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

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.

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Source
http://pubs.acs.org/doi/10.1021/acsmedchemlett.8b00506
Publisher Site
http://dx.doi.org/10.1021/acsmedchemlett.8b00506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466545PMC
April 2019
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