HIV-1 protease inhibitors with a transition-state mimic comprising a tertiary alcohol: improved antiviral activity in cells.
By a small modification in the core structure of the previously reported series of HIV-1 protease inhibitors that encompasses a tertiary alcohol as part of the transition-state mimicking scaffold, up to 56 times more potent compounds were obtained exhibiting EC(50) values down to 3 nM. Three of the inhibitors also displayed excellent activity against selected resistant isolates of HIV-1. The synthesis of 25 new and optically pure HIV-1 protease inhibitors is reported, along with methods for elongation of the inhibitor P1' side chain using microwave-accelerated, palladium-catalyzed cross-coupling reactions, the biological evaluation, and X-ray data obtained from one of the most potent analogues cocrystallized with both the wild type and the L63P, V82T, I84 V mutant of the HIV-1 protease.
Mahalingam
A K
AK
Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, BMC, Uppsala University, Box 574, SE-751 23 Uppsala, Sweden.
Axelsson
Linda
L
Ekegren
Jenny K
JK
Wannberg
Johan
J
Kihlström
Jacob
J
Unge
Torsten
T
Wallberg
Hans
H
Samuelsson
Bertil
B
Larhed
Mats
M
Hallberg
Anders
A
D000438:Alcohols / Q000138:chemical synthesis* / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D016333:HIV Protease / Q000235:genetics; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1 / Q000235:genetics; D020128:Inhibitory Concentration 50; D018716:Molecular Mimicry; D020125:Mutation, Missense
D000438:Alcohols; D000998:Antiviral Agents; D017320:HIV Protease Inhibitors; D016333:HIV Protease