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Efficient synthesis and biological evaluation of dibenzo[b,e]oxepin-11(6H)-ones as potential anthelmintic agents
* 1 , 1 , 1, 2 , 1 , 2 , 3
1  Instituto de Química del Sur, INQUISUR (CONICET-UNS), Departamento de Química, Universidad Nacional del Sur, Avenida Alem 1253, 8000 Bahía Blanca, Argentina.
2  Instituto de Investigaciones Bioquímicas de Bahía Blanca, INIBIBB (CONICET-UNS), Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur, Camino La Carrindanga km 7, 8000 Bahía Blanca, Argentina.
3  Instituto Universitario de Bio-Orgánica, IUBO, Departamento de Química Orgánica, Universidad de La Laguna, C/Astrofísico Francisco Sánchez 2, 38206 La Laguna, Tenerife, Spain.


Helminthiasis is a serious problem worldwide resulting in high human morbidity and enormous economic losses in livestock, especially in tropical and sub-tropical countries. Anthelmintic drugs are used for the control of parasitic infections caused by helminths. Resistance to current anthelmintics has prompted the search for new drugs. In this context, the tricyclic dibenzo[b,e]oxepin-11(6H)-one scaffold emerges as an interesting synthetic target because a large number of compounds having this privileged structure present relevant biological activities; such as antidepressant, anxiolytic, antipsychotic, antitumor, and anti-inflammatory properties.

Herein, we describe the development of first systematic study for the generation of a small library of dibenzo[b,e]oxepin-11(6H)-ones by direct intramolecular acylation from readily available 2-(phenoxymethyl)benzoic acids. For this purpose, a novel and efficient cooperative system consisting of SnCl2 and Cl2CHOCH3 (DCME) is presented. This new methodology show be compatible with a wide variety of functional groups in good to excellent yields and high regioselectivity. The generality of present protocol was applied to the scalable and reproducible synthesis of tricyclic antidepressant doxepin. The synthesized dibenzo[b,e]oxepinones were evaluated for their biological activity using the free-living nematode Caenorhabditis elegans as effective and cost-efficient model system for anthelmintic discovery. 

Keywords: synthesis, dibenzo[b,e]oxepin-11(6H)-one, intramolecular acylation, Caenorhabditis elegans, anthelmintic activity.