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

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 2,1benzothiazine 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 mu M 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.

Automated summary

Researchers designed and synthesized a series of sulfonyl anthranilic acid (SAA) derivatives that showed potential inhibition against dengue virus (DENV) infection in cells. These derivatives did not affect the activity of DENV NS5 polymerase. Compounds 26 and 39 exhibited the best inhibitory effects, with EC50 values in the range of 0.54-1.36 μM against cells infected with all four dengue serotypes. The study suggests that SAA derivatives could serve as a valuable starting point for the development of effective antiviral therapeutics for dengue.