Synthesis and antiprotozoan evaluation of new alkyl-linked bis(2-thioxo-[1,3,5]thiadiazinan-3-yl) carboxylic acids Julieta Coro, a Rolando Pe ´rez, b, * Hortensia Rodrı ´guez, a Margarita Sua ´rez, a Celeste Vega, c Miriam Rolo ´n, c David Montero, c Juan Jose ´ Nogal c and Alicia Go ´ mez-Barrio c a Laboratorio de Sı ´ntesis Orga ´ nica, Facultad de Quı ´mica, Universidad de la Habana, 10400-Ciudad Habana, Cuba b Departamento de Quı ´mica Fina, ICIDCA, 11000 Ciudad Habana, Cuba c Departamento de Parasitologı ´a, Facultad de Farmacia, Universidad Complutense de Madrid, Ciudad Universitaria s/n, 28040 Madrid, Spain Received 7 December 2004; revised 2 March 2005; accepted 2 March 2005 Available online 31 March 2005 Abstract—Two new series of several alkyl-linked bis(2-thioxo-[1,3,5]thiadiazinan-3-yl) carboxylic acids were synthesized in a two step procedure from the corresponding alkyl bis-dithiocarbamic salt intermediary. The novel compounds were evaluated for their activity in vitro against Trypanosoma cruzi strain CL (clone CL B5) and Trichomonas vaginalis strain JH 31A. Ó 2005 Elsevier Ltd. All rights reserved. 1. Introduction The antibacterial, 1,2 antifungal, 3,4 anthelmintic, 5 and tuberculostatic 6 properties of tetrahydro-(2H)-1,3,5-thi- adiazine-2-thione derivatives (THTT) has been known for several decades. Besides its renowned antimicrobial activity this versatile heterocycle has found increased application in the drug research arena as a biolabile pro- drug 7 in the design of drug delivery system (DDS) due to its high lipid solubility and enzymatic rate of hydrolysis. In this regard, several aminoacids, 8 peptides, 9,10 and pri- mary-amine-containing drugs 11–13 have been success- fully attached to the THTT moiety to enhance their cellular uptake by improving lipophilicity in the area where the drug molecule is released by the physiological and/or enzyme catalytic effects. Another important advantage of THTT derivatives is their stability in sim- ulated gastric fluid (SGF), which facilitates their stom- ach absorption in a less ionized form in the case of oral administration. 8 The excellent physico-chemical properties of this hetero- cycle have prompted us to use it as the main core in our integral project for the development of new antiparasitic agents. In a previous work we have described the synthe- sis of several tetrahydro-(2H)-1,3,5-thiadiazine 2-thiones bearing furfuryl, cyclohexyl, and carboxypentyl radicals at N-3 and carboxyalkyl residues at N-5 14 (Fig. 1). The synthesized molecules were evaluated in vitro and in vivo against Trypanosoma cruzi and Trichomonas vagi- nalis showing significant antiprotozoal activity that, in some cases, was further correlated to a non-specific tox- icity effect. 15 In another study the remarkable cytotoxic- ity properties of these derivatives against HeLa and HT- 29 cells were also tested. 16 Recently, we reported the antiparasitic properties of some 3-furfuryl-5-carboxyalkyl tetrahydro-(2H)- 1,3,5-thiadiazine-2-thione against both extracellular 0968-0896/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmc.2005.03.009 Keywords: Chemotherapy; Antiparasitics; Thiadiazine-2-thione. * Corresponding author. Tel.: +53 7878 1398; fax: +53 1320 2075615; e-mail: rolando.perez@icida.edu.cu N N S S R 1 R 2 1 2 3 4 5 6 O N O HO R 1 = R 2 = Carboxyalkylresidues Figure 1. Bioorganic & Medicinal Chemistry 13 (2005) 3413–3421