Design, synthesis and biological evaluation of novel 5-((substituted quinolin-3-yl/1-naphthyl) methylene)-3-substituted imidazolidin-2,4-dione as HIV-1 fusion inhibitors

Tarek S. Ibrahim, Riham M. Bokhtia, Amany M.M. AL-Mahmoudy, Ehab S. Taher, Mohammed A. AlAwadh, Mohamed Elagawany, Eatedal H. Abdel-Aal, Siva Panda, Ahmed M. Gouda, Hany Z. Asfour, Nabil A. Alhakamy, Bahaa G.M. Youssif

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

A series of novel 5-(substituted quinolin-3-yl or 1-naphthyl)methylene)-3-substituted imidazolidin-2,4-dione 9–26 was designed and synthesized. The prepared compounds were identified using 1H NMR, 13C NMR as well as elemental analyses. The inhibitory activity of 9–26 on HIV-1IIIB replication in MT-2 cells was evaluated. Some derivatives showed good to excellent anti-HIV activities as compounds 13, 18, 19, 20, 22 and 23. They showed EC50 of 0.148, 0.460, 0.332, 0.50, 0.271 and 0.420 μM respectively being more potent than compound I (EC50 = 0.70 μM) and II ( EC50 = 2.40 μM) as standards. The inhibitory activity of 9–26 on infected primary HIV-1 domain, 92US657 (clade B, R5) was investigated. All the tested compounds consistently inhibited infection of this virus with EC50 from 0.520 to 11.857 μM. Results from SAR studies showed that substitution on ring A with 6/7/8-methyl group resulted in significant increase in the inhibitory activity against HIV-1IIIB infection (5- >300 times) compared to the unsubstituted analog 9. The cytotoxicity of these compounds on MT-2 cells was tested and their CC50 values ranged from 11 to 85 μM with selectivity indexes ranged from 0.53 to 166. The docking study revealed nice fitting of the new compounds into the hydrophobic pocket of HIV-1 gp41 and higher affinity than NB-64. Compound 13, the most active in preventing HIV-1IIIB infection, adopted a similar orientation to compound IV. Molecular docking analysis of the new compounds revealed hydrogen bonding interactions between the imidazolidine-2,4-dione ring and LYS574 which were missed in the weakly active derivatives.

Original languageEnglish (US)
Article number103782
JournalBioorganic Chemistry
Volume99
DOIs
StatePublished - Jun 2020

Keywords

  • Gp41
  • HIV
  • Imidazolidine-2,4-dione
  • Inhibitors
  • Quinoline

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Drug Discovery
  • Organic Chemistry

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    Ibrahim, T. S., Bokhtia, R. M., AL-Mahmoudy, A. M. M., Taher, E. S., AlAwadh, M. A., Elagawany, M., Abdel-Aal, E. H., Panda, S., Gouda, A. M., Asfour, H. Z., Alhakamy, N. A., & Youssif, B. G. M. (2020). Design, synthesis and biological evaluation of novel 5-((substituted quinolin-3-yl/1-naphthyl) methylene)-3-substituted imidazolidin-2,4-dione as HIV-1 fusion inhibitors. Bioorganic Chemistry, 99, [103782]. https://doi.org/10.1016/j.bioorg.2020.103782