کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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1360557 | 981439 | 2009 | 9 صفحه PDF | دانلود رایگان |
To create novel HIV-1 protease (HIV PR) inhibitors, we have extended our investigations of the N→CO interaction as a moiety that reproduces electrostatic properties of the transition state of peptidolysis. Consequently, we prepared a series of compounds with an unusual hydrazino-urea core. In polar protic media, these adopt solely a cyclic constitution displaying the interaction on one side of the molecule while offering a urea moiety on the opposite side meant to hydrogen-bond with the enzyme flaps. Each inhibitor candidate was obtained via a key series of three synthetic steps employing carbonyl-di-imidazole (CDI). It was thus possible to efficiently fuse two independent building blocks, a hydrazine and a protected aminoaldehyde in a convergent manner. NMR and UV analysis proved that all compounds, when dissolved in polar protic media, existed exclusively in the cyclic constitution exhibiting the N→CO interaction. In total, five inhibitor candidates were tested with HIV PR for their potency. The one carrying the least bulk in peripheral substituents showed the highest activity. Its very low molecular weight (365 g/mol) holds great promise for future improvements in affinity without violating Lipinski’s rule of remaining within the limit of 500 g/mol.
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Journal: Bioorganic & Medicinal Chemistry - Volume 17, Issue 10, 15 May 2009, Pages 3671–3679