Synthesis of novel, potent, diol-based HIV-1 protease inhibitors via intermolecular pinacol homocoupling of (2S)-2-benzyloxymethyl-4-phenylbutanal.
The synthesis of novel, potent, diol-based HIV-1 protease inhibitors, having phenethyl groups (-CH(2)CH(2)Ph) in P1/P1' position is described. An intermolecular pinacol homocoupling of (2S)-2-benzyloxymethyl-4-phenylbutanal 16 was the key step in the synthesis. From this reaction sequence four carba analogues, compounds 8a, 8b, 9a, and 9b, were prepared, having the inverted configuration of one or both of the stereogenic centers carrying the diol hydroxyls as compared to the parent series represented by inhibitors 6 and 7. Inhibitor 8b was found to be a potent inhibitor of HIV-1 protease (PR), showing excellent antiviral activity in the cell-based assay and in the presence of 40% human serum. The absolute stereochemistry of the central diol of the potent inhibitor (8b) was determined from the X-ray crystallographic structure of its complex with HIV-1 PR.
Mühlman
A
A
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden.
Lindberg
J
J
Classon
B
B
Unge
T
T
Hallberg
A
A
Samuelsson
B
B
D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D016333:HIV Protease / Q000737:chemistry / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000577:Amides; D017320:HIV Protease Inhibitors; C438591:N1,N6-bis(hydroxy-1-indanyl)-3,4-dihydroxy-2,5-bis(2-phenylethyl)hexanediamide; D016333:HIV Protease