Abstract:
Viral infections have become biggest threat to the humanity. Synthesis of effective drugs to treat viral infections has become the need of the time. Direct Acting Anti HIV and HCV drugs have been efficaciously established by targeting the viral proteases. Likewise, dengue virus (DENV) protease, which is comprised of NS2B and NS3pro proteins, can also be exploited for finding new anti-dengue drugs. Here, we have established two alternate series of novel hybrids, namely S-alkylphthalimideoxadiazole-benzenesulfonamides (8a-j & 14a-f) and Sbenzyloxadiazolebenzenesulfonamides (9a-c & 15a-e). To obtain first series of hybrids, the reaction of paminobenzoic acid (1) with 4-methyl and 4-trifluoromethylbenzene-sulfonyl chloride (2a-b) provided 4-{[(4methylphenyl)sulfonyl]-amino}benzoic acid (3a) and 4-{[(4- trifluoromethylphenyl)sulfonyl]amino}benzoic acid (3b), respectively. The sequential esterification, hydrozinolysis and cyclizaation of carboxylic acid group of (3a-b) resulted 4-{[(4- methylphenyl)sulfonyl]amino}phenyl 1,3,4-oxadiazole-2-thiol (6a) and 4-{[(4trifluoromethylphenyl)sulfonyl]amino}phenyl 1,3,4-oxadiazole-2-thiol (6b). The intermediate (6a-b) reacted with Nbromoalkyl substituted phthalimides (7`a-f) and trifluoromethylated benzyl chlorides (7ac) to afford 8a-j & 9a-c in good yields. To access second series of hybrids, probenecid (10) was converted into 4[(dipropylamino)sulfonyl]benzene 1,3,4-oxadiazole-2-thiol (13) and d similarly elaborated to sulfonamido-1,3,4oxadiazole-2-thiols (13) which is then bifurcated to Salkylphthalimide and S-benzyl 4[(dipropylamino)sulfonyl]benzene 1,3,4-oxadiazole-2-thiol hybrids (14a-f) and (15a-e), respectively. Bioactivity screenings revealed that 8g and 8h are found to be the most potent inhibitors of DENV NS2B/NS3 protease among the synthesized analogs, possessing the IC50 values of 13.9 µM and 15.1 µM, respectively. Molecular docking studies anticipated the binding of the inhibitors at an allosteric site generated in the open conformation of DENV2 NS2B/NS3pro. All these inhibition findings establish that the synthesized novel S-benzyl- and Salkylphthalimideoxadiazole-benzenesulfonamide hybrids possess a great potential for further antiviral drug development.
Page(s):
0-0
DOI:
DOI not available
Published:
Journal: First International Conference on Revamped Scientific Outlook of 21st Century (Abstract Book), Volume: 0, Issue: 0, Year: 2022
Keywords:
protease
,
Antiviral drug
,
Hybrids
,
dengue virus