ORIGINAL PAPER Synthesis and anti-arrhythmic activity of some piperidine-based 1,3-thiazole, 1,3,4-thiadiazole, and 1,3-thiazolo[2,3-c]-1,2,4- triazole derivatives Hatem A. Abdel-Aziz Æ Bakr F. Abdel-Wahab Æ Marwa A. M. Sh. El-Sharief Æ Mohamed M. Abdulla Received: 29 July 2008 / Accepted: 3 August 2008 / Published online: 30 September 2008 Ó Springer-Verlag 2008 Abstract The reaction of 1-[4-(piperidin-1-yl)benzylidene] thiosemicarbazide with hydrazonoyl chlorides afforded 1,3-thiazole derivatives. Cyclization of two compounds of the latter 1,3-thiazole by means of bromine in the pres- ence of sodium acetate at room temperature gave 1,3- thiazolo[2,3-c]-1,2,4-triazole derivatives. The reaction of 2-cyano-3-(4-piperidin-1-ylphenyl)prop-2-enethioamide with hydrazonoyl chlorides under reflux in ethanol in the presence of triethylamine yielded 1,3-thiazoles. Treatment of 3-oxo- 3-(piperidin-1-yl)propanenitrile with phenyl isothiocyanate in DMF, in the presence of KOH, at ambient temperature, resulted in the formation of 3-anilino-3-mercapto-2-(piper- idin-1-ylcarbonyl)acrylonitrile which was reacted with hydrazonoyl chlorides to yield the corresponding 1,3,4- thiadiazole derivatives. Some of the newly synthesized compounds had significant anti-arrhythmic activity. Keywords Heterocycles Á Cyclizations Á 1,3-Thiazole Á 1,3,4-Thiadiazole Á Anti-arrhythmic activity Introduction In the course of our research efforts towards the prepara- tion of new biologically active heterocycles [1–6] specifically 1,3-thiazoles [1] and 1,3,4-thiadiazoles [2], we have reported that some of the newly synthesized heterocycles had antihypertensive [1], antibacterial [2–4], antifungal [5], and anti-arrhythmic [6] activities. On the other hand, piperidines are an important class of hetero- cycles found in numerous natural products and medicinal structures [7], such as raloxifene [8] and thioridazine [9]. The piperidine moiety is also part of the well known vasodilator minoxidil (Fig. 1), which is used to treat high blood pressure and androgenetic alopecia in men [10]. Furthermore, 1,3-thiazole has interesting pharmacological properties [11] and is a key structural component of several drugs. For example, clomethiazole (Fig. 1) is a potent sedative and hypnotic drug [12] containing the 1,3-thiazole moiety. Moreover, some 1,3,4-thiadiazole derivatives are highly potent inhibitors of HIV-1 [13] and useful as anti-inflam- matory agents [14]. In addition, 1,3,4-thiadiazole is a common structural feature in many biologically active molecules, for example methazolamide (Fig. 1), which is used clinically in the treatment of some forms of epilepsy [15]. In the light of previous information, we wish to report herein the utility of 4-piperidin-1-ylbenzaldehyde (1) and 3-oxo-3-(piperidin-1-yl)propanenitrile (11) in the synthesis of some piperidine-based polyfunctional 1,3-thiazole, 1,3,4-thiadiazole, and 1,3-thiazolo[2,3-c]-1,2,4-triazole derivatives to evaluate their anti-arrhythmic activity. Results and discussion Chemistry 4-Piperidin-1-ylbenzaldehyde (1) was prepared by reaction of 4-fluorobenzaldehyde and piperidine in DMSO, in the presence of K 2 CO 3 [16]. The reaction of the latter aldehyde with thiosemicarbazide in ethanol under reflux afforded H. A. Abdel-Aziz Á B. F. Abdel-Wahab Á M. A. M. Sh. El-Sharief (&) Applied Organic Chemistry Department, National Research Centre, Dokki, Cairo, Egypt e-mail: marwaelsharif@yahoo.com M. M. Abdulla Research Units, Hi-Care Pharmaceutical Co., Cairo, Egypt 123 Monatsh Chem (2009) 140:431–437 DOI 10.1007/s00706-008-0053-y