5,6-Dihydroxypyrimidine Scaffold to Target HIV-1 Nucleocapsid Protein
2020
The HIV-1 nucleocapsid
(NC) protein is a small basic DNA and RNA
binding protein that is absolutely necessary for viral replication
and thus represents a target of great interest to develop new anti-HIV
agents. Moreover, the highly conserved sequence offers the opportunity
to escape the drug resistance (DR) that emerged following the highly
active antiretroviral therapy (HAART) treatment. On the basis of our
previous research, nordihydroguaiaretic acid 1 acts as
a NC inhibitor showing moderate antiviral activity and suboptimal
drug-like properties due to the presence of the catechol moieties.
A bioisosteric catechol replacement approach led us to identify the
5-dihydroxypyrimidine-6-carboxamide substructure as a privileged
scaffold of a new class of HIV-1 NC inhibitors. Hit validation efforts
led to the identification of optimized analogs, as represented by
compound 28, showing improved NC inhibition and antiviral
activity as well as good ADME and PK properties.
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