874889-42-6Relevant articles and documents
Synthesis and Biological Evaluation of Benzophenone Derivatives as Potential HIV-1 Inhibitors
Song, Zhendong,Wang, Ping,Huang, Shanshan,Wang, Changyuan,Wang, Rui-Rui,Yang, Liu-Meng,Zhen, Yuhong,Liu, Kexin,Zheng, Yong-Tang,Ma, Xiaodong
, p. 398 - 405 (2017/06/23)
Background: Although a number of agents can achieve high response in acquired immunodeficiency syndrome (AIDS) patients, safer and more active HIV inhibitors are still needed for the growing number of patients infected with resistant HIV virus strains. GW678248 is one of the most potent benzophenone derivatives, exhibiting high potency against a panel of HIV-1 virus (wild-type, K103N mutant, Y181C, etc.) at 1 nmol/L concentrations. However, the safety issues associated with rash and liver metabolic enzymes ultimately led to discontinue its further deve-lopment. As a continuation of our structural modifications on this template, in this manuscript, a new series of benzophenones are described as potential HIV inhibitors. Methods: All the title molecules were synthesized according to the routes in Scheme 1 and Scheme 2, and were tested for anti-HIV-1 activity using the MTT method. In the molecular simulation, the docking program of AutoDock 4.0.1 in parallel with the default parameters were used. Results: A series of novel benzophenone derivatives (BPs) with nanomolar anti-HIV-1 activity were identified. Of these inhibitors, analogue 10i (EC50 = 2.9 nmol/L), the most active inhibitor, was comparable to the lead compound GW678248 in inhibiting the wild-type HIV-1 virus. Additionally, analogue 13b, which not only exhibited strong inhibitory activity against the HIV-1 virus (EC50 = 4.2 nmol/L), but also has very low cytotoxicity with a TI value of more than 219178.1 was also discovered. Conclusion: This study led to the identification of a series of benzophenone derivatives with nanomolar level of anti-HIV-1 activity. Analogues 10i and 13b, with low cytotoxicity along with high activity are worthy of further development.
Structure-activity relationship studies of novel benzophenones leading to the discovery of a potent, next generation HIV nonnucleoside reverse transcriptase inhibitor
Romines, Karen R.,Freeman, George A.,Schaller, Lee T.,Cowan, Jill R.,Gonzales, Steve S.,Tidwell, Jeffrey H.,Andrews III, Clarence W.,Stammers, David K.,Hazen, Richard J.,Ferris, Robert G.,Short, Steven A.,Chan, Joseph H.,Boone, Lawrence R.
, p. 727 - 739 (2007/10/03)
Despite the progress of the past two decades, there is still considerable need for safe, efficacious drugs that target human immunodeficiency virus (HIV). This is particularly true for the growing number of patients infected with virus resistant to currently approved HIV drugs. Our high throughput screening effort identified a benzophenone template as a potential nonnucleoside reverse transcriptase inhibitor (NNRTI). This manuscript describes our extensive exploration of the benzophenone structure-activity relationships, which culminated in the identification of several compounds with very potent inhibition of both wild type and clinically relevant NNRTI-resistant mutant strains of HIV. These potent inhibitors include 70h (GW678248), which has in vitro antiviral assay IC50 values of 0.5 nM against wild-type HIV, 1 nM against the K103N mutant associated with clinical resistance to efavirenz, and 0.7 nM against the Y181C mutant associated with clinical resistance to nevirapine. Compound 70h has also demonstrated relatively low clearance in intravenous pharmacokinetic studies in three species, and it is the active component of a drug candidate which has progressed to phase 2 clinical studies.
