Synthesis and evaluation of 2-pyridinylpyrimidines as inhibitors of HIV-1 structural protein assembly

Abstract

In an effort to identify an HIV-1 capsid assembly inhibitor with improved solubility and potency, we synthesized two series of pyrimidine analogues based on our earlier lead compound N-(4-(ethoxycarbonyl)phenyl)-2-(pyridine-4-yl)quinazoline-4-amine. In vitro binding experiments showed that our series of 2-pyridine-4-ylpyrimidines had IC50 values higher than 28μM. Our series of 2-pyridine-3-ylpyrimidines exhibited IC50 values ranging from 3 to 60μM. The congeners with a fluoro substituent introduced at the 4-N-phenyl moiety, along with a methyl at C-6, represent potent HIV capsid assembly inhibitors binding to the C-terminal domain of the capsid protein.

Application of an NMR/Crystallography Fragment Screening Platform for the Assessment and Rapid Discovery of New HIV‐CA Binding Fragments

“…This CAI binding region was studied extensively, and compound 3 was generated as part of a bioisostere strategy, arising from hits identified as part of a HTS campaign. [12] CAP-1 (4), also obtained through virtual screening, was the first HIV-CA inhibitor reported. [13] In this case the virtual screen was carried out on the β-hairpin gap of the NTD.…”

“…This region of the CTD spans helices 1 and 2 and has been shown to inhibit the assembly of mature CA. This CAI binding region was studied extensively, and compound 3 was generated as part of a bioisostere strategy, arising from hits identified as part of a HTS campaign [12] …”

Application of an NMR/crystallography fragment screening platform for the assessment and rapid discovery of new HIV-CA binding fragments

“…This CAI binding region was studied extensively, and compound 3 was generated as part of a bioisostere strategy, arising from hits identified as part of a HTS campaign. 12…”