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Targeting the entrance channel of NNIBP: Discovery of diarylnicotinamide 1,4-disubstituted 1,2,3-triazoles as novel HIV-1 NNRTIs with high potency against wild-type and E138K mutant virus.

Publication ,  Journal Article
Tian, Y; Liu, Z; Liu, J; Huang, B; Kang, D; Zhang, H; De Clercq, E; Daelemans, D; Pannecouque, C; Lee, K-H; Chen, C-H; Zhan, P; Liu, X
Published in: Eur J Med Chem
May 10, 2018

Inspired by our previous efforts on the modifications of diarylpyrimidines as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTI) and reported crystallography study, novel diarylnicotinamide derivatives were designed with a "triazole tail" occupying the entrance channel in the NNRTI binding pocket of the reverse transcriptase to afford additional interactions. The newly designed compounds were then synthesized and evaluated for their anti-HIV activities in MT-4 cells. All the compounds showed excellent to good activity against wild-type HIV-1 strain with EC50 of 0.02-1.77 μM. Evaluations of selected compounds against more drug-resistant strains showed these compounds had advantage of inhibiting E138K mutant virus which is a key drug-resistant mutant to the new generation of NNRTIs. Among this series, propionitrile (3b2, EC50(IIIB) = 0.020 μM, EC50(E138K) = 0.015 μM, CC50 = 40.15 μM), pyrrolidin-1-ylmethanone (3b8, EC50(IIIB) = 0.020 μM, EC50(E138K) = 0.014 μM, CC50 = 58.09 μM) and morpholinomethanone (3b9, EC50(IIIB) = 0.020 μM, EC50(E138K) = 0.027 μM, CC50 = 180.90 μM) derivatives are the three most promising compounds which are equally potent to the marketed drug Etravirine against E138K mutant strain but with much lower cytotoxicity. Furthermore, detailed SAR, inhibitory activity against RT and docking study of the representative compounds are also discussed.

Duke Scholars

Published In

Eur J Med Chem

DOI

EISSN

1768-3254

Publication Date

May 10, 2018

Volume

151

Start / End Page

339 / 350

Location

France

Related Subject Headings

  • Triazoles
  • Structure-Activity Relationship
  • Point Mutation
  • Niacinamide
  • Molecular Docking Simulation
  • Medicinal & Biomolecular Chemistry
  • Humans
  • HIV-1
  • HIV Reverse Transcriptase
  • HIV Infections
 

Citation

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Tian, Y., Liu, Z., Liu, J., Huang, B., Kang, D., Zhang, H., … Liu, X. (2018). Targeting the entrance channel of NNIBP: Discovery of diarylnicotinamide 1,4-disubstituted 1,2,3-triazoles as novel HIV-1 NNRTIs with high potency against wild-type and E138K mutant virus. Eur J Med Chem, 151, 339–350. https://doi.org/10.1016/j.ejmech.2018.03.059
Tian, Ye, Zhaoqiang Liu, Jinghan Liu, Boshi Huang, Dongwei Kang, Heng Zhang, Erik De Clercq, et al. “Targeting the entrance channel of NNIBP: Discovery of diarylnicotinamide 1,4-disubstituted 1,2,3-triazoles as novel HIV-1 NNRTIs with high potency against wild-type and E138K mutant virus.Eur J Med Chem 151 (May 10, 2018): 339–50. https://doi.org/10.1016/j.ejmech.2018.03.059.
Tian Y, Liu Z, Liu J, Huang B, Kang D, Zhang H, De Clercq E, Daelemans D, Pannecouque C, Lee K-H, Chen C-H, Zhan P, Liu X. Targeting the entrance channel of NNIBP: Discovery of diarylnicotinamide 1,4-disubstituted 1,2,3-triazoles as novel HIV-1 NNRTIs with high potency against wild-type and E138K mutant virus. Eur J Med Chem. 2018 May 10;151:339–350.
Journal cover image

Published In

Eur J Med Chem

DOI

EISSN

1768-3254

Publication Date

May 10, 2018

Volume

151

Start / End Page

339 / 350

Location

France

Related Subject Headings

  • Triazoles
  • Structure-Activity Relationship
  • Point Mutation
  • Niacinamide
  • Molecular Docking Simulation
  • Medicinal & Biomolecular Chemistry
  • Humans
  • HIV-1
  • HIV Reverse Transcriptase
  • HIV Infections