- Synthesis and Evaluation of Bifunctional Aminothiazoles as Antiretrovirals Targeting the HIV-1 Nucleocapsid Protein
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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.
- 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
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supporting information
p. 463 - 468
(2019/04/25)
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- Inhibitors of glycogen synthase kinase 3
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New pyrimidine or pyridine based compounds, compositions and methods of inhibiting the activity of glycogen synthase kinase (GSK3) in vitro and of treatment of GSK3 mediated disorders in vivo are provided. The methods, compounds and compositions of the invention may be employed alone, or in combination with other pharmacologically active agents in the treatment of disorders mediated by GSK3 activity, such as diabetes, Alzheimer's disease and other neurodegenerative disorders, obesity, atherosclerotic cardiovascular disease, essential hypertension, polycystic ovary syndrome, syndrome X, ischemia, traumatic brain injury, bipolar disorder, immunodeficiency or cancer.
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- Inhibitors of glycogen synthase kinase 3
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Novel pyridine and pyrimidine derivatives which selectively inhibit glycogen synthase kinase 3 are provided and methods of preparing these compounds are provided. These compounds are useful in treating certain conditions which may be mediated by glycogen synthase kinase 3.
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