Table 3. hRSV CPE Assay Potency, Cytotoxicity, Selectivity Index, Logarithmic Reduction in Viral Plaques, and Solubility Assessments for Analogs with Tandem Structural Variations in the (R1) and (R2) Regions of Hit Compound 2.
| solubility (μM) |
|||||||||
|---|---|---|---|---|---|---|---|---|---|
| entry | cmpd | R1 | R2 | RSV CPE potency ± standard deviation EC50 (μM)a | HEp-2 cellular toxicity ± standard deviation CC50 (μM)b | selectivity index (CC50/ EC50) | viral titer reduction at 10 μM (log) | PBSc | mediad |
| 1 | 2 | CH2-4-methylphenyl | NH(CH2)3OCH3 | 2.1 ± 0.5e | >50.0e | >23.8 | 4.2 | 0.1 | 2.5 |
| 2 | 43 | CH2-4-nitrophenyl | NHCH2-3-oxetane | 1.3 ± .05 | .05 > 50.0 | >38.5 | >6.2 | 1.4 | 7.2 |
| 3 | 44 | CH2-4-i-propylphenyl | NHCH2-3-oxetane | 0.4 ± .01 | 3.6 ± .08 | 9.0 | 5.8 | NT | NT |
| 4 | 45 | CH2-4-CO2H-phenyl | NHCH2-3-oxetane | >50.0 | >50.0 | NA | NT | 98.1 | NT |
| 5 | 46 | CH2-4-N(CH3)2-phenyl | NHCH2-3-oxetane | 1.1 ± 0.2 | 44.7 ± 7.2 | 41.8 | >6.2 | 11.2 | 18.5 |
| 6 | 47 | CH2-4-tert butylphenyl | NHCH2-3-oxetane | 1.6 ± .08 | 3.7 ± 0.3 | 2.3 | 3.4 | NT | NT |
| 7 | 48 | CH2-4-i-propylphenyl | NHCH2-2-furyl | 1.2 ± 0.1 | >50.0 | >41.7 | 2.8 | 0.3 | NT |
| 8 | 49 | CH2-4- chlorophenyl | NHCH2-2-furyl | 0.8 ± .01 | >50.0 | >62.5 | NT | NT | 10.2 |
| 9 | 50 | CH2-4-i-propylphenyl | NH-2-CH3O-pyridyl | 0.5 ± .06 | <1.6 | <3.3 | NT | NT | NT |
a
Data were an average of ≥3 experiments.
b
Data are an average of ≥2 experiments.
c
Kinetic solubility in 1×PBS, pH 7.4.
d
Kinetic solubility in CPE assay media: (DMEM/F12(r) (Sigma, Cat # D6434)/1×Pen/Strep/Glutamine (Gibco, Cat # 10378)/2% Heat Inactivated FBS (Gibco Cat # 10082)). NT = not tested; NA = not applicable. Data were analyzed using Microsoft Excel 2010.
e
Data were an average of outcomes from two separate lots of compound 2.