title: Design, synthesis, and biological activity of novel 5-((arylfuran/1H-pyrrol-2-yl)methylene)-2-thioxo-3-(3-(trifluoromethyl)phenyl)thiazolidin-4-ones as HIV-1 fusion inhibitors targeting gp41.
abstract: On the basis of our earlier molecular docking analysis, we designed and synthesized 5-((arylfuran/1H-pyrrol-2-yl)methylene)-2-thioxo-3-(3-(trifluoromethyl)phenyl)thiazolidin-4-ones (12a-o) as HIV-1 entry inhibitors. Compounds 12a-o effectively inhibited infection by both laboratory-adapted and primary HIV-1 strains and blocked HIV-1 mediated cell-cell fusion and gp41 six-helix bundle formation. Molecular docking analyses on two highly active inhibitors, 12b, containing a carboxylic acid group, and 12m, containing a tetrazole group, indicated that they both fit snugly into the hydrophobic cavity of HIV-1 gp41 from which each has important ionic interactions with lysine 574 (K574). By contrast, molecular docking of 12i, a less active compound containing a pyrrole instead of a furan ring, indicated a completely different orientation from 12b and 12m and missed critical interactions.
authors.affiliation: Lindsley F. Kimball Research Institute, New York Blood Center, New York 10065, United States. sjiang@nybloodcenter.org
authors.forename: Shibo
authors.initials: S
authors.lastname: Jiang
authors.forename: Srinivasa R
authors.initials: SR
authors.lastname: Tala
authors.forename: Hong
authors.initials: H
authors.lastname: Lu
authors.forename: Nader E
authors.initials: NE
authors.lastname: Abo-Dya
authors.forename: Ilker
authors.initials: I
authors.lastname: Avan
authors.forename: Kapil
authors.initials: K
authors.lastname: Gyanda
authors.forename: Lu
authors.initials: L
authors.lastname: Lu
authors.forename: Alan R
authors.initials: AR
authors.lastname: Katritzky
authors.forename: Asim K
authors.initials: AK
authors.lastname: Debnath
mesh_terms: D002460:Cell Line; D015195:Drug Design; D005663:Furans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015700:HIV Envelope Protein gp41 / Q000378:metabolism*; D023581:HIV Fusion Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000302:isolation & purification / Q000502:physiology; D006801:Humans; D008958:Models, Molecular; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D053778:Thiazolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D053586:Virus Internalization
chemical_list: D005663:Furans; D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D011758:Pyrroles; D053778:Thiazolidines