title: Small molecule fusion inhibitors: design, synthesis and biological evaluation of (Z)-3-(5-(3-benzyl-4-oxo-2-thioxothiazolidinylidene)methyl)-N-(3-carboxy-4-hydroxy)phenyl-2,5-dimethylpyrroles and related derivatives targeting HIV-1 gp41.
abstract: By a scaffold elongation strategy, a series of (Z)-3-(5-(3-benzyl-4-oxo-2-thioxothiazolidinylidene)methyl)-N-(3-carboxy-4-hydroxy)phenyl-2,5-dimethylpyrroles and related derivatives with a linear multi-aromatic-ring skeleton were designed, synthesized, and evaluated in HIV-1 gp41 and cellular assays. Among them, the most active compounds, 12e, 12g, and 12k with a one-carbon linker (n=1) between the rhodanine (C) and phenyl (D) rings, exhibited very promising inhibitory potency with IC50 values of 1.8-2.6 μM and EC50 values of 0.3-1.5 μM against gp41 6-HB formation and HIV-1 replication in MT-2 cells, respectively. Additionally, they were almost equally effective against both T20-sensitive and resistant strains. The related SAR studies and molecular modeling results provided potential for further developing a new class of non-peptide small molecular fusion inhibitors targeting the HIV-1 gp41.
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
authors.forename: Xiao-Yang
authors.initials: XY
authors.lastname: He
authors.forename: Lu
authors.initials: L
authors.lastname: Lu
authors.forename: Jiayin
authors.initials: J
authors.lastname: Qiu
authors.forename: Peng
authors.initials: P
authors.lastname: Zou
authors.forename: Fei
authors.initials: F
authors.lastname: Yu
authors.forename: Xing-Kai
authors.initials: XK
authors.lastname: Jiang
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.forename: Shibo
authors.initials: S
authors.lastname: Jiang
authors.forename: Shuwen
authors.initials: S
authors.lastname: Liu
authors.forename: Lan
authors.initials: L
authors.lastname: Xie
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D015195:Drug Design; D015700:HIV Envelope Protein gp41 / Q000737:chemistry / Q000378:metabolism*; D023581:HIV Fusion Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D062105:Molecular Docking Simulation; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D019380:Anti-HIV Agents; D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D011758:Pyrroles; D054852:Small Molecule Libraries
keywords: 3-Substituted N-(3-carboxy-4-hydroxy)phenyl-2,5-dimethylpyrrole derivatives; Anti-HIV agents; HIV-1 gp41; Small-molecule fusion inhibitors