Synthesis and biological evaluation of (±)-benzhydrol derivatives as potent non-nucleoside HIV-1 reverse transcriptase inhibitors Xiao-Dong Ma a,  , Xuan Zhang d,e,  , Shi-Qiong Yang a , Hui-Fang Dai c , Liu-Meng Yang d , Shuang-Xi Gu a , Yong-Tang Zheng d , Qiu-Qin He a , Fen-Er Chen a,b,⇑ a Department of Chemistry, Fudan University, Shanghai 200433, PR China b Institute of Biomedical Science, Fudan University, Shanghai 200433, PR China c School of Pharmacy, Fudan University, Shanghai 200031, PR China d Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, PR China e Graduate School of the Chinese Academy of Sciences, Beijing 100039, PR China article info Article history: Received 16 June 2011 Revised 1 July 2011 Accepted 2 July 2011 Available online 13 July 2011 Keywords: HIV NNRTIs Benzophenone derivatives Benzhydrol SAR abstract A series of (±)-benzhydrol derivatives featuring the essential sulfonamide group at the para position on the C-ring were synthesized and evaluated for the potential anti-HIV activity in C8166 cells. Most of these analogues demonstrated low concentration inhibitory activity with EC 50 values less than 1 lM against the wild-type HIV-1. In particular, compound 7h was identified as the highest active inhibitor of wild- type HIV-1 with an EC 50 value of 0.12 lM and selectivity index value of 312.73. Furthermore, some of them also exhibited moderate activity against the double mutant strain A 17 (K103N + Y181C) with EC 50 values lower than 5 lM. In addition, the binding modes with RT and the preliminary structure– activity relationships of these derivatives were also explored for further chemical modifications. Crown Copyright Ó 2011 Published by Elsevier Ltd. All rights reserved. 1. Introduction As novel non-nucleoside reverse transcriptase inhibitors (NNRTIs), 1–5 benzophenone derivatives (BPs, Fig. 1), originated in a high-throughput screening in 1995, 6 have attracted considerable attention due to their excellent activity against most current clinically relevant HIV-1 mutants. 7–14 Hitherto, lots of constructive work for optimizing the initial benzophenone 1, have led to dis- cover several highly potent compounds against both wild-type and mutant HIV-1 viruses, such as 2 (GW45119 9 ), 3 (GW678248 10,11 ) and its prodrug 4 (GW695634 11 ). Previous stud- ies on the structure modifications of BPs have shown that the carbonyl group between the A- and B-rings was essential for main- taining high anti-HIV activity, 7,12 so little attention has been paid on this keto template in the following studies. Considering that the flexibility of benzhydrol derivatives might be more adaptive to bind with HIV-1 RT, herein, we reduced the carbonyl to hydroxy group and afforded a series of (±)-benzhydrol derivatives (7a–t) bearing the sulfonamide group at the para position on the C-ring, which pointed directly into the exterior water through a rather small window in the protein surface and played an important role in the capacity to inhibit HIV-1 replication. 12 Furthermore, all of these analogues evaluated the activity against the wild-type HIV-1 virus and the double mutant strain A 17 (K103N + Y181C). 0968-0896/$ - see front matter Crown Copyright Ó 2011 Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.bmc.2011.07.003 ⇑ Corresponding author. Tel./fax: +86 21 65643811. E-mail address: rfchen@fudan.edu.cn (F.-E. Chen).   These authors contributed equally to this work. O H N O O A B C 1 O O N O Cl H N O SO 2 NHR 3 O R 2 R 1 2,R 1 = F, R 2 = CF 3 ,R 3 = H (GW4511) 3,R 1 = Cl, R 2 = CN, R 3 = H (GW678248) 4,R 1 = Cl, R 2 = CN, R 3 = propionyl (GW695634) Figure 1. Structures of potent benzophenones. Bioorganic & Medicinal Chemistry 19 (2011) 4704–4709 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry journal homepage: www.elsevier.com/locate/bmc