- 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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p. 463 - 468
(2019/04/25)
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- Structure-based design, synthesis and biological evaluation of N-pyrazole, N′-thiazole urea inhibitors of MAP kinase p38α
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In this paper, we present the structure-based design, synthesis and biological activity of N-pyrazole, N′-thiazole-ureas as potent inhibitors of p38α mitogen-activated protein kinase (p38α MAPK). Guided by complex crystal structures, we employed the initially identified N-aryl, N′-thiazole urea scaffold and introduced key structural elements that allowed the formation of novel hydrogen bonding interactions within the allosteric site of p38α, resulting in potent type III inhibitors. [4-(3-tert-Butyl-5-{[(1,3-thiazol-2-ylamino)carbonyl]amino}-1H-pyrazol-1-yl) -phenyl]acetic acid 18c was found to be the most potent compound within this series and inhibited p38α activity with an IC50 of 135 ± 21 nM. Its closest analog, ethyl [4-(3-tert-butyl-5-{[(1,3-thiazol-2-ylamino) carbonyl]amino}-1H-pyrazol-1-yl)phenyl]acetate 18b, effectively inhibited p38α mediated phosphorylation of the mitogen activated protein kinase activated protein kinase 2 (MK2) in HeLa cells.
- Getlik, Matth?us,Grütter, Christian,Simard, Jeffrey R.,Nguyen, Hoang D.,Robubi, Armin,Aust, Beate,Van Otterlo, Willem A.L.,Rauh, Daniel
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