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Title: 5,6-Dihydroxypyrimidine Scaffold to Target HIV-1 Nucleocapsid Protein
Authors: Malancona, Savina
Mori, Mattia 
Fezzardi, Paola
Santoriello, Marisabella
Basta, Andreina
Nibbio, Martina
Kovalenko, Lesia
Speziale, Roberto
Battista, Maria Rosaria
Cellucci, Antonella
Gennari, Nadia
Monteagudo, Edith
Di Marco, Annalise
Giannini, Alessia
Sharma, Rajhans
Pires, Manuel
Real, Eleonore
Zazzi, Maurizio
Dasso Lang, Maria Chiara
De Forni, Davide
Saladini, Francesco
Mely, Yves
Summa, Vincenzo
Harper, Steven
Botta, Maurizio 
Issue Date: 2020
Project: None 
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.
ISSN: 1948-5875
DOI: 10.1021/acsmedchemlett.9b00608
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