Arch Pharm Res Vol 35, No 6, 975-986, 2012 DOI 10.1007/s12272-012-0604-y 975 Arylazolyl(azinyl)thioacetanilide. Part 9 # : Synthesis and Biological Investigation of Thiazolylthioacetamides Derivatives as a Novel Class of Potential Antiviral Agents Peng Zhan 1 , Liu Wang 1 , Hong Liu 1 , Xuwang Chen 1 , Xiao Li 1 , Xin Jiang 1 , Qiangqiang Zhang 1 , Xinyong Liu 1 , Christophe Pannecouque 2 , Lieve Naesens 2 , Erik De Clercq 2 , Ailin Liu 3 , and Guanhua Du 3 1 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology of Natural Products (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Ji’nan, ShanDong, China, 2 Rega Institute for Medical Research, K.U. Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium, and 3 Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China (Received October 30, 2011/Revised December 6, 2011/Accepted December 22, 2011) In continuation of our endeavor to develop new, potent, selective and less toxic antiviral agents, a novel series of 2-(2-amino/chloro-4-(2,4-dibromophenyl) thiazol-5-ylthio)acetamide derivatives was synthesized via an expeditious route and evaluated for their anti-HIV activi- ties against wild-type virus and clinically relevant mutant strains, and for their anti-influenza virus activities against influenza A (H1N1 and H3N2) and influenza B in cellular assays. The selected active compounds were also assayed for their enzymic inhibitory activities. The results showed that some 2-chloro substituted thiazolylthioacetamide derivatives possessed potent activity against wild type HIV-1 and several key mutant strains (E138K, K103N, L100I) of HIV-1 in MT-4 cells with EC 50 values in micromolar range. Two 2-amino substituted thiazole derivatives 8a7 and 8a8 displayed significant potency against influenza A/H1N1 in MDCK cells with EC 50 values much lower than that of oseltamivir carboxylate, ribavirin, amantadine and rimantadine. Though the mechanism of actions is still unclear, these novel thiazolylthioacetamides might serve as original leads for further pharmacological investiga- tions as potential therapeutic agents against HIV-1 or influenza virus. Key words: HIV, Influenza virus, NNRTIs, Thiazolylthioacetamides, Synthesis, Bioactivity, SAR INTRODUCTION Currently, there has been considerable interest in the discovery of original molecules with broad-spec- trum antiviral activity and favorable pharmacokinetic profiles, to be used as an alternative to the approved antiviral drugs, should they fail as therapeutics. Heterocyclic compounds continue to play an increas- ingly important role in lead discovery and biological activities in the antiviral drug research field (Zhan et al., 2008). Among all the aromatic heterocycles, five- membered aromatic rings containing oxygen and sulfur, with the exclusion of their benzannulated derivatives, are key building blocks used in novel antiviral drug development (Spector et al., 1998; Liuzzi et al., 2004; Ghaemmaghami et al., 2010; Xia et al., 2010; Gallardo- Godoy et al., 2011; Zhan et al., 2011). Recently, triazole/tetrazole thioacetanilides derivatives (L1 and L2, Fig. 1) were reported as potent and bioav- ailable HIV-1 reverse transcriptase (RT) inhibitors, # Parts 1-8 reported in our previous articles. Correspondence to: Xinyong Liu, Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong Uni- versity, Ji’nan, ShanDong, China Tel: 86-531-88380270, Fax: 86-531-88382731 E-mail: xinyongl@sdu.edu.cn Fig. 1. Triazole/tetrazole thioacetanilide based NNRTIs.