title: Design, synthesis, and structure-activity relationship of a novel series of 2-aryl 5-(4-oxo-3-phenethyl-2-thioxothiazolidinylidenemethyl)furans as HIV-1 entry inhibitors.
abstract: We previously identified two small molecules targeting the HIV-1 gp41, N-(4-carboxy-3-hydroxy)phenyl-2,5-dimethylpyrrole 12 (NB-2) and N-(3-carboxy-4-chloro)phenylpyrrole 13 (NB-64), that inhibit HIV-1 infection at low micromolar levels. On the basis of molecular docking analysis, we designed a series of 2-aryl 5-(4-oxo-3-phenethyl-2-thioxothiazolidinylidenemethyl)furans. Compared with 12 and 13, these compounds have bigger molecular size (437-515 Da) and could occupy more space in the deep hydrophobic pocket on the gp41 NHR trimer. Fifteen 2-aryl 5-(4-oxo-3-phenethyl-2-thioxothiazolidinylidenemethyl)furans (11a-o) were synthesized by Suzuki-Miyaura cross-coupling followed by a Knoevenagel condensation and tested for their anti-HIV-1 activity and cytotoxicity on MT-2 cells. We found that all 15 compounds had improved anti-HIV-1 activity and 3 of them (11a, 11b, and 11d) exhibited inhibitory activity against replication of HIV-1(IIIB) and 94UG103 at <100 nM range, more than 20-fold more potent than 12 and 13, suggesting that these compounds can serve as leads for development of novel small molecule HIV fusion inhibitors.
authors.affiliation: Department of Chemistry, Center for Heterocyclic Compounds, University of Florida, Gainesville, Florida 32611, USA.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Katritzky
authors.forename: Srinivasa R
authors.initials: SR
authors.lastname: Tala
authors.forename: Hong
authors.initials: H
authors.lastname: Lu
authors.forename: Anatoliy V
authors.initials: AV
authors.lastname: Vakulenko
authors.forename: Qi-Yin
authors.initials: QY
authors.lastname: Chen
authors.forename: Jothilingam
authors.initials: J
authors.lastname: Sivapackiam
authors.forename: Keyur
authors.initials: K
authors.lastname: Pandya
authors.forename: Shibo
authors.initials: S
authors.lastname: Jiang
authors.forename: Asim K
authors.initials: AK
authors.lastname: Debnath
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D015195:Drug Design; D005663:Furans / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D015700:HIV Envelope Protein gp41 / Q000737:chemistry / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology*; D008958:Models, Molecular; D008970:Molecular Weight; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D053586:Virus Internalization / Q000187:drug effects*
chemical_list: D019380:Anti-HIV Agents; D005663:Furans; D015700:HIV Envelope Protein gp41