Original article Dibenzo[1,4,5]thiadiazepine: A hardly-known heterocyclic system with neuroprotective properties of potential usefulness in the treatment of neurodegenerative diseases Gema C. González-Muñoz a , Mariana P. Arce a , Concepción Pérez a , Alejandro Romero b,1 , Mercedes Villarroya b , Manuela G. López b , Santiago Conde a, * , María Isabel Rodríguez-Franco a, * a Instituto de Química Médica, Consejo Superior de Investigaciones Científicas (IQM-CSIC), C/ Juan de la Cierva 3, 28006 Madrid, Spain b Instituto Teo  filo Hernando and Departamento de Farmacología y Terape  utica, Facultad de Medicina, Universidad Auto  noma de Madrid, C/Arzobispo Morcillo 4, 28029 Madrid, Spain article info Article history: Received 17 February 2014 Received in revised form 8 April 2014 Accepted 25 April 2014 Available online 12 May 2014 Keywords: Dibenzo[1,4,5]thiadiazepines Neuroprotection Antioxidant Mitochondrial oxidative stress Calcium modulation Alzheimer’s disease abstract In this work we describe a new family of dibenzo[1,4,5]thiadiazepines (2e12) that showed an interesting in vitro biological profile, namely neuroprotective and antioxidant properties, as well as blockade of cytosolic calcium entry. They showed no cytotoxic effects and the majority were predicted as CNS- permeable compounds. In human neuroblastoma cells they displayed good neuroprotective properties against mitochondrial oxidative stress which, in many cases, almost reached the full protection (>90%) when compounds were incubated with cells 24 h before the addition of toxic stressors. In co-incubation conditions these figures were smaller, although some compounds maintained an interesting level of neuroprotection, higher than 50%. Four selected compounds (2, 5, 8, and 11) were found to be effective antioxidant agents by sequestering mitochondrial radical oxygen species (ROS). Moreover, compound 2 showed a remarkable calcium-channel modulating activity. The interest of these compounds is increased by the fact that dibenzo[1,4,5]thiadiazepine is a barely known structure that is not difficult to synthesize and presents very few described derivatives, opening a new and broad line of research in Medicinal Chemistry. Ó 2014 Elsevier Masson SAS. All rights reserved. 1. Introduction The known figures of the prevalence of Alzheimer’s disease (AD), the most extended senile dementia, are really impressive and worrying. Although age is the highest risk factor for AD, about 5.2 million USA citizens of all ages are thought to suffer AD in 2013; among them, approximately 4% are under 65 years old, 13% are 65e 74, 44% are 75e84 and 38% are 85 years and older. Namely, one out of nine (11%) USA citizens age 65 and older [1]. The terrible symptoms and long process of AD, the subsequent impact on the caregivers and burden for the Public Health Systems and families are also well-known. AD is a multifunctional disease in which a number of physio- logical processes change progressively into closely connected pathological ones. The most striking hallmarks of these changes are the occurrence of amyloid senile plaques, neurofibrillary tangles and dysfunction of the cholinergic neurotransmission in the framework of a massive neuronal loss, as well as other not so visible events such as a progressive failure of the endogenous antioxidant systems [2] and an imbalance in the cytosolic calcium concentra- tions [3]. Thus, several neuroprotective strategies involving the capture of mitochondrial free radicals [4,5] or the cytosolic calcium modulation [6] have been proposed for the treatment of AD. Continuously, new structures designed to act on one (standard drugs) or more than one (multifunctional drugs) of the pathological processes of AD appear published [7]. Of course, the ultimate goal Abbreviations: AD, Alzheimer’s disease; AChE, acetylcholinesterase; BBB, bloodebrain barrier; BuChE, butyrylcholinesterase; CNS, central nervous system; DCFH-DA, 2 0 ,7 0 -dichlorfluorescein-diacetate; HPLC-MS, high performance liquid chromatographyemass spectrometry; LDH, lactate dehydrogenase; PAMPA, parallel artificial membrane permeation assay; ROS, reactive oxygen species. * Corresponding authors. E-mail addresses: sconde@iqm.csic.es (S. Conde), isabelrguez@iqm.csic.es (M.I. Rodríguez-Franco). 1 Present address: Departamento de Toxicología y Farmacología, Facultad de Veterinaria, Universidad Complutense de Madrid, Avda. Puerta de Hierro s/n, 28040 Madrid, Spain. Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech http://dx.doi.org/10.1016/j.ejmech.2014.04.075 0223-5234/Ó 2014 Elsevier Masson SAS. All rights reserved. European Journal of Medicinal Chemistry 81 (2014) 350e358