Design, synthesis, protein-ligand X-ray structure, and biological evaluation of a series of novel macrocyclic human immunodeficiency virus-1 protease inhibitors to combat drug resistance.
The structure-based design, synthesis, and biological evaluation of a series of nonpeptidic macrocyclic HIV protease inhibitors are described. The inhibitors are designed to effectively fill in the hydrophobic pocket in the S1'-S2' subsites and retain all major hydrogen bonding interactions with the protein backbone similar to darunavir (1) or inhibitor 2. The ring size, the effect of methyl substitution, and unsaturation within the macrocyclic ring structure were assessed. In general, cyclic inhibitors were significantly more potent than their acyclic homologues, saturated rings were less active than their unsaturated analogues and a preference for 10- and 13-membered macrocylic rings was revealed. The addition of methyl substituents resulted in a reduction of potency. Both inhibitors 14b and 14c exhibited marked enzyme inhibitory and antiviral activity, and they exerted potent activity against multidrug-resistant HIV-1 variants. Protein-ligand X-ray structures of inhibitors 2 and 14c provided critical molecular insights into the ligand-binding site interactions.
Ghosh
Arun K
AK
Department of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, Indiana 47907, USA. akghosh@purdue.edu
Kulkarni
Sarang
S
Anderson
David D
DD
Hong
Lin
L
Baldridge
Abigail
A
Wang
Yuan-Fang
YF
Chumanevich
Alexander A
AA
Kovalevsky
Andrey Y
AY
Tojo
Yasushi
Y
Amano
Masayuki
M
Koh
Yasuhiro
Y
Tang
Jordan
J
Weber
Irene T
IT
Mitsuya
Hiroaki
H
D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D018360:Crystallography, X-Ray; D015195:Drug Design; D024882:Drug Resistance, Viral / Q000187:drug effects*; D016333:HIV Protease / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D008024:Ligands; D047028:Macrocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D008968:Molecular Conformation; D009154:Mutation
D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D008024:Ligands; D047028:Macrocyclic Compounds; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1