QSAR exercises

  1. Deduce Correlations in Data
  2. Salicylamides; LogP etc.
  3. Fluoroquinolone Antibacterials
  4. Phthalides as potential antiepileptics
  5. Irritant properties of Phorbol esters
  6. Anticonvulsant Benzodiazepines
  7. Salicylamides binding at the D2 receptor

  1. See if you can deduce correlations for the following two sets of data.

  2. (i) Isonarcotic Activity in Tadpoles

    Esters, Ketones, and Ethers

    Alcohols

    Compound

    log (1/C)

    log P

    Compound

    log (1/C)

    log P

    CH3COCH3

    0.65

    -0.73

    CH3OH

    0.30

    -1.27

    CH3CO2CH3

    1.10

    -0.38

    C2H5OH

    0.50

    -0.75

    C2H5COCH3

    1.10

    -0.27

    (CH3)2CHOH

    0.90

    -0.36

    HCO2C2H5

    1.20

    -0.38

    (CH3)3COH

    0.90

    0.07

    C2H5COC2H5

    1.20

    0.59

    CH3CH2CH2OH

    1.00

    -0.23

    CH3CO2C2H5

    1.50

    0.14

    (CH3)2C(C2H5)OH

    1.20

    0.59

    C2H5COC2H5

    1.50

    0.31

    CH3(CH2)3OH

    1.40

    0.29

    CH3CH2CH2COCH3

    1.70

    0.31

    (CH3)2CHCH2OH

    1.40

    0.16

    CH3CO2CH2C2H5

    2.00

    0.66

    CH3(CH2)4OH

    1.60

    0.81

    C2H5CO2C2H5

    2.00

    0.66

         

    (CH3)2CHCO2C2H5

    2.20

    1.05

         

    Source: S.P. Gupta

    (ii)Growth Inhibition for Hamster Ovary Cells

    R

    IC50, mM

    Log1/IC50

    sigma

    pi

    H

    1.2

    -0.079

    0

    0.00

    m-NO2

    96

    -1.982

    0.71

    -0.28

    p-SO2Me

    174

    -2.241

    0.72

    -1.63

    m-SO2Me

    76

    -1.881

    0.63

    -1.63

    p-CONMe2

    14.6

    -1.164

    0.36

    -0.71

    m-CONMe2

    7.6

    -0.881

    0.35

    -0.71

    p-SMe

    1.62

    -0.210

    0

    0.61

    p-CH3

    0.4

    0.398

    -0.14

    0.56

    m-CH3

    1.2

    -0.079

    -0.06

    0.56

    p-OMe

    0.45

    0.347

    -0.28

    -0.02

    m-OMe

    2.7

    -0.431

    0.1

    -0.02

    p-NH2

    0.071

    1.149

    -0.66

    -1.23

    m-NH2

    0.38

    0.420

    -0.16

    -1.23

    Source: C. Hansch


  3. Salicylamides. Define the terms logP and pi, and briefly describe how they are obtained. The influence of the aromatic substituent X in a series of monosubstituted salicylamides on their ability to displace [3H]-spiperone (measured by IC50 values in nM) leads to the equation


    salicylamide derivatives

     log(1/IC50) = 1.28 pi - 0.52 pi2 + 1.54

    n = 12     r2 = 0.94     s = 0.40    F = 19.9

    From the equation and the table below, what is the best value for pi, the corresponding IC50 value, and best substituent, X?
     

    Substituent H F Cl Br I NO2 CH3 C2H5 C3H5 C3H7

    pi

    0.00 0.14 0.71 0.86 1.12 -0.28 0.56 1.02 1.14 1.55



  4. Fluoroquinolone antibacterials. In QSAR studies of fluoroquinolone antibacterial agents,

    Ofloxacin Antibacterials


    the following two equations were used to determine the best substituents for positions
    1 and 8:

    for position 1 :   log (1/MIC)  =  -0.49 (L1)2  +  4.10 (L1)  -  2.00

    for position 8 :   log (1/MIC)  =  -1.00 (B4)2   +  3.73 (B4)  +  1.3

    (a)  Define the parameters L1, B4  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 L1 and B values
     

