Dengue fever is one of major health problem around the world including Malaysia. It is caused by the arthropode-borne flavivirus and transmitted by the bite of the Aedes aegypti or Aedes albopictus mosquito infected with one of the four dengue virus serotypes (DENV-1, DENV-2, DENV-3, or DENV-4). In this study, a screening exercise of various Malaysian medicinal plants showed that the extracts of Lawsonia inermis, Dryobalanops aromatica, Punica granatum, Zizyphus jujuba Lam. and Zingiber zerumbet exhibited potent inhibitory activity against NS2B-NS3 serine protease. The methanol extracts of Dryobalanops aromatica showed inhibition of 99.70 % at concentration of 200 μg/mL with IC50 value of 0.30 ± 0.16 μg/mL.

The NS2B/NS3 protease is crucial for the pathogenesis of the DENV. Therefore, the inhibition of this protease is considered to be the key strategy for the development of new antiviral drugs. In the present study, malabaricones C (3) and E (4), acylphenols from the fruits of Myristica cinnamomea King, have been respectively identified as moderate (27.33 ± 5.45 μM) and potent (7.55 ± 1.64 μM) DENV-2 NS2B/NS3 protease inhibitors, thus making this the first report on the DENV-2 NS2B/NS3 protease inhibitory activity of acylphenols. Based on the molecular docking studies, compounds 3 and 4 both have π-π interactions with Tyr161. While compound 3 has hydrogen bonding interactions with Gly151, Gly153 and Tyr161, compound 4 however, forms hydrogen bonds with Ser135, Asp129, Phe130 and Ile86 instead. The results from the present study suggests that malabaricones C (3) and E (4) could be employed as lead compounds for the development of new dengue antivirals from natural origin.