@misc{10481/108033,
year = {2025},
month = {11},
url = {https://hdl.handle.net/10481/108033},
abstract = {Thioflavin T (ThT) is a well-established fluorescence probe with selectivity for G-quadruplex (G4) structures. Over
the past few years, G4 ligands have emerged as promising
candidates for the development of antiparasitic agents. Building
on this concept, we explored extending ThT’s benzothiazole
scaffold by introducing various 2-ethenyl aromatic and heteroaromatic moieties, aiming to enhance G4 binding affinity and
potential therapeutic effect. A series of benzothiazolium derivatives
were synthesized and evaluated for their antiproliferative and
antiparasitic activity. Several 2-ethenyl benzothiazole derivatives
showed submicromolar activity against Leishmania spp. and Trypanosoma brucei parasites, with up to 200-fold selectivity over MRC5 human lung fibroblasts. Notably, compound 2b demonstrated remarkable potency, with an IC50 of 0.48 nM and a selectivity index
of 46,151 against Leishmania major amastigotes, and an IC50 of 0.019 nM and a selectivity index of 79,206 against T. brucei. In fact,
compound 2b demonstrated superior efficacy and selectivity in comparison to the clinically used drugs suramin, fexinidazole,
miltefosine, and amphotericin B. Biophysical studies revealed that all tested derivatives exhibited significant G4 stabilization,
surpassing ThT. Location of compound 2b inside the nucleus and the kinetoplast, as well as partially in the mitochondria, opens up
the possibility of 2b acting against the parasite through binding to G4.},
organization = {Ministerio de Ciencia, Innovación y Universidades, España (Proyectos PID2021-127109OB-I00 y PID2022-138474OB-I00)},
organization = {NextGenerationEU / European Union (Beca Maria Zambrano Fellowship)},
organization = {European Research Council (ERC) (Proyecto COG 648239)},
organization = {EPSRC - Engineering and Physical Sciences Research Council, UK (CDTs TECS EP/S024107/1, EP/L015366/1, GCRF EP/T020288/1)},
organization = {Ministerio de Universidades, España (Beca FPU22/04095)},
organization = {Fundação para a Ciência e a Tecnologia (FCT), Portugal (UID/00686; SFRH/BD/05278/2020)},
publisher = {American Chemical Society},
keywords = {Leishmaniasis},
keywords = {African trypanosomiasis},
keywords = {Antiparasitic agents},
title = {Extending Thioflavin T Fluorescence Probe to 2‑Ethenylbenzothiazole Derivatives: Drug-like Quadruplex Ligands with Potent Antitrypanosomatid Activity},
doi = {10.1021/acsinfecdis.5c00691},
author = {Gonçalves, Raquel C. R. and Peñalver, Pablo and Allen, Nina M. and Belmonte Reche, Efres and García Pérez, Belén and Costa, Susana P. G. and Pérez-Victoria, José María and Galán, M. Carmen and M. Raposo, M. Manuela and Morales Vega, Juan Carlos},
}