Synthesis and Evaluation of Bifunctional Aminothiazoles as Antiretrovirals Targeting the HIV‑1 Nucleocapsid Protein

Small molecule inhibitors of the HIV-1 nucleocapsid protein (NC) are considered as promising agents in the treatment of HIV/AIDS. In an effort to exploit the privileged 2-amino-4-phenylthiazole moiety in NC inhibition, here we conceived, synthesized, and tested in vitro 18 NC inhibitors (NCIs) beari...

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Published in:ACS medicinal chemistry letters 2019-04, Vol.10 (4), p.463-468
Main Authors: Mori, Mattia, Dasso Lang, Maria Chiara, Saladini, Francesco, Palombi, Nastasja, Kovalenko, Lesia, De Forni, Davide, Poddesu, Barbara, Friggeri, Laura, Giannini, Alessia, Malancona, Savina, Summa, Vincenzo, Zazzi, Maurizio, Mely, Yves, Botta, Maurizio
Format: Article
Language:English
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Letter
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Summary:Small molecule inhibitors of the HIV-1 nucleocapsid protein (NC) are considered as promising agents in the treatment of HIV/AIDS. In an effort to exploit the privileged 2-amino-4-phenylthiazole moiety in NC inhibition, here we conceived, synthesized, and tested in vitro 18 NC inhibitors (NCIs) bearing a double functionalization. In these NCIs, one part of the molecule is deputed to interact noncovalently with the NC hydrophobic pocket, while the second portion is designed to interact with the N-terminal domain of NC. This binding hypothesis was verified by molecular dynamics simulations, while the linkage between these two pharmacophores was found to enhance antiretroviral activity both on the wild-type virus and on HIV-1 strains with resistance to currently licensed drugs. The two most interesting compounds 6 and 13 showed no cytotoxicity, thus becoming valuable leads for further investigations.
ISSN:1948-5875
1948-5875
DOI:10.1021/acsmedchemlett.8b00506