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 IC50values higher than 28 μM. Our series of 2-pyridine-3-ylpyrimidines exhibited IC50values ranging from 3 to 60 μM. 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.
Kožíšek, M., Štěpánek, O., Parkan, K., Berenguer Albiñana, C., Pávová, M., Weber, J., … Machara, A. (2016). Synthesis and evaluation of 2-pyridinylpyrimidines as inhibitors of HIV-1 structural protein assembly. Bioorganic and Medicinal Chemistry Letters, 26(15), 3487–3490. https://doi.org/10.1016/j.bmcl.2016.06.039