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Título : Palladium-mediated synthesis and biological evaluation of C-10b substituted Dihydropyrrolo[1,2-b]isoquinolines as antileishmanial agents
Autor : Barbolla Cuadrado, Iratxe.
Hernández Suárez, Leidi.
Quevedo Tumailli, Viviana.
Nocedo Mena, Deyani.
Arrasate Gil, Sonia.
Dea Ayuela, María Auxiliadora.
González Díaz, Humberto.
Sotomayor Anduiza, María Nuria.
Lete Expósito, María Esther.
Materias: Leishmaniasis - Farmacoterapia.Pyrroloisoquinoline.Paladio - Uso terapéutico.Palladium - Therapeutic use.Leishmaniasis - Treatment - Mathematical models.Machine learning.Aprendizaje automático (Inteligencia artificial)Leishmaniasis - Chemotherapy.Leishmaniasis - Tratamiento - Modelos matemáticos.Pirroloisoquinolina.
Editorial : Elsevier
Citación : Barbolla, I., Hernández-Suárez, L., Quevedo-Tumailli, V., Nocedo-Mena, D., Arrasate, S., Dea-Ayuela, M. A., González-Díaz, H., Sotomayor, N. & Lete, E. (2021). Palladium-mediated synthesis and biological evaluation of C-10b substituted Dihydropyrrolo[1,2-b]isoquinolines as antileishmanial agents. European Journal of Medicinal Chemistry, vol. 220 (aug.), art. 113458. DOI: https://doi.org/10.1016/j.ejmech.2021.113458
Resumen : The development of new molecules for the treatment of leishmaniasis is, a neglected parasitic disease, is urgent as current anti-leishmanial therapeutics are hampered by drug toxicity and resistance. The pyrrolo[ 1,2-b]isoquinoline core was selected as starting point, and palladium-catalyzed Heck-initiated cascade reactions were developed for the synthesis of a series of C-10 substituted derivatives. Their in vitro leishmanicidal activity against visceral (L. donovani) and cutaneous (L. amazonensis) leishmaniasis was evaluated. The best activity was found, in general, for the 10-arylmethyl substituted pyrroloisoquinolines. In particular, 2ad (IC50 ¼ 3.30 mM, SI > 77.01) and 2bb (IC50 ¼ 3.93 mM, SI > 58.77) were approximately 10-fold more potent and selective than the drug of reference (miltefosine), against L. amazonensis on in vitro promastigote assays, while 2ae was the more active compound in the in vitro amastigote assays (IC50 ¼ 33.59 mM, SI > 8.93). Notably, almost all compounds showed low cytotoxicity, CC50 > 100 mg/mL in J774 cells, highest tested dose. In addition, we have developed the first Perturbation Theory Machine Learning (PTML) algorithm able to predict simultaneously multiple biological activity parameters (IC50, Ki, etc.) vs. any Leishmania species and target protein, with high values of specificity (>98%) and sensitivity (>90%) in both training and validation series. Therefore, this model may be useful to reduce time and assay costs (material and human resources) in the drug discovery process.
Descripción : Este artículo se encuentra disponible en la siguiente URL: https://www.sciencedirect.com/science/article/pii/S022352342100307X?via%3Dihub
URI : http://hdl.handle.net/10637/13564
Derechos: http://creativecommons.org/licenses/by/4.0/deed.es
ISSN : 0223-5234
Fecha de publicación : 26-ago-2021
Aparece en las colecciones: Dpto. Farmacia

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