Heteroatom Chemistry Volume 18, Number 4, 2007 Nitroimidazoles, Part 4: Synthesis and Anti-HIV Activity of New 5-alkylsulfanyl and 5-(4 ′ -arylsulfonyl)piperazinyl-4-nitroimidazole Derivatives Yaseen A. Al-Soud, 1 Najim A. Al-Masoudi, 2 Erik De Clercq, 3 and Christoph Paneccoque 3 1 Department of Chemistry, College of Science, University of Al al-Bayt, Al-Mafraq, Jordan 2 Formerly Fachbereich Chemie, Universit ¨ at Konstanz, Postfach 5560, D-78457 Konstanz, Germany 3 Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium Received 20 June 2006; revised 14 July 2006 ABSTRACT: The development of new HIV nonnucle- oside reverse transcriptase inhibitors (NNRTIs) offers the possibility of generating structures of increased po- tency. On this basis, a series of 5-alkylsulfanyl and 5-(4 ′ -arylsulfonyl)piperazine derivatives of 1-phenyl- 2-alkyl-4-nitroimidazoles 5–21 was synthesized with the aim to develop new NNRTIs. The new synthesized compounds were assayed against HIV-1 and HIV-2 in MT-4 cells. Compounds 9 and 13, with an alkyl- sulfanyl group at C-5 of the 4-nitroimidazole back- bone, showed inhibition of HIV-1 with EC 50 4.04 μg/mL and 2.37 μg/mL, and therapeutic indexes (SI) of 17 and 13, respectively. C  2007 Wiley Periodicals, Inc. Heteroatom Chem 18:333–340, 2007; Published on- line in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20301 INTRODUCTION Nitro-substituted imidazoles have important ap- plications, particularly as antibacterial agents Correspondence to: Najim A. Al-Masoudi; e-mail: dr@al-masoudi. de. c  2007 Wiley Periodicals, Inc. and in cancer chemotherapy [1–4]. Dacarbazine ® (DTIC) [5] and misonidazole [1-methoxy-3-(4- nitroimidazol-1-yl)propan-2-ol, 1] [6] are approved drugs for inhibition of de novo purine synthe- sis in addition to the potent anticancer activ- ity. Some compounds of nitroimidazoles are re- ported as potent whereas selective histamine H-3 receptor agonists [7–9], mitogen-activated protein (MAP) kinases inhibitors [10–15], nitric-oxide syn- thase inhibitors [16], and anti-inflammatory agents [17]. 5-Nitro-substituted-haloimidazoles, the inter- esting class of such compounds, showed an impor- tant biological activity as potential radiosensitizers [18]. Other imidazole derivatives having 5-alkylsul- fanyl residues exhibited remarkable antitumor activity [19]. Clotrinazole [1-(2-chlorotrityl)-1 H- imidazole] [20,21] and metronidazole (Flagyl ® [2-(2-methyl-5-nitro-imidazol-1-yl)ethanol, 2] [22] are considered as potent fungicides and antipro- tozoal agents especially for treatment of Tri- chomonas vaginalis, Entamoeba histolytica, and Gardia lamblia. Capravirine S-1153 3 [23] is re- ported as a new imidazole analogue with a high anti-HIV inhibitory activity. Many laboratories [24– 32] have engaged in the development of new 333