Research paper 1,2,4-Thiadiazolidin-3,5-diones as novel hydrogen sulfide donors Beatrice Severino a, *, 1 , Angela Corvino a, 1 , Ferdinando Fiorino a , Paolo Luciano a , Francesco Frecentese a , Elisa Magli a , Irene Saccone a , Paola Di Vaio a , Valentina Citi b , Vincenzo Calderone b , Luigi Servillo c , Rosario Casale c , Giuseppe Cirino a , Valentina Vellecco a , Mariarosaria Bucci a , Elisa Perissutti a , Vincenzo Santagada a , Giuseppe Caliendo a a Department of Pharmacy, School of Medicine, University of Naples «Federico II», Via D. Montesano, 49, 80131 Napoli, Italy b Department of Pharmacy, University of Pisa, Via Bonanno, 6, I-56126 Pisa, Italy c Department of Biochemistry, Biophysics and General Pathology, Universit a della Campania “Luigi Vanvitelli”, Via L. De Crecchio 7, 80138 Napoli, Italy article info Article history: Received 8 September 2017 Received in revised form 3 October 2017 Accepted 24 October 2017 Available online xxx Keywords: Hydrogen sulfide H 2 S donors 1,2,4-Thiadiazolidine-3,5-diones Release mechanism abstract Hydrogen sulfide (H 2 S) is an endogenous modulator that plays significant physio-pathological roles in several biological systems. In this research field there is a large interest in developing selective CBS and CSE inhibitors and H 2 S releasing moieties, that could be either used as therapeutic agents or linked to known drugs. One of the major problem is the limited availability of chemicals that ensure a controlled release of H 2 S in vitro as well in vivo. Aiming to obtain novel H 2 S donors, whose release properties could be appropriately modulated, we have synthesized a series of 1,2,4-thiadiazolidine-3,5-diones (THIA 1 e10) as innovative donors that could release H 2 S in controlled manner. All the synthesized compounds were evaluated for their H 2 S releasing properties by an amperometric approach and for their vaso- relaxant ability on aorta rings. In order to rationalize the obtained results, a detailed study on the release mechanism has been performed using the most efficient H 2 S donor, THIA 3 (C max 65.4 mM and EC 50 1.7 mM). © 2017 Elsevier Masson SAS. All rights reserved. 1. Introduction Hydrogen sulfide (H 2 S) is a gasotransmitter acting as an endogenous modulator that plays significant physio-pathological roles in several biological systems [1].H 2 S is mainly derived from two pyridoxal-5 0 -phosphate (PLP)-dependent enzymes, cys- tathionine-b-synthase (CBS) and cystathionine-g-lyase (CSE) [2], or from a third pathway (PLP-independent) that combines the actions of 3-mercaptopyruvate sulfurtransferase (3-MST) and cysteine aminotransferase (CAT) [3]. Inorganic source of H 2 S, such as NaHS, and relatively selective inhibitors of either CBS or CSE have been used for evaluating the physiopathological involvement of H 2 S pathway in the regulation of several biological functions. In more recent years the research has been focused on the development of organic donors with controlled release and on the discovery of more selective enzyme inhibitors [4,5]. As concerns H 2 S donors, the research has been focused on the development of novel releasing moieties [6], whose properties could be modulated by means of appropriate chemical modifications. The slow kinetic of H 2 S release is a relevant phar- macological feature already attributed to naturally occurring compounds, such as the diallylpolysulfides of garlic [7] (Allium sativum) and the isothiocyanates typical of Brassicaceae [8]. Garlic has long been felt beneficial as an antioxidant, and recent evidence suggests that a number of beneficial effects of garlic derive from H 2 S production. The best characterized naturally occurring H 2 S- donating compound from garlic is allicin (diallylthiosulfinate) which decomposes in water to a number of compounds, such as diallyldisulfide (DADS) and diallyltrisulfide (DATS). In particular, H 2 S release from DATS was suggested to mediate the vasoactivity of garlic [9]. Sulforaphane, an isothiocyanate, has proved to be an effective chemoprotective agent in several cancer models [10]. Currently available H 2 S sources and/or donors are limited. NaHS, although widely used as a research tool, causes a fast burst of H 2 S that rapidly declines, as clearly reported in both in vitro and in vivo * Corresponding author. E-mail address: bseverin@unina.it (B. Severino). 1 B.S. and A.C. equally contributed to the paper. Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech https://doi.org/10.1016/j.ejmech.2017.10.068 0223-5234/© 2017 Elsevier Masson SAS. All rights reserved. European Journal of Medicinal Chemistry xxx (2017) 1e10 Please cite this article in press as: B. Severino, et al.,1,2,4-Thiadiazolidin-3,5-diones as novel hydrogen sulfide donors, European Journal of Medicinal Chemistry (2017), https://doi.org/10.1016/j.ejmech.2017.10.068