Ahmad Matloob, Aslam Sana, Rizvi Syed Umar Farooq, Muddassar Muhammad, Ashfaq Usman Ali, Montero Catherine, Ollinger Olivia, Detorio Mervi, Gardiner John M, Schinazi Raymond F
Department of Chemistry, Government College University, Faisalabad 38000, Pakistan.
Department of Chemistry, Government College Women University, Faisalabad, Pakistan.
Bioorg Med Chem Lett. 2015 Mar 15;25(6):1348-51. doi: 10.1016/j.bmcl.2015.01.007. Epub 2015 Jan 22.
Two series of fifteen N-substituted benzyl/phenyl-2-(3,4-dimethyl-5,5-dioxidopyrazolo[4,3-c][1,2]benzothiazin-2(4H)-yl)acetamides were screened for anti-HIV-1 activity and cytotoxicity. The compounds 6a, 6d, 6e, 6g and 6i from the series 6a-i of benzylamides and 7a, 7b, 7c, 7d and 7e from the series 7a-f of anilides were identified as effective anti-HIV-1 agents with EC50 values <20μM. Among these compounds that displayed anti-HIV-1 activity, 6a, 6e, 6g and 6i showed no toxicity in human PBM, CEM and Vero cells, with the exception of 6a which displayed toxicity in Vero cells. Molecular docking of these compounds provided insight into the molecular mechanism and it was found that 6e, 6g and 6i bound deeply in the NNRTI binding pocket of the HIV-1 reverse transcriptase, using RT-bound nevirapine X-ray data and molecular docking for validation, showing the potential of these new structures as inhibitors of this viral enzyme.
对两组共15种N-取代苄基/苯基-2-(3,4-二甲基-5,5-二氧代吡唑并[4,3-c][1,2]苯并噻嗪-2(4H)-基)乙酰胺进行了抗HIV-1活性和细胞毒性筛选。苄基酰胺系列6a-i中的化合物6a、6d、6e、6g和6i以及苯胺系列7a-f中的化合物7a、7b、7c、7d和7e被鉴定为有效的抗HIV-1药物，其EC50值<20μM。在这些显示抗HIV-1活性的化合物中，6a、6e、6g和6i在人外周血单核细胞、CEM细胞和Vero细胞中无毒性，但6a在Vero细胞中显示有毒性。这些化合物的分子对接提供了对分子机制的深入了解，利用RT结合的奈韦拉平X射线数据和分子对接进行验证，发现6e、6g和6i在HIV-1逆转录酶的NNRTI结合口袋中深度结合，显示出这些新结构作为这种病毒酶抑制剂的潜力。
