2. Academic Validation
  3. Functionalized sulfonyl anthranilic acid derivatives inhibit replication of all the four dengue serotypes

Functionalized sulfonyl anthranilic acid derivatives inhibit replication of all the four dengue serotypes

  • Eur J Med Chem. 2023 Apr 5;252:115283. doi: 10.1016/j.ejmech.2023.115283.
Tommaso Felicetti 1,  Chin Piaw Gwee 2,  Maria Sole Burali 1,  Kitti Wing Ki Chan 2,  Sylvie Alonso 3,  Maria Chiara Pismataro 1,  Stefano Sabatini 1,  Maria Letizia Barreca 1,  Violetta Cecchetti 1,  Subhash G Vasudevan 4,  Giuseppe Manfroni 5
Affiliations

Affiliations

  • 1 Dipartimento di Scienze Farmaceutiche, Università degli Studi di Perugia, Via Del Liceo, 1-06123, Perugia, Italy.
  • 2 Program in Emerging Infectious Diseases, Duke-NUS Medical School, 169857, Singapore.
  • 3 Infectious Diseases Translational Research Programme, Department of Microbiology & Immunology, Yong Loo Lin School of Medicine, Singapore; Immunology programme, Life Sciences Institute, National University of Singapore, Singapore.
  • 4 Program in Emerging Infectious Diseases, Duke-NUS Medical School, 169857, Singapore; Institute for Glycomics, Griffith University, Queensland, 4222, Australia. Electronic address: [email protected].
  • 5 Dipartimento di Scienze Farmaceutiche, Università degli Studi di Perugia, Via Del Liceo, 1-06123, Perugia, Italy. Electronic address: [email protected].
PMID: 36965228 DOI: 10.1016/j.ejmech.2023.115283
Abstract

Dengue virus (DENV), a mosquito-borne Flavivirus, continues to be a major public health threat in many countries and no approved Antiviral therapeutics are available yet. In this work, we designed and synthesized a series of sulfonyl anthranilic acid (SAA) derivatives using a ligand-based scaffold morphing approach of the 2,1-benzothiazine 2,2-dioxide core, previously used by us to develop DENV polymerase inhibitors resulting devoid of any cell-based Antiviral activity. Several derivatives based on the new SAA chemotype exhibited potent inhibition against DENV Infection in the cell-based assay but did not inhibit DENV NS5 polymerase activity in the in vitro de novo initiation and elongation assays. Notably, best compounds 26 and 39 showed EC50 values in the range of 0.54-1.36 μM against cells infected with the four dengue serotypes (DENV-1-4). Time-of-drug-addition assay revealed that analogue 26 is a post-entry replication inhibitor that appears to be specific for cells of primate origin, implicating a host target with a high barrier to resistance. In conclusion, SAA derivatives offer a valuable starting point for developing effective Dengue Antiviral therapeutics.

Keywords

Antiviral agent; Dengue; Flavivirus; Host-targeting agents; Scaffold morphing; Sulfonyl anthranilic acid.

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