5,6-Dihydroxypyrimidine Scaffold to Target HIV‑1 Nucleocapsid Protein

• Published in: ACS medicinal chemistry letters Vol. 11; no. 5; pp. 766 - 772
• Main 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
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 14-05-2020
• Subjects: Biochemistry, Molecular Biology; Letter; Life Sciences; dihydroxypyrimidine; antiretroviral; drug resistance; HIV; Nucleocapsid protein; NC inhibitors
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/acsmedchemlett.9b00608

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.