    Substituents H F Cl Br I Me Et i-Pr t-Bu i-Pentyl
    L1 2.06 2.65 3.52 3.83 4.23 3.00 4.11 4.11 4.11 4.73
    B4 1.00 1.35 1.80 1.95 2.15 2.04 2.97 3.16 2.97 3.99



  5. Phthalides from Celery.  Since antiquity, celery extracts have been used in Chinese folk medicine to treat hypertension.  More recently, investigations have also shown that celery seeds contain an oily liquid, 3-(S)-n-butylphthalide, which also has potential for development as an anti-epileptic agent.

    butylphthalides

    QSAR analysis of a set of 6-substituted analogues of 3-(S)-n-butylphthalide gave the following Hansch equation.  In the equation, ED50 (mol kg-1) is the effective dose to protect mice against spasms induced by maximum electric shock.

    log 1/ED50  = 0.74 log P - 0.13 (log P )2 + 0. 35 MR6 + 2.23

         n = 24  r = 0.91  s = 0.15  F = 33.12

    (a) Define the terms log P and MR6.  How does log P differ from the parameter, pi ?

    (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 MR6.

    (d) From the table given below, what is the best substituent for the 6-position?

    (e) Calculate the corresponding ED50 for your 6-substituted 3-(S)-n-butylphthalide.

    (f) The 6-amino ( 6-NH2- ) analogue, has a log 1/ED50  of 4.40.  Compare this value with your ED50 and offer a possible explanation for any difference.
     

    R6 H OH Cl Br NO2 CN CONH2
    logP 3.12 3.12 3.53 4.24 2.92 2.39 2.25
    MR6 0.10 0.29 0.60 0.80 0.74 0.63 0.98



  6. Phorbol Esters. Two researchers studied the irritant properties of a series of phorbol esters.

    Phorbol and phorbol esters

    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 curve-fitting are given under the plots.

    phorbol esters

    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 pi.

    (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 pi 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(C2) butyl(C4) hexyl(C6) octyl(C8) decyl(C10) dodecyl(C12) tetradecyl(C14)
    pi 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.



  7. Anticonvulsant Benzodiazepines. A study of the affect on anticonvulsant activity of substituents, R, in 1,4-benzodiazepinones (structure shown) gave the following regression equation:


    Benzodiazepine

    Log 1/C = -0.31pi2 + 0.14pi +1.29 sigma + 4.56

    n = 10 r = 0.87 s = 0.47

    C is the ED50 concentration (moles per kilogram), in the anti-pentylenetetrazol induced seizure test in mice, a measure of anticonvulsant activity.

    (a) Define pi and  sigma.

    (b) Comment briefly on the validity of the equation.

    (c) Determine the best values for pi and sigma  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 1,4-benzodiazepinone, what is the log P for your substituted 1,4-benzodiazepinone?
     

    Substituents NH2 OH CN NO2 H F SO2Ph OEt CH3 Cl CF3 N(Et)2
    pi -1.23 -0.67 -0.57 -0.28 0.0 0.14 0.270 0.38 0.56 0.71 0.88 1.18
    sigma -0.66 -0.37 0.66 0.78 0.0 0.06 0.70 -0.24 -0.17 0.23 0.54 -0.90



  8. Salicylamides. A series of mono-substituted salicylamides was investigated to determine the influence of the aromatic substituent, X, on their ability to displace 3H-spiperone from dopamine D2 receptors in vitro.  Analysis of the resulting data gave the following Hansch equation:

    log  1/IC50 =  1.28pi - 0.52pi2 - 0.69sigmam + 1.50      

    n = 12, r2 = 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, pi and  sigmam?

    (c) From the table of substituents, what is the best substituent for X?

    (d) What is the IC50 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 3-D plot for the above equation.

    X CONH2 NH2 OH CN NHCH3 NO2 NHC2H5 NMe2 NHC3H7 NHC4H9
    pi -1.49 -1.23 -0.67 -0.57 -0.47 -0.28 0.08 0.18 0.62 1.16
    sigmam 0.28 -0.16 0.12 0.56 -0.30 0.71 -0.24 -0.15 -0.24 -0.34

Index

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