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

  • Katritzky A
  • Tala S
  • Lu H
 et al. 
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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. Oil 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 oil 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 HIB-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.

Author-supplied keywords

  • acids
  • core structure
  • derivatives
  • domain
  • fusion
  • glycoprotein
  • immunodeficiency-virus type-1
  • infection
  • targeting gp41

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  • A R Katritzky

  • S R Tala

  • H Lu

  • A V Vakulenko

  • Q Y Chen

  • J Sivapackiam

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