ACS Med Chem Lett 2019 Apr 7;10(4):463-468. Epub 2018 Dec 7.
Department of Biotechnology, Chemistry and Pharmacy, "Department of Excellence 2018-2022", University of Siena, via Aldo Moro 2, 53100 Siena, Italy.
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 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 and showed no cytotoxicity, thus becoming valuable leads for further investigations.