(i) Isonarcotic Activity in Tadpoles 

Esters, Ketones, and Ethers 
Alcohols  
Compound 
log (1/C) 
log P 
Compound 
log (1/C) 
log P 
CH_{3}COCH_{3} 
0.65 
0.73 
CH_{3}OH 
0.30 
1.27 
CH_{3}CO_{2}CH_{3} 
1.10 
0.38 
C_{2}H_{5}OH 
0.50 
0.75 
C_{2}H_{5}COCH_{3} 
1.10 
0.27 
(CH_{3})_{2}CHOH 
0.90 
0.36 
HCO_{2}C_{2}H_{5} 
1.20 
0.38 
(CH_{3})_{3}COH 
0.90 
0.07 
C_{2}H_{5}COC_{2}H_{5} 
1.20 
0.59 
CH_{3}CH_{2}CH_{2}OH 
1.00 
0.23 
CH_{3}CO_{2}C_{2}H_{5} 
1.50 
0.14 
(CH_{3})_{2}C(C_{2}H_{5})OH 
1.20 
0.59 
C_{2}H_{5}COC_{2}H_{5} 
1.50 
0.31 
CH_{3}(CH_{2})_{3}OH 
1.40 
0.29 
CH_{3}CH_{2}CH_{2}COCH_{3} 
1.70 
0.31 
(CH_{3})_{2}CHCH_{2}OH 
1.40 
0.16 
CH_{3}CO_{2}CH_{2}C_{2}H_{5} 
2.00 
0.66 
CH_{3}(CH_{2})_{4}OH 
1.60 
0.81 
C_{2}H_{5}CO_{2}C_{2}H_{5} 
2.00 
0.66 

(CH_{3})_{2}CHCO_{2}C_{2}H_{5} 
2.20 
1.05 
Source: S.P. Gupta
(ii)Growth Inhibition for Hamster Ovary Cells 

R 
IC_{50, }mM 
Log1/IC_{50} 


H 
1.2 
0.079 
0 
0.00 
mNO_{2} 
96 
1.982 
0.71 
0.28 
pSO_{2}Me 
174 
2.241 
0.72 
1.63 
mSO_{2}Me 
76 
1.881 
0.63 
1.63 
pCONMe_{2} 
14.6 
1.164 
0.36 
0.71 
mCONMe_{2} 
7.6 
0.881 
0.35 
0.71 
pSMe 
1.62 
0.210 
0 
0.61 
pCH_{3} 
0.4 
0.398 
0.14 
0.56 
mCH_{3} 
1.2 
0.079 
0.06 
0.56 
pOMe 
0.45 
0.347 
0.28 
0.02 
mOMe 
2.7 
0.431 
0.1 
0.02 
pNH_{2} 
0.071 
1.149 
0.66 
1.23 
mNH_{2} 
0.38 
0.420 
0.16 
1.23 
Source: C. Hansch
log(1/IC_{50}) = 1.28  0.52 ^{2} + 1.54
n = 12 r^{2} = 0.94 s = 0.40 F = 19.9
From the equation and the table below, what is the best value for , the
corresponding IC_{50} value, and best substituent, X?
Substituent  H  F  Cl  Br  I  NO_{2}  CH_{3}  C_{2}H_{5}  C_{3}H_{5}  C_{3}H_{7} 

