Antileishmanial activity of 5-nitroindazole derivatives.
| Autor: | Mollineda-Diogo N; Universidad Central 'Marta Abreu' de Las Villas, Centro de Bioactivos Químicos, Carretera a Camajuaní Km. 5 ½, Santa Clara, Villa Clara, Cuba., Chaviano-Montes de Oca CS; Universidad Central 'Marta Abreu' de Las Villas, Centro de Bioactivos Químicos, Villa Clara, Cuba., Sifontes-Rodríguez S; Unidad de Investigación UNAM-INC, División de Investigación, Facultad de Medicina, Instituto Nacional de Cardiología Ignacio Chávez, Ciudad de México, México., Espinosa-Buitrago T; Facultad de Farmacia, Departamento de Parasitología, Universidad Complutense de Madrid, Madrid, España., Monzote-Fidalgo L; Instituto de Medicina Tropical 'Pedro Kourí' (IPK), Departamento de Parasitología, La Habana, Cuba., Meneses-Marcel A; Universidad Central 'Marta Abreu' de Las Villas, Centro de Bioactivos Químicos, Villa Clara, Cuba., Morales-Helguera A; Universidad Central 'Marta Abreu' de Las Villas, Centro de Bioactivos Químicos, Villa Clara, Cuba., Perez-Castillo Y; Grupo de Bio-Quimioinformática and Área de Ciencias Aplicadas, Facultad de Ingeniería y Ciencias Aplicadas, Universidad de Las Américas, Quito, CP 170125, Ecuador., Arán-Redó V; Instituto de Química Médica del Consejo Superior de Investigaciones Científicas de España, Madrid, España. |
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| Jazyk: | angličtina |
| Zdroj: | Therapeutic advances in infectious disease [Ther Adv Infect Dis] 2023 Oct 30; Vol. 10, pp. 20499361231208294. Date of Electronic Publication: 2023 Oct 30 (Print Publication: 2023). |
| DOI: | 10.1177/20499361231208294 |
| Abstrakt: | Background: Currently, there is no safe and effective vaccine against leishmaniasis and existing therapies are inadequate due to high toxicity, cost and decreased efficacy caused by the emergence of resistant parasite strains. Some indazole derivatives have shown in vitro and in vivo activity against Trichomonas vaginalis and Trypanosoma cruzi . On that basis, 20 indazole derivatives were tested in vitro against Leishmania amazonensis . Objective: To evaluate the in vitro activity of twenty 2-benzyl-5-nitroindazolin-3-one derivatives against L. amazonensis . Design: For the selection of promising compounds, it is necessary to evaluate the indicators for in vitro activity. For this aim, a battery of studies for antileishmanial activity and cytotoxicity were implemented. These results enabled the determination of the substituents in the indazole derivatives responsible for activity and selectivity, through the analysis of the structure-activity relationship (SAR). Methods: In vitro cytotoxicity against mouse peritoneal macrophages and growth inhibitory activity in promastigotes were evaluated for 20 compounds. Compounds that showed adequate selectivity were tested against intracellular amastigotes. The SAR from the results in promastigotes was represented using the SARANEA software. Results: Eight compounds showed selectivity index >10% and 50% inhibitory concentration <1 µM against the promastigote stage. Against intracellular amastigotes, four were as active as Amphotericin B. The best results were obtained for 2-(benzyl-2,3-dihydro-5-nitro-3-oxoindazol-1-yl) ethyl acetate, with 50% inhibitory concentration of 0.46 ± 0.01 µM against amastigotes and a selectivity index of 875. The SAR study showed the positive effect on the selectivity of the hydrophilic fragments substituted in position 1 of 2-benzyl-5- nitroindazolin-3-one, which played a key role in improving the selectivity profile of this series of compounds. Conclusion: 2-bencyl-5-nitroindazolin-3-one derivatives showed selective and potent in vitro activity, supporting further investigations on this family of compounds as potential antileishmanial hits. Competing Interests: The authors declare that there is no conflict of interest. (© The Author(s), 2023.) |
| Databáze: | MEDLINE |
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