1. Synthesis and Evaluation of Bifunctional Aminothiazoles as Antiretrovirals Targeting the HIV-1 Nucleocapsid Protein
- Author
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Francesco Saladini, Alessia Giannini, Savina Malancona, Maurizio Zazzi, Maria Chiara Dasso Lang, Barbara Poddesu, Yves Mély, Maurizio Botta, Mattia Mori, Davide De Forni, Vincenzo Summa, Laura Friggeri, Lesia Kovalenko, Nastasja Palombi, Mori, M., Dasso Lang, M. C., Saladini, F., Palombi, N., Kovalenko, L., De Forni, D., Poddesu, B., Friggeri, L., Giannini, A., Malancona, S., Summa, V., Zazzi, M., Mely, Y., and Botta, M.
- Subjects
Stereochemistry ,antiretroviral ,01 natural sciences ,Biochemistry ,Virus ,chemistry.chemical_compound ,Aminothiazole ,aminothiazole ,Drug Discovery ,Moiety ,Cytotoxicity ,Bifunctional ,drug resistance ,HIV ,NC inhibitors ,Nucleocapsid protein ,010405 organic chemistry ,Organic Chemistry ,Small molecule ,In vitro ,0104 chemical sciences ,3. Good health ,010404 medicinal & biomolecular chemistry ,NC inhibitor ,chemistry ,Pharmacophore - Abstract
[Image: see text] 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.
- Published
- 2018