Original article Synthesis and anti-inflammatory activity evaluation of unsymmetrical selenides Federico Martı ´nez-Ramos a, * , Hector Salgado-Zamora b , Maria Elena Campos-Aldrete b , Estela Melendez-Camargo c , Yazmı ´n Ma ´rquez-Flores c , Manuel Soriano-Garcı ´a d a Departamento de Quı ´mica Inorga ´ nica, Escuela Nacional de Ciencias Biolo ´ gicas, I.P.N. Prolongacio ´n de Carpio y Plan de Ayala S/N, 11340 Me ´xico D.F., Mexico b Departamento de Quı ´mica Orga ´nica, Escuela Nacional de Ciencias Biolo ´gicas, I.P.N. Prolongacio ´n de Carpio y Plan de Ayala S/N, 11340 Me ´xico D.F., Mexico c Departamento de Farmacia, Escuela Nacional de Ciencias Biolo ´gicas, I.P.N. Prolongacio ´n de Carpio y Plan de Ayala S/N, 11340 Me ´xico D.F., Mexico d Departamento de Bioestructura, Instituto de Quı ´mica, UNAM, Circuito Exterior, C.U., Coyoaca ´n, 04510 Me ´xico D.F., Mexico Received 11 January 2007; received in revised form 18 September 2007; accepted 27 September 2007 Available online 10 October 2007 Abstract The alkylation reaction of 2,2 0 -diseleno and 4,4 0 -diseleno-bis(benzoic acid) derivatives in the presence of sodium borohydride and alkyl ha- lides allowed the synthesis of various new o- and p-alkylselenenylated benzoic acid derivatives in good yields. The anti-inflammatory activity of selected selenide derivatives on granuloma induced by subcutaneous implantation of cotton pellets in Wistar rats was examined. Selenium de- rivatives 2a, 2c and 2e showed anti-inflammatory activity although to a lesser extent as compared to indomethacin, however they were found less toxic than the latter. Ó 2007 Elsevier Masson SAS. All rights reserved. Keywords: Anti-inflammatory activity; Alkylselenenyl benzoic acid derivatives; Granuloma bioassay 1. Introduction Organoselenium compounds have been extensively applied in organic synthesis [1,2] in particular selenol esters have been used in liquid crystals [3] and other selenium derivatives have been investigated in a wide range of pharmacological re- sponses, thus they have been evaluated as anti-inflammatory [4], anti-atherosclerotic, anti-cancer, anti-microbial and anti- viral agents as well as immuno-stimulants, cytokine inducers and nitric oxide synthase inhibitors. In this area, a great deal of attention has been focused in the design of molecules in- volved in the study of the important enzyme glutathione per- oxidase (GSH-PX) [5e9]. On the other hand, the search for non-steroidal anti-inflam- matory drugs has continued and many efforts are being made in order to find alternative drugs with an increased perfor- mance. We were particularly interested in exploring a possible anti-inflammatory activity of 2-alkylselenenyl benzoic acid derivatives and p-alkylselenobenzamides. Accordingly and taking into account that selenides may be prepared in the pres- ence of other functional groups [10e12], slightly modified lit- erature protocols were applied to synthesize the target selenides. Then the anti-inflammatory activity on selected syn- thesized compounds was evaluated. 2. Chemistry Compound 1 (2,2 0 -carboxydiphenyl diselenide) was conve- niently prepared in 88% yield from anthranilic acid diazonium salt and sodium diselenide (NaSeSeNa). Diselenide 1 was also * Corresponding author. Fax: þ52 57296300x46211. E-mail address: f_martin57@hotmail.com (F. Martı ´nez-Ramos). 0223-5234/$ - see front matter Ó 2007 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmech.2007.09.029 Available online at www.sciencedirect.com European Journal of Medicinal Chemistry 43 (2008) 1432e1437 http://www.elsevier.com/locate/ejmech