3,5-Bis(arylidene)-4-piperidones as potential dengue protease inhibitors

Hasnah Osman; Nor Hashima Idris; Ezatul Ezleen Kamarulzaman; Habibah A Wahab; Mohd Zaheen Hassan

doi:10.1016/j.apsb.2017.04.009

3,5-Bis(arylidene)-4-piperidones as potential dengue protease inhibitors

Acta Pharm Sin B. 2017 Jul;7(4):479-484. doi: 10.1016/j.apsb.2017.04.009. Epub 2017 May 4.

Authors

Hasnah Osman¹, Nor Hashima Idris¹, Ezatul Ezleen Kamarulzaman², Habibah A Wahab², Mohd Zaheen Hassan¹

Affiliations

¹ School of Chemical Sciences, Universiti Sains Malaysia, Pulau Pinang 11800 USM, Malaysia.
² School of Pharmaceutical Sciences, Universiti Sains Malaysia, Pulau Pinang 11800 USM, Malaysia.

Abstract

Dengue is a severe mosquito-borne viral infection causing half a million deaths annually. Dengue virus NS2B/NS3 protease is a validated target for anti-dengue drug design. A series of hitherto unreported 3,5-bis(arylidene)-4-piperidones analogues 4a-4j were synthesized and screened in silico against DENV2 NS2B/NS3 protease to elucidate their binding mechanism and orientation around the active sites. Results were validated through an in vitro DENV2 NS2B/NS3 protease assay using a fluorogenic Boc-Gly-Arg-Arg-AMC substrate. Nitro derivatives of 3,5-bis(arylidene)-4-piperidones (4e and 4j) emerged as promising lead molecules for novel protease inhibitors with an IC₅₀ of 15.22 and 16.23 µmol/L, respectively, compared to the standard, panduratin A, having IC₅₀ of 57.28 µmol/L.

Keywords: Dengue virus; NS2B/NS3 protease; Piperidone; Protease inhibitors; α,β-Unsaturated ketone.