Page 21 - I. Chemical biology and drug discovery

Synthesis and biological evaluation of gramistilbenoids and vinyl-stilbene series

Dipesh S. Harmalkar, Sreenivasulu Godesi, DongIk Kwak, and Kyeong Lee*
College of Pharmacy, Dongguk University-Seoul, Goyang, Republic of Korea ,10326
INTRODUCTION

• Norovirus (NV), is the most common cause of acute gastroenteritis worldwide which causes approximately 200,000 deaths annually and estimated to cost
$60 billion worldwide due to healthcare costs and lost productivity. To date, there have been no specific drugs or vaccines to treat NV infections; thus, there
is a pressing need to develop effective anti-NV therapeutics.
• We evaluated the inhibitory effect of natural stilbenes, Gramistilbenoids A-C (isolated from Arundina Graminifolia) and different stilbene-based analogs on
RNA genome replication of human NV (HNV) using a virus replicon-bearing cell line (HG23) which led to the identification of a hit containing stilbene
scaffold 5.
• Compound 18k demonstrated an excellent safety profile, the highest suppressive effect, and was selective for HNV replication via a viral RNA polymerase-
independent manner. Its potential host-targeting antiviral mechanism was further supported by specific activation of heat shock factor 1-dependent stress-
inducible pathway by 18k. These results suggest that 18k might be a promising lead compound for developing novel NV inhibitors with the novel antiviral
mechanism.

RESULTS & DISCUSSION

Table 1. Dose-dependent Response of Compounds 16c, 18e, 18f, and 18k a A
Dose-dependent response o Does-
n cell viability and NV Therapeutic dependent
replication response on
Comp index viral protein
CC /EC
CC (µM) EC (µM) 50 50 expression
50
50
EC 50 (µM)
16c > 10 4.4 > 2.2 8.0
18e > 100 2.0 > 50 0.71
B
18f > 100 1.44 > 69 1.97

18k > 100 2.43 > 41.2 0.8

2CMC b 12.2 4.0 3.1 4.8
Table 2 . Liver Microsomal Stability Assay a Fig. 1. Dose-dependent effects of 18e, 18f, and

Metabolic Stability Assay 18k on (A) HNV replication; (B) HNV viral
protein expression B
A C
Human (%) Mouse (%)
Comp
(+) NADP (+) NADP
(-) NADPH (-) NADPH
H H
Fig. 2. (A) Effects of the representative compounds 18e, 18f,
18e 20.0 92.1 67.7 88.4 and 18k on HNV RdRp activity at 10 µM. PPNDS was used as
a positive control; (B) Dose-dependent effects of 18k on MNV-
18f 44.1 > 100 38.3 83.1 1 and (C) Dose-dependent effects of 18k on FCV infections.

18k 89.1 94.3 70.5 99.2 ACKNOWLEDGEMENTS

Verapamil 13.6 - - - This work was supported by the National
Research Foundation of Korea (NRF), grant
CONCLUSION REFERENCES funded by the Korea government (MSIT). (No.
2018R1A5A2023127 and
• An additional series of structurally-diverse stilben 2016R1D1A1B03933100).
oids was synthesized and evaluated based on the h • D. S. Harmalkar; Q. Lu; K. Lee; J.
it compound 5, resulting in the identification of no Nat. Prod. 2018, 81, 798-805. Contact information
vel NV inhibitors that inhibited NV replication in • D. S. Harmalkar; S. J. Lee; Q. Lu; M.
the very low μM or sub-μM range. I. Kim; J. Park; H. Lee; M. Park; A.
Lee; C. Lee; K. Lee; Eur. J. Med.
• Compounds 18e, 18f, and 18k exhibited excellent Chem. 184 (2019) 111753.
anti-NV activity with TIs in the range of 40 to 70.