba histolytica. Future studies should be conducted to analyze the in vivo riluzole anti-amoebic effect on the resolution of amebic liver abscess in a susceptible model, as this will contribute to developing new therapeutic agents with anti-amoebic activity.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Riluzole, a Derivative of Benzothiazole as a Potential Anti-Amoebic Agent against Entamoeba histolytica

et al. 2023

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“…Therefore, important research efforts from public organizations (DNDi, 2023b), pharmaceutical companies (Peña et al., 2015) and academic research groups (Cassiano Martinho et al., 2022; Ferreira et al., 2021; Jacques Dit Lapierre et al., 2023; Koovits, Dessoy, Matheeussen, Maes, Caljon, Ferreira, et al., 2020; Lal et al., 2023; McNamara et al., 2022) have been performed over the last decades, in order to identify clinical candidates which might overcome the shortcomings of the current treatments (Chatelain, 2015; Field et al., 2017; Koovits, Dessoy, Matheeussen, Maes, Caljon, Mowbray, et al., 2020). Among the resulting literature from such works, benzothiazole‐containing compounds can be encountered in numerous studies targeting diverse parasites, in which the inclusion of a benzothiazole fragment provides compounds active against Trypanosoma brucei (Berg et al., 2001; Brown et al., 2020; de Oliveira Viana et al., 2019; Linciano et al., 2019), T. cruzi (Berg et al., 2001; Cuevas‐Hernández et al., 2020; Fleau et al., 2019; Martínez‐Cerón et al., 2021), L. infantum (de Oliveira Viana et al., 2019), Plasmodium falciparum (Berg et al., 2001), and Cryptosporidium parvum (Oboh et al., 2023), among others. Thus, we selected as initial hit for this work the acylaminobenzothiazole 1 , of which the antitrypanosomal activity was identified in a primary HTS screening of the NIH compound collection against T. cruzi performed by the Broad Institute (bioassay number AID 1885) (P. B.…”

Section: Introductionmentioning

confidence: 99%

Evaluation and discovery of novel benzothiazole derivatives as promising hits against Leishmania infantum

Lapierre,

Farago,

de Moura Lodi Cruz

et al. 2024

Chem Biol Drug Des

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An early exploration of the benzothiazole class against two kinetoplastid parasites, Leishmania infantum and Trypanosoma cruzi, has been performed after the identification of a benzothiazole derivative as a suitable antileishmanial initial hit. The first series of derivatives focused on the acyl fragment of its class, evaluating diverse linear and cyclic, alkyl and aromatic substituents, and identified two other potent compounds, the phenyl and cyclohexyl derivatives. Subsequently, new compounds were designed to assess the impact of the presence of diverse substituents on the benzothiazole ring or the replacement of the endocyclic sulfur by other heteroatoms. All compounds showed relatively low cytotoxicity, resulting in decent selectivity indexes for the most active compounds. Ultimately, the in vitro ADME properties of these compounds were assessed, revealing a satisfying water solubility, gastrointestinal permeability, despite their low metabolic stability and high lipophilicity. Consequently, compounds 5 and 6 were identified as promising hits for further hit‐to‐lead exploration within this benzothiazole class against L. infantum, thus providing promising starting points for the development of antileishmanial candidates.

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“…Further attempts to develop improved trypanocidal agents have included studies on benzazoles − and their amidine derivatives, − where enhancement of activity has been achieved through optimization of physicochemical parameters and ADME properties. The introduction of nitrogen atoms into the aromatic rings can change the lipophilicity and polarity of the resulting aza analogues, enabling them to cross the BBB. , Some benzimidazole − and benzothiazole − derivatives have been shown to have potent anti-trypanosomatid activity. As an example, 6-(trifluoromethyl)benzothiazole, which contains a cyclopropanecarboxamide moiety, was identified as a lead with improved antiparasitic activity and promising in vivo efficacy .…”

Section: Introductionmentioning

confidence: 99%

“…The introduction of nitrogen atoms into the aromatic rings can change the lipophilicity and polarity of the resulting aza analogues, enabling them to cross the BBB. 24 , 25 Some benzimidazole 26 − 28 and benzothiazole 29 − 32 derivatives have been shown to have potent anti-trypanosomatid activity. As an example, 6-(trifluoromethyl)benzothiazole, which contains a cyclopropanecarboxamide moiety, was identified as a lead with improved antiparasitic activity and promising in vivo efficacy.…”

Section: Introductionmentioning

confidence: 99%

Bis-6-amidino-benzothiazole Derivative that Cures Experimental Stage 1 African Trypanosomiasis with a Single Dose

Racané,

Ptiček,

Kostrun

et al. 2023

J. Med. Chem.

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We designed and synthesized a series of symmetric bis-6-amidino-benzothiazole derivatives with aliphatic central units and evaluated their efficacy against bloodstream forms of the African trypanosome Trypanosoma brucei. Of these, a dicationic benzothiazole compound (9a) exhibited subnanomolar in vitro potency with remarkable selectivity over mammalian cells (>26,000-fold). Unsubstituted 5-amidine groups and a cyclohexyl spacer were the crucial determinants of trypanocidal activity. In all cases, mice treated with a single dose of 20 mg kg −1 were cured of stage 1 trypanosomiasis. The compound displayed a favorable in vitro ADME profile, with the exception of low membrane permeability. However, we found evidence that uptake by T. brucei is mediated by endocytosis, a process that results in lysosomal sequestration. The compound was also active in low nanomolar concentrations against cultured asexual forms of the malaria parasite Plasmodium falciparum. Therefore, 9a has exquisite cross-species efficacy and represents a lead compound with considerable therapeutic potential.

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Phenylbenzothiazole derivatives: effects against a Trypanosoma cruzi infection and toxicological profiles

Cited by 7 publications

References 54 publications

Riluzole, a Derivative of Benzothiazole as a Potential Anti-Amoebic Agent against Entamoeba histolytica

Riluzole, a Derivative of Benzothiazole as a Potential Anti-Amoebic Agent against Entamoeba histolytica

Evaluation and discovery of novel benzothiazole derivatives as promising hits against Leishmania infantum

Bis-6-amidino-benzothiazole Derivative that Cures Experimental Stage 1 African Trypanosomiasis with a Single Dose

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