title: Design, synthesis, structure-activity relationship and mechanism of action studies of a series of 4-chloro-1-phthalazinyl hydrazones as a potent agent against Leishmania braziliensis.
abstract: With the aim to identify a potential drug candidate to treat cutaneous leishmaniasis, a series of 1-phthalazinyl hydrazones were synthesized and tested against Leishmania braziliensis parasite, one of the main responsible of this disease in the world. A structure-activity relationship permitted to identify two phthalazines containing nitroheterocyclic moiety 3l and 3m as promising new lead compounds. These compounds showed a significant antileishmanial activity against promastigote form of L. braziliensis, with EC50values in sub-micromolar and nanomolar ranges. The phthalazine 3l also displayed a selective and excellent activity against the clinically relevant intracellular amastigotes form, with a EC50value in sub-micromolar range (0.59 μM), without affecting the viability of the host cells. Oxidative stress was identified as the possible mode of action of the most active phthalazine. Considering their significant antileishmanial activity and ease synthesis, the phthalazine containing nitroheterocyclic represents a promising agent against Leishmania braziliensis for the rational design of new leads.
authors.affiliation: Laboratorio de Química Medicinal y Heterociclos, Departamento de Química, Universidad Simón Bolívar, Valle de Sartenejas, Baruta, Caracas 1080-A, Apartado 89000, Venezuela. Electronic address: angel.romero12@ucv.ve.
authors.forename: Angel H
authors.initials: AH
authors.lastname: Romero
authors.affiliation: Laboratorio de Bioquímica, Estructura y Función de Proteínas, Área de Salud, Instituto de Estudios Avanzados (IDEA), Caracas, Venezuela.
authors.forename: Rafael
authors.initials: R
authors.lastname: Medina
authors.affiliation: Laboratorio de Biología y Quimioterapia de Parasitosis Tropicales, Área de Salud, Instituto de Estudios Avanzados (IDEA), Caracas, Venezuela.
authors.forename: Anamaría
authors.initials: A
authors.lastname: Alcala
authors.affiliation: Laboratorio de Biología y Quimioterapia de Parasitosis Tropicales, Área de Salud, Instituto de Estudios Avanzados (IDEA), Caracas, Venezuela.
authors.forename: Yael
authors.initials: Y
authors.lastname: García-Marchan
authors.affiliation: Laboratorio de Biología y Quimioterapia de Parasitosis Tropicales, Área de Salud, Instituto de Estudios Avanzados (IDEA), Caracas, Venezuela.
authors.forename: Jorge
authors.initials: J
authors.lastname: Núñez-Duran
authors.affiliation: Laboratorio de Biología y Quimioterapia de Parasitosis Tropicales, Área de Salud, Instituto de Estudios Avanzados (IDEA), Caracas, Venezuela.
authors.forename: Jacques
authors.initials: J
authors.lastname: Leañez
authors.affiliation: Laboratorio de Biología y Quimioterapia de Parasitosis Tropicales, Área de Salud, Instituto de Estudios Avanzados (IDEA), Caracas, Venezuela.
authors.forename: Ali
authors.initials: A
authors.lastname: Mijoba
authors.affiliation: Laboratorio de Neuropéptidos, Unidad de Farmacología, Facultad de Farmacia, Universidad Central de Venezuela, Apartado 47206, Los Chaguaramos, 1041-A, Caracas, Venezuela.
authors.forename: Carlos
authors.initials: C
authors.lastname: Ciangherotti
authors.affiliation: Laboratorio de Biología y Quimioterapia de Parasitosis Tropicales, Área de Salud, Instituto de Estudios Avanzados (IDEA), Caracas, Venezuela.
authors.forename: Xenón
authors.initials: X
authors.lastname: Serrano-Martín
authors.affiliation: Laboratorio de Química Medicinal y Heterociclos, Departamento de Química, Universidad Simón Bolívar, Valle de Sartenejas, Baruta, Caracas 1080-A, Apartado 89000, Venezuela. Electronic address: slopez@usb.ve.
authors.forename: Simón E
authors.initials: SE
authors.lastname: López
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D002460:Cell Line; D015195:Drug Design; D006835:Hydrazones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D007892:Leishmania braziliensis / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D008958:Models, Molecular; D010793:Phthalazines / Q000737:chemistry*; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013482:Superoxide Dismutase / Q000737:chemistry / Q000378:metabolism
chemical_list: D000981:Antiprotozoal Agents; D006835:Hydrazones; D010793:Phthalazines; C043388:phthalazine; D013482:Superoxide Dismutase
keywords: Antileishmanial activity; Leishmania braziliensis; Nitroheterocycle; Phthalazine; Promastigotes; Superoxide dismutase