Investigation of the mechanism of action of nickel(II) complexes of camphor-based dithiocarbazate Schiff bases against dengue virus envelope protein.

Dengue incidences are soaring high nowadays with the reported cases in Malaysia alone are up by 211% compared to the same period in 2022. Despite the estimation that 6 billion people are at risk of dengue infection, there is still no approved therapeutic drugs available to cure the disease. Our preliminary findings demonstrated that some nickel(II) complexes of camphor-based dithiocarbazate Schiff bases possess low IC50 of about 300 to 700 nM with high selectivity index against all dengue virus serotypes, possibly by targeting envelope protein. There remains room for the improvement of their anti-dengue efficacy following a recent discovery of different class of compounds with IC50 value in the picomolar range. However, the lack of understanding of the mechanism(s) of action (MOA) for these complexes has hindered the rational design for more safe and effective therapeutics. The present proposal hypothesizes that the Ni(II) complexes exert their inhibition by interacting within the groove region of envelope protein and prevent the membrane fusion with the host cells. Therefore, we propose herein the investigation of the MOA on the inhibition of envelope protein of these nickel(II) complexes, their interaction with the protein target, and identification of more potent inhibitors with similar MOA.