Table 4.
Inactivation rate constants (ki) of isoxazol-3-yl dialkylcarbamates for rAgAChE (WT and G119S), and rhAChE (h)
| Compound | R | WT ki (mM−1 min−1)a | G119S ki (mM−1 min−1)a | h ki (mM−1 min−1)a | WT/G119S SRb |
|---|---|---|---|---|---|
| 15a | Me | 0.0323 ± 0.0082c | 0.0224 ± 0.0125 | 0.118 ± 0.019 | 1.4 ± 0.9 |
| 15b | c-Pr | 3.02 ± 0.13 | 0.30 ± 0.03 | 2.02 ± 0.27 | 10 ± 1 |
| 15c | i-Pr | 7.71 ± 0.20 | 0.50 ± 0.04 | 4.46 ± 0.12 | 15 ± 1 |
| 15d | c-Bu | 6.84 ± 0.20 | 0.44 ± 0.04 | 1.86 ± 0.10 | 16 ± 2 |
| 15e | s-Bu | 323 ± 6 | 20.4 ± 0.6 | 60.1 ± 1.8 | 16 ± 1 |
| 15f | c-pentyl | 64.7 ± 2.7 | 1.94 ± 0.04 | 4.62 ± 0.07 | 33 ± 2 |
| 15g | 2-pentyl | 416 ± 7 | 30.6 ± 0.5 | 50.9 ± 1.0 | 14 ± 1 |
| 15h | 3-pentyl | 221 ± 7 | 10.5 ± 0.7 | 9.04 ± 0.31 | 21 ± 2 |
| 15i | 3-heptyl | 2.85 ± 0.11 | 0.26 ± 0.01 | 2.13 ± 0.09 | 11 ± 1 |
| 15j | i-Bu | 10.6 ± 0.5 | 0.87 ± 0.06 | 1.59 ± 0.08 | 12 ± 1 |
| 15k | 2-methylbutyl | 7.64 ± 0.21 | 0.50 ± 0.05 | 1.70 ± 0.09 | 15 ± 2 |
| 15l | neo-pentyl | 0.12 ± 0.03 | 0.05 ± 0.01 | 0.44 ± 0.04 | 2.4 ± 0.7 |
| 15m | 3- methylbutyl | 3.12 ± 0.16 | 0.37 ± 0.03 | 1.91 ± 0.04 | 8.3 ± 0.8 |
| 15n | CH2CH2-c-Pr | 23.5 ± 1.1 | 2.01 ± 0.05 | 8.26 ± 0.26 | 12 ± 1 |
| 15o | CH2CH2-c-Bu | 5.08 ± 0.23 | 0.62 ± 0.03 | 7.24 ± 0.90 | 8.2 ± 0.6 |
| 15p | CH2CH2-c-C5H9 | 0.60 ± 0.05 | 0.12 ± 0.03 | 13.1 ± 0.4 | 5.2 ± 1.2 |
| 23g | 2-pentyl | 24.5 ± 0.5 | 3.37 ± 0.20 | 9.14 ± 1.97 | 7.3 ± 0.5 |
| 25g | 2-pentyl | 12.4 ± 0.1c | 2.24 ± 0.08c | 1.62 ± 0.07c | 5.5 ± 0.2 |
| 26g | 2-pentyl | 18.6 ± 0.3c | 2.30 ± 0.10c | 2.68 ± 0.06c | 8.1 ± 0.4 |
a
Measured at 23 ± 1°C, pH 7.7, 0.1% (v/v) DMSO. Recombinant sources of AgAChE are rAgAChE-WT and rAgAChE-G119S.
b
Enzymatic sensitivity ratio (SR) is calculated as ki(WT)/ki(G119S). Standard error in the ratio is calculated according to a standard propagation of error formula.20
c
ki values extrapolated from single point incubation at various inhibitor concentration, e.g. t = 10 min.