On the inhibition of HIV-1 protease by hydrazino-ureas displaying the N-->C=O interaction.
To create novel HIV-1 protease (HIV PR) inhibitors, we have extended our investigations of the N-->C=O 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-->C=O 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.
Waibel
Michael
M
Laboratoire de Chimie, UMR CNRS 5182, Université de Lyon-ENS, 46 allée d'Italie, 69364 Lyon cedex 07, France.
Pitrat
Delphine
D
Hasserodt
Jens
J
D016333:HIV Protease / Q000737:chemistry / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D006834:Hydrazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006860:Hydrogen Bonding; D007700:Kinetics; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
D017320:HIV Protease Inhibitors; D006834:Hydrazines; D014508:Urea; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1