title: Design, synthesis, and biological evaluation of N-carboxyphenylpyrrole derivatives as potent HIV fusion inhibitors targeting gp41.
abstract: On the basis of the structures of small-molecule hits targeting the HIV-1 gp41, N-(4-carboxy-3-hydroxy)phenyl-2,5-dimethylpyrrole (2, NB-2), and N-(3-carboxy-4-chloro)phenylpyrrole (A(1), NB-64), 42 N-carboxyphenylpyrrole derivatives in two categories (A and B series) were designed and synthesized. We found that 11 compounds exhibited promising anti-HIV-1 activity at micromolar level and their antiviral activity was correlated with their inhibitory activity on gp41 six-helix bundle formation, suggesting that these compounds block HIV fusion and entry by disrupting gp41 core formation. The structure-activity relationship and molecular docking analysis revealed that the carboxyl group could interact with either Arg579 or Lys574 to form salt bridges and two methyl groups on the pyrrole ring were favorable for interaction with the residues in gp41 pocket. The most active compound, N-(3-carboxy-4-hydroxy)phenyl-2,5-dimethylpyrrole (A(12)), partially occupied the deep hydrophobic pocket, suggesting that enlarging the molecular size of A(12) could improve its binding affinity and anti-HIV-1 activity for further development as a small-molecule HIV fusion and entry inhibitor.
authors.affiliation: Beijing Institute of Pharmacology & Toxicology, 27 Tai-Ping Road, Beijing, 100850, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Liu
authors.forename: Hong
authors.initials: H
authors.lastname: Lu
authors.forename: Ling
authors.initials: L
authors.lastname: Hou
authors.forename: Zhi
authors.initials: Z
authors.lastname: Qi
authors.forename: Cátia
authors.initials: C
authors.lastname: Teixeira
authors.forename: Florent
authors.initials: F
authors.lastname: Barbault
authors.forename: Bo-Tao
authors.initials: BT
authors.lastname: Fan
authors.forename: Shuwen
authors.initials: S
authors.lastname: Liu
authors.forename: Shibo
authors.initials: S
authors.lastname: Jiang
authors.forename: Lan
authors.initials: L
authors.lastname: Xie
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000737:chemistry*; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D015700:HIV Envelope Protein gp41 / Q000737:chemistry*; D023581:HIV Fusion Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D017433:Protein Structure, Secondary; D011758:Pyrroles / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D019380:Anti-HIV Agents; D000998:Antiviral Agents; D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D011758:Pyrroles