Full Paper Stereoselective Synthesis and Antiviral Activity of (1E,2Z,3E)-1- (Piperidin-1-yl)-1-(arylhydrazono)-2-[(benzoyl/benzothiazol- 2-oyl)hydrazono]-4-(aryl 1 )but-3-enes Hatem A. Abdel-Aziza 1,2 , Bakr F. Abdel-Wahab 2 , and Farid A. Badria 3 1 Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia 2 Applied Organic Chemistry Department, National Research Centre, Dokki, Cairo, Egypt 3 Department of Pharmacognosy, Faculty of Pharmacy, University of Mansoura, Mansoura, Egypt The reaction of benzoyl hydrazine 1a or benzothiazole-2-carbohydrazide 1b with 2-oxo-N-arylpro- panehydrazonoyl chlorides 2a–d yielded (1Z,2E)-2-[(benzoyl/benzothiazol-2-oyl)hydrazono]-N-(aryl)- propanehydrazonoyl chlorides 3a–e. The reaction of 3a–c with sodium benzenesulphinate fur- nished sulphones 5a–c while the reaction of 5d, e with hydroxyl amine afforded hydroxomoyl deriv- atives 6a, b. The one-pot sterioselective reaction of N-(aryl)propanehydrazonoyl chlorides 3 with cer- tain aromatic aldehydes in the presence of piperidine resulted in the formation of (1E,2Z,3E)-1-(piper- idin-1-yl)-1-(arylhydrazono)-2-[(benzoyl/benzothiazol-2-oyl)hydrazono]-4-(aryl 1 )-but-3-enes 7a–g. X- ray analysis of piperidinyl amidrazone 7g showed a conversion of its geometrical structure with respect to that of compound 3 and confirmed the stereoselectivity of the latter reaction. The piperi- dinyl amidrazones 7a–g possessed a significant antiviral activity against herpes simplex viruses (HSV-1). Compound 7d reduced the number of viral plaques of herpes simplex type-1 (HSV-1) by 67%, with respect to the effect of reference drug Aphidicolin. Keywords: Antiviral activity / Benzothiazole / HSV-1 / Hydrazones / X-ray crystallography / Received: August 15, 2009; Accepted: November 20, 2009 DOI 10.1002/ardp.200900195 Introduction Viral infections are considered one of the principle threats to human life and health worldwide. The viral dis- eases caused by herpes simplex viruses, HSV-1 and HSV-2, were categorized into several distinct disorders based on the site of infection. HSV infection may affect the face (orofacial herpes), genitalia (genital herpes), hand (herpes whitlow), eye (herpes keratitis), or the brain (herpes ence- phalitis) [1–4]. The common opportunistic ocular infec- tions, corneal epithelial and stromal keratitis, are caused by herpes simplex virus, HSV-1; they are a leading cause of blindness [5]. Moreover, AIDS patients are prone to severe complications from HSV infections. HSV-1 appeared to be particularly damaging to the nervous sys- tem, and it increases the risk of developing Alzheimer's disease [6–8]. Hydrazones have been reported as useful antiviral agents. Some acetylhydrazones revealed a remarkable antiviral activity against HSV-1 [9], whereas arylhydra- zones inhibited the replication of HIV-1 [10]. Further- more, an excellent antiviral activity has been demon- strated by several heteroarylhydrazones versus influenza A 2 ,A 3 , and semliki forest viruses [11]. Additionally, 2-sub- stituted benzothiazoles were intensively studied as anti- viral agents. For example, the in-vivo antiviral activity of 2-aminobenzothiazole has a potency quite comparable to that of the antiviral drug Amantadine against influenza A 2 strains [12]. A series of 2-substituted benzothiazoles have been reported for treating HIV infection and AIDS [13], also some amidino benzothiazoles have been described as potent anti-HIV agents [14]. Moreover, fused benzothiazoles exerted antiviral activity versus herpes simplex virus HSV-1 [15]. Correspondence: Hatem A. Abdel-Aziz, Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia. E-mail: hatem_741@yahoo.com Fax: +966 146 76220 i 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim 152 Arch. Pharm. Chem. Life Sci. 2010, 343, 152 – 159