title: Design, synthesis, in vitro evaluation and preliminary SAR studies of N-(2-(heteroaryloxy)propyl)phenothiazines against Rhipicephalus microplus cattle tick.
abstract: A family of 15 N-substituted phenothiazines was designed, synthesized and their acaricidal activity against Rhipicephalus microplus was determined in vitro. The synthetic methodology is simple and can be employed in multigram scale. The rationale for the structure-based design of these compounds is the potential for azines and phenothiazine to engage in π-π interactions; these fragments, joined together by a short, flexible alkoxide linker, structurally resemble phenothiazine-based cholinesterase inhibitors, while their weak basicity implies a neutral active form, rather than a cationic one, thus facilitating penetration of the cuticle of ticks. One compound displayed excellent acaricidal activity (LD50=0.58 μg/mL). Preliminary SAR analysis suggests that the activity is influenced by the presence of a weakly basic nitrogen atom, as well as the substitution pattern within the heterocycles.
authors.affiliation: Facultad de Química, Departamento de Química Orgánica, Universidad Nacional Autónoma de México, 04510 México, D.F., Mexico.
authors.forename: Mauricio
authors.initials: M
authors.lastname: Maldonado-Domínguez
authors.affiliation: Facultad de Química, Departamento de Química Orgánica, Universidad Nacional Autónoma de México, 04510 México, D.F., Mexico.
authors.forename: David
authors.initials: D
authors.lastname: Alavez-Rosas
authors.affiliation: Facultad de Química, Departamento de Química Orgánica, Universidad Nacional Autónoma de México, 04510 México, D.F., Mexico.
authors.forename: Humberto
authors.initials: H
authors.lastname: Aguilar
authors.affiliation: Facultad de Química, Departamento de Química Orgánica, Universidad Nacional Autónoma de México, 04510 México, D.F., Mexico.
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Méndez-Stivalet
authors.affiliation: Facultad de Química, Departamento de Química Orgánica, Universidad Nacional Autónoma de México, 04510 México, D.F., Mexico.
authors.forename: Margarita
authors.initials: M
authors.lastname: Romero-Ávila
authors.affiliation: Facultad de Química, Departamento de Química Orgánica, Universidad Nacional Autónoma de México, 04510 México, D.F., Mexico.
authors.forename: Blas
authors.initials: B
authors.lastname: Flores-Pérez
authors.affiliation: Facultad de Medicina Veterinaria y Zootecnia, Universidad Nacional Autónoma de México, 04510 México, D.F., Mexico.
authors.forename: Froylán
authors.initials: F
authors.lastname: Ibarra
authors.affiliation: Facultad de Medicina Veterinaria y Zootecnia, Universidad Nacional Autónoma de México, 04510 México, D.F., Mexico.
authors.forename: Yazmín
authors.initials: Y
authors.lastname: Alcalá-Canto
authors.affiliation: Facultad de Medicina Veterinaria y Zootecnia, Universidad Nacional Autónoma de México, 04510 México, D.F., Mexico.
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Vera-Montenegro
authors.affiliation: Facultad de Química, Departamento de Química Orgánica, Universidad Nacional Autónoma de México, 04510 México, D.F., Mexico. Electronic address: hector.garcia@unam.mx.
authors.forename: Héctor
authors.initials: H
authors.lastname: García-Ortega
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D015394:Molecular Structure; D010640:Phenothiazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D048494:Rhipicephalus / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013983:Tick Control
chemical_list: D010640:Phenothiazines; C031637:phenothiazine
keywords: Acaricides; Phenothiazines; Pyridines; Rhipicephalus microplus; SAR; Ticks