2. Academic Validation
  3. Design, Synthesis, and Biological Evaluation of 1,2-Dihydroisoquinolines as HIV-1 Integrase Inhibitors

Design, Synthesis, and Biological Evaluation of 1,2-Dihydroisoquinolines as HIV-1 Integrase Inhibitors

  • ACS Med Chem Lett. 2015 Aug 10;6(10):1065-70. doi: 10.1021/acsmedchemlett.5b00230.
Vibha Tandon 1,  Urvashi 2,  Pooja Yadav 2,  Souvik Sur 2,  Sheenu Abbat 3,  Vinod Tiwari 2,  Raymond Hewer 4,  Maria A Papathanasopoulos 5,  Rameez Raja 6,  Akhil C Banerjea 6,  Akhilesh K Verma 2,  Shrikant Kukreti 2,  Prasad V Bharatam 3
Affiliations

Affiliations

  • 1 Department of Chemistry, University of Delhi , Delhi 110007, India ; Special Centre for Molecular Medicine, Jawaharlal Nehru University , New Delhi 110067, India.
  • 2 Department of Chemistry, University of Delhi , Delhi 110007, India.
  • 3 National Institute of Pharmaceutical Education and Research , S. A. S Nagar, Mohali, Punjab 160062, India.
  • 4 Biomedical Advanced Material Division, Mintek , Private Bag X3015, Randburg 2125, Johannesburg, South Africa.
  • 5 Department of Molecular Medicine and Haematology, University of the Witwatersrand Medical School , Parktown 2193, Johannesburg, South Africa.
  • 6 Laboratory of Virology, National Institute of Immunology , New Delhi 110067, India.
PMID: 26487913 DOI: 10.1021/acsmedchemlett.5b00230
Abstract

6-Endo-dig-cyclization is an efficient method for the synthesis of 1,2-dihydroisoquinolines. We have synthesized few 1,2-dihydroisoquinolines having different functionality at the C-1, C-3, C-7, and N-2 positions for evaluation against HIV-1 integrase (HIV1-IN) inhibitory activity. A direct nitro-Mannich condensation of o-alkynylaldimines and dual activation of o-alkynyl aldehydes by inexpensive cobalt chloride yielded desired compounds. Out of 24 compounds, 4m and 6c came out as potent integrase inhibitors in in vitro strand transfer (ST) assay, with IC50 value of 0.7 and 0.8 μM, respectively. Molecular docking of these compounds in integrase revealed strong interaction between metal and ligands, which stabilizes the enzyme-inhibitor complex. The ten most active compounds were subjected to Antiviral assay. Out of those, 6c reduced the level of p24 viral antigen by 91%, which is comparable to RAL in Antiviral assay. Interestingly, these compounds showed similar ST inhibitory activity in G140S mutant, suggesting they can act against resistant strains.

Keywords

Multicomponent reaction; integrase; integrase inhibitors; molecular docking.

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