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. Author manuscript; available in PMC: 2014 Mar 28.
Published in final edited form as: J Med Chem. 2013 Mar 7;56(6):2270–2282. doi: 10.1021/jm301643a

Table 1.

Biological results obtained for derivatives 3a, 4a-j, 5a, and 6a.

graphic file with name nihms453870t1.jpg
cpds R R' SPR on
NS5B
 NS5B
functional
assay
 Replicon assay on Huh 5-2 cells
 LLE (KD)g LLE (IC50)h
KD
(µM)a 		IC50
(µM)b 		EC50
(µM)c 		EC90
(µM)d 		CC50
(µM)e 		SIf
3a 3-F OMe >300 NDi, j 172 ± 10 NDi >323 2 - -
4a 3-F graphic file with name nihms453870t2.jpg 75±12 21.0±2.8 7.5 ± 2.5 42 ± 2 >370 >49 1.85 2.40
4b 2-F graphic file with name nihms453870t3.jpg 162±63 14.2±0.6 6.4 ± 0.2 NDi >231 >36 1.61 2.66
4c 4-F graphic file with name nihms453870t4.jpg NDi 3.9±0.3 23 ± 13 NDi >231 >10 - 3.11
4d H graphic file with name nihms453870t5.jpg 53±6 19.8±3.6 14 ± 1 NDi >239 >17 2.18 2.61
4e 3-NO2 graphic file with name nihms453870t6.jpg 14±6 NDi, j >220 >220 >220 ≥1 3.41 -
4f 2-NO2 graphic file with name nihms453870t7.jpg 35±3 20±0.4 17.8 ± 0.1 NDi >220 >12.4 2.84 3.09
4g 4-NO2 graphic file with name nihms453870t8.jpg NDi 7.7±1.3 7.9 ± 1.0 NDi 55 ± 8 7.0 - 3.80
4h 3-NH2 graphic file with name nihms453870t9.jpg 163±8 NDi, j 9.2 ± 0.9 NDi 20 ± 6 2.2 2.52 -
4i 2-NH2 graphic file with name nihms453870t10.jpg 106±42 39.9±1.7 26 ± 2 NDi >232 >9 2.66 3.08
4j 4-NH2 graphic file with name nihms453870t11.jpg 165±16 18.2±2.1 12 ± 1 NDi 25 ± 5 2 2.53 3.48
5a 3-F graphic file with name nihms453870t12.jpg 161±103 NDi, j 19 ± 2 NDi >270 >14 0.99 -
6a 3-F graphic file with name nihms453870t13.jpg 63±8 NDi, j 88 ± 10 NDi >185 >2 1.87 -
a

KD= Dissociation equilibrium constant. At this concentration 50% of all binding site are occupied. Values as averages and standard deviation (SD) from duplicate or triplicate runs.

b

IC50 = concentration of compound that inhibits 50% enzyme activity in vitro. The reported values represent the means ± SD of data derived from two independent experiments performed in duplicate.

c

EC50 = the effective concentration required to inhibit virus induced cytopathic effect by 50%. The reported values represent the means ± SD of data derived at least from three independent experiments.

d

EC90 = the effective concentration required to inhibit virus induced cytopathic effect by 90%. The reported value represents the means ± SD of data derived at least from three independent experiments.

e

CC50 = is the concentration required to reduce the bioreduction of MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxy-phenyl)-2-(4-sulfophenyl)-2H-tetrazolium) into formazan by 50%. The reported value represents the means ± SD of data derived at least from three independent experiments.

f

SI = selectivity index (ratio of CC50 to EC50).

g

LLE(KD) = pKD – predicted logP.

h

LLE(IC50) = pIC50 – predicted logP.

i

ND = not determined.

j

Compounds that did not reach the 50% inhibition and show a maximum % inhibition @ 50 µM: 3a 10.6%, 4e 33.7%, 4h 45.8%, 6a 21.4%, 5a 31.5%.