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Synthesis, biological evaluation and molecular docking study of N-(2-methoxyphenyl)-6-((4-nitrophenyl)sulfonyl)benzamide derivatives as potent HIV-1 Vif antagonists.
- Source :
-
European Journal of Medicinal Chemistry . Mar2017, Vol. 129, p310-324. 15p. - Publication Year :
- 2017
-
Abstract
- Viral infectivity factor (Vif) is protective against APOBEC3G (A3G)-mediated viral cDNA hypermutations, and development of molecules that inhibit Vif mediated A3G degradation is a novel strategy for blocking HIV-1 replication. Through optimizations of the central ring of N -(2-methoxyphenyl)-2-((4-nitrophenyl)thio)benzamide ( RN-18 ), we found a potent compound 12c with EC 50 value of 1.54 μM, enhancing the antiviral activity more than 150-fold compared with RN-18 in nonpermissive H9 cells. 12c protected A3G from degradation by inhibiting Vif function. Besides, 12c suppressed different HIV-1 clinical strains (HIV-1 KM018 , HIV-1 TC-1 and HIV-1 WAN ) and drug-resistant strains (NRTI, NNRTI, PI, and FI) with relatively high activities. Amidation of 12c with glycine gave a prodrug 13a , improving the water solubility about 2600-fold compared with 12c . Moreover, 13a inhibited the virus replication efficiently with an EC 50 value of 0.228 μM. These results suggested that the prodrug 13a is a promising candidate agent for the treatment of AIDS. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 02235234
- Volume :
- 129
- Database :
- Academic Search Index
- Journal :
- European Journal of Medicinal Chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 121493700
- Full Text :
- https://doi.org/10.1016/j.ejmech.2017.01.010