2. Academic Validation
  3. Multistep Synthesis of Analogues of Remdesivir: Incorporating Heterocycles at the C-1' Position

Multistep Synthesis of Analogues of Remdesivir: Incorporating Heterocycles at the C-1' Position

  • J Org Chem. 2023 Jun 5. doi: 10.1021/acs.joc.3c00754.
Savio Cardoza 1,  Manoj Kumar Shrivash 2,  Laura Riva 3,  Arnab K Chatterjee 3,  Ajay Mandal 4,  Vibha Tandon 1
Affiliations

Affiliations

  • 1 Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi 110067, India.
  • 2 Department of Applied Sciences, Indian Institute of Information Technology Allahabad, Allahabad 211012, Uttar Pradesh, India.
  • 3 Calibr, Scripps Research, La Jolla, 11119 North Torrey Pines Road Suite 100, California 92037, United States.
  • 4 Symbol Discovery Ltd, ASPIRE-TBI, School of Life Sciences, University of Hyderabad, Gachibowli, Hyderabad 500046, India.
PMID: 37276453 DOI: 10.1021/acs.joc.3c00754
Abstract

Studies suggest that the 1'β-CN moiety in remdesivir sterically clashes with the Ser861 residue of the RNA-dependent-RNA polymerase (RdRp), causing a delayed chain termination in the RNA replication process. Replacing C1'β-CN with 5-membered heterocycles such as tetrazoles, oxadiazoles, and triazoles can augment the inhibitory activity and pharmacokinetic profile of C-nucleotides. Synthesis of tetrazole-, triazole-, and oxadiazole-integrated C1' analogues of remdesivir was attempted using general synthetic routes. The final compounds 26, 28, and 29 did not inhibit viral replication; however, the synthetic intermediates, i.e., 27 and 50, exhibited an IC90 = 14.1 μM each. The trifluoromethyl-substituted 1,2,4-oxadiazole 59 showed an IC90 of 33.5 μM. This work adds to the growing evidence of the beneficial medicinal impact of C1,1'-disubstituted C-nucleotides.

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