0.00  0.14  0.71  0.86  1.12  0.28  0.56  1.02  1.14  1.55 
the following two equations were used to determine the best
substituents for positions
1 and 8:
for position 1 : log (1/MIC) = 0.49 (L_{1})^{2} + 4.10 (L_{1})  2.00
for position 8 : log (1/MIC) = 1.00 (B_{4})^{2} + 3.73 (B_{4}) + 1.3
(a) Define the parameters L_{1}, B_{4} and MIC.
(b) From the equations
(c) Briefly describe the mode of action of the fluoroquinolone antibacterial agents and suggest how the QSAR results support this mechanism. (See T. Rosen's work)
Table of L_{1} and B_{4 }
values
Substituents  H  F  Cl  Br  I  Me  Et  iPr  tBu  iPentyl 
L_{1}  2.06  2.65  3.52  3.83  4.23  3.00  4.11  4.11  4.11  4.73 
B_{4}  1.00  1.35  1.80  1.95  2.15  2.04  2.97  3.16  2.97  3.99 
QSAR analysis of a set of 6substituted analogues of 3(S)nbutylphthalide gave the following Hansch equation. In the equation, ED_{50} (mol kg^{1}) is the effective dose to protect mice against spasms induced by maximum electric shock.
log _{} = 0.74 log P  0.13 (log P )^{2} + 0. 35 MR_{6} + 2.23
n = 24 r = 0.91 s = 0.15 F = 33.12
(a) Define the terms log P and MR_{6}. How does log P differ from the parameter, ?
(b) Comment briefly on the significance of the values of n, r, s and F. How valid is this equation?
(c) Determine the best combination of values for log P and MR_{6.}
(d) From the table given below, what is the best substituent for the 6position?
(f) The 6amino ( 6NH_{2} ) analogue, has a log _{}
of 4.40. Compare this value with your ED_{50} and
offer a possible explanation for any difference.
R_{6}  H  OH  Cl  Br  NO_{2}  CN  CONH_{2} 
logP  3.12  3.12  3.53  4.24  2.92  2.39  2.25 
MR_{6}  0.10  0.29  0.60  0.80  0.74  0.63  0.98 
They plotted the same data for concentration, C, to produce skin irritancy in the mouse ear test versus log P values, but fitted the two different curves, A and B. The statistics for each curvefitting are given under the plots.
Curve A statistics  Curve B statistics 
n = 6; r = 0.98; s = 0.32; F = 32.39  n = 6; r = 1.00; s = 0.04; F = 1,389.47 
(a) Define log P and .
(b) Decide which of the two plots gives the best fit to the data, giving reasons. From the curve you have chosen, what is the best value for log P and for C?
(c) From the table below of values of alkyl groups, calculate which group gives the best activity for phorbol esters. Log P of the parent molecule, phorbol, is 0.12.
R  ethyl(C_{2})  butyl(C_{4})  hexyl(C_{6})  octyl(C_{8})  decyl(C_{10})  dodecyl(C_{12})  tetradecyl(C_{14}) 
0.87  1.93  3.00  4.06  5.12  6.18  7.25 
(d) Give an explanation for the trend shown by the curve shapes above
in terms of the structures and physicochemical properties of the
phorbol esters.
Log 1/C = 0.31^{2} + 0.14 +1.29 + 4.56
n = 10 r = 0.87 s = 0.47
C is the ED_{50 }concentration (moles per kilogram), in the antipentylenetetrazol induced seizure test in mice, a measure of anticonvulsant activity.
(a) Define and .
(b) Comment briefly on the validity of the equation.
(c) Determine the best values for and that give maximum anticonvulsant activity.
(d) From the table below, which substituent is the best choice to give this maximum? What physicochemical properties does the substituent have?
(e) If log P is 2.11 for the unsubstituted 1,4benzodiazepinone, what
is the log P for your substituted 1,4benzodiazepinone?
Substituents  NH_{2}  OH  CN  NO_{2}  H  F  SO_{2}Ph  OEt  CH_{3}  Cl  CF_{3}  N(Et)_{2} 
1.23  0.67  0.57  0.28  0.0  0.14  0.270  0.38  0.56  0.71  0.88  1.18  
0.66  0.37  0.66  0.78  0.0  0.06  0.70  0.24  0.17  0.23  0.54  0.90 
log _{} = 1.28  0.52^{2 } 0.69_{m }+ 1.50
n = 12, r^{2 }= 0.94, s = 0.40, F = 19.9
(a) How valid is the equation? Briefly describe how this type of equation is obtained.
(b) What are the best values for the substituent parameters, and _{m}?
(c) From the table of substituents, what is the best substituent for X?
(d) What is the IC_{50} for the salicylamide with the substituent you have chosen?
(e) Briefly comment on how the properties of this substituent contribute to the activity of the salicylamide.
(f) Sketch the general shape of the 3D plot for the above equation.
X  CONH_{2}  NH_{2}  OH  CN  NHCH_{3}  NO_{2}  NHC_{2}H_{5}  NMe_{2}  NHC_{3}H_{7}  NHC_{4}H_{9} 
1.49  1.23  0.67  0.57  0.47  0.28  0.08  0.18  0.62  1.16  
_{m}  0.28  0.16  0.12  0.56  0.30  0.71  0.24  0.15  0.24  0.34 
For help contact Ted Lloyd