Fluorine-containing benzothiazole as a novel trypanocidal agent: design, in silico study, synthesis and activity evaluation

Cuevas‐Hernández, Roberto I.; Correa‐Basurto, José; Flores-Sandoval, César A.; Padilla‐Martínez, Itzia I.; Nogueda‐Torres, Benjamín; Villa-Tanaca, María de Lourdes; Tamay‐Cach, Feliciano; Fidencio, Juan Jesús Nolasco; Trujillo‐Ferrara, José G.

doi:10.1007/s00044-015-1475-9

Cited by 19 publications

(14 citation statements)

References 35 publications

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“…This work supports the fact that the kDNA seems to be the main target to explain the anti-T. cruzi effect of BT3 and BT10. Indeed, the concentrations required to inhibit the triosephosphate isomerase are higher than those required to kill trypanosomatids (14,15,23). These data break the paradigm that the trypanocidal effect of benzothiazoles is due to the inhibition of triosephosphate isomerase, as traditionally proposed (13,24,25).…”

Section: Discussionmentioning

confidence: 57%

“…S1 in the supplemental material). Because BT3 was used as the lead (14) for choosing and synthesizing BT1 to BT14, it was selected for further experiments so as to use this information to unveil the structure/activity relationship of these compounds.…”

Section: Resultsmentioning

confidence: 99%

“…In the present work, we obtained and evaluated a collection of 14 benzothiazoles (BT1 to BT14) related to previously studied 4-[5-(trifluoromethyl)-1,3-benzothiazol-2-yl] benzoic acid (BT3), which showed relevant anti-T. cruzi trypomastigote activity (14). The antiproliferation activity for all these compounds was initially evaluated in a screening with 25 M each compound.…”

Section: Discussionmentioning

confidence: 99%

“…In the last 2 decades, large libraries of compounds of diverse chemical nature have been screened for trypanocidal agents (12). Among the selected chemical structures, benzothiazoles (BZTs) have been studied in detail and have been suggested as trypanocides (13)(14)(15). BZTs are a class of bicyclic compounds with a broad spectrum of biological applications, such as neuroprotectors (16), anticonvulsants (17), antioxidants (18), kinase inhibitors (19), anticancer agents (20,21), antimicrobials (22), and leishmanicidals (23).…”

mentioning

confidence: 99%

“…In particular, it has been suggested that the trypanocidal effects of benzothiazoles are related to the inhibition of triosephosphate isomerase (TIM) (24,25). In previous work, we reported the development of 4-[5-(trifluoromethyl)-1,3benzothiazol-2-yl] benzoic acid, named BT3, which showed excellent trypanocidal activity on bloodstream trypomastigotes of T. cruzi (14); thus, it was proposed as a new nucleus for the development of trypanocidal agents. The aim of this contribution was to determine the trypanocidal activity of a collection of 14 benzothiazoles structurally related to BT3.…”

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confidence: 99%

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A Fluorinated Phenylbenzothiazole Arrests the Trypanosoma cruzi Cell Cycle and Diminishes the Infection of Mammalian Host Cells

Cuevas‐Hernández

Girard

Martínez-Cerón

et al. 2020

Antimicrob Agents Chemother

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Chagas disease (CD) is a human infection caused by Trypanosoma cruzi. CD was traditionally endemic to the Americas; however, due to migration it has spread to countries where it is not endemic. The current chemotherapy to treat CD induces several side effects, and its effectiveness in the chronic phase of the disease is controversial. In this contribution, substituted phenylbenzothiazole derivatives were synthesized and biologically evaluated as trypanocidal agents against Trypanosoma cruzi. The trypanocidal activities of the most promising compounds were determined through systematic in vitro screening, and their modes of action were determined as well. The physicochemical-structural characteristics responsible for the trypanocidal effects were identified, and their possible therapeutic application in Chagas disease is discussed. Our results show that the fluorinated compound 2-methoxy-4-[5-(trifluoromethyl)-1,3-benzothiazol-2-yl] phenol (BT10) has the ability to inhibit the proliferation of epimastigotes [IC50(Epi) = 23.1 ± 1.75 μM] and intracellular forms of trypomastigotes [IC50(Tryp) = 8.5 ± 2.9 μM] and diminishes the infection index by more than 80%. In addition, BT10 has the ability to selectively fragment 68% of the kinetoplastid DNA compared with 5% of nucleus DNA. The mode of action for BT10 on T. cruzi suggests that the development of fluorinated phenylbenzothiazole with electron-withdrawing substituent is a promising strategy for the design of trypanocidal drugs.

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Section: Discussionmentioning

confidence: 57%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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A Fluorinated Phenylbenzothiazole Arrests the Trypanosoma cruzi Cell Cycle and Diminishes the Infection of Mammalian Host Cells

Cuevas‐Hernández

Girard

Martínez-Cerón

et al. 2020

Antimicrob Agents Chemother

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

et al. 2021

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Design, synthesis and evaluation of benzothiazole derivatives as multifunctional agents

Djuidje

Sciabica

Buzzi

et al. 2020

Bioorganic Chemistry

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Oxidative stress is the product or aetiology of various multifactorial diseases; on the other hand, the development of multifunctional compounds is a recognized strategy for the control of complex diseases. To this end, a series of benzothiazole derivatives was synthesized and evaluated for their multifunctional effectiveness as antioxidant, sunscreen (filter), antifungal and antiproliferative agents. Compounds were easily synthesized via condensation reaction between 2-aminothiophenols and different benzaldehydes. SAR study, particularly in position 2 and 6 of benzothiazoles, led to the identification of 4g and 4k as very interesting potential compounds for the design of multifunctional drugs. In particular, compound 4g is the best blocker of hERG potassium channels expressed in HEK 293 cells exhibiting 60.32% inhibition with IC 50 = 4.79 μM.

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Fluorine-containing benzothiazole as a novel trypanocidal agent: design, in silico study, synthesis and activity evaluation

Cited by 19 publications

References 35 publications

A Fluorinated Phenylbenzothiazole Arrests the Trypanosoma cruzi Cell Cycle and Diminishes the Infection of Mammalian Host Cells

A Fluorinated Phenylbenzothiazole Arrests the Trypanosoma cruzi Cell Cycle and Diminishes the Infection of Mammalian Host Cells

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

Design, synthesis and evaluation of benzothiazole derivatives as multifunctional agents

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