QSAR attempts to quantify physicochemical properties like hydrophobicity, electronics, and steric effects and relate them to biological activity. Log P measures hydrophobicity and is often plotted against biological activity, sometimes giving a straight line and other times a parabolic curve. Other parameters like π, σ, and Es measure substituent hydrophobicity, electronic effects, and steric effects. QSAR equations combine these parameters to model and predict biological activity for a series of compounds.

5. Log P: Hydrophobicity

7. Log P Note that one is not always measuring biological activity, sometimes binding!

8. *RELATIVELY FEW DRUGS EXIST WHOSE ACTIVITY IS RELATED TO LOG P ALONE!!! --those that do are the general anesthetics--partition into cell membranes, & thereby affect membrane structure & nerve function --no specific drug-receptor interactions

9. Log P Values: Uses With these equations for anesthetics (ethers only), it is possible to predict activity if log P known (doesn’t work if structure very different) ether chloroform halothane 0.98 1.97 2.3 (anesthetic activity increases in same order) Drugs with Log P values close to 2 should be able to enter the CNS efficiently e.g . barbiturates have log P values close to 2 also; want to make sure log P value is much lower if you don’t want possible CNS side effects

10. Example: decreased CNS side effects

14.  values for various substituents on aromatic rings Theoretical Log P for chlorobenzene = log P for benzene +  for Cl = 2.13 + 0.71 = 2.84 0.14 0.86 0.71 1.16 -1.49 -0.67 1.68 0.52 F Br Cl CF 3 CONH 2 OH t-Bu CH 3

15.  values for various substituents on aromatic rings Theoretical Log P for meta-chlorobenzamide = log P for benzene +  for Cl +  for CONH 2 = 2.13 + 0.71 - 1.49 = 1.35 0.14 0.86 0.71 1.16 -1.49 -0.67 1.68 0.52 F Br Cl CF 3 CONH 2 OH t-Bu CH 3

17. Electronic Effects: The Hammett Constant  Hammett constant (1940)  Measure e-withdrawing or e-donating effects (compared to benzoic acid & how affected its ionization)

18. Electronic Effects: The Hammett Constant  Electron Withdrawing Groups: Equilibrium shifts Right & K x > K benzoic Since  x = log K x – log K benzoic , then  will be positive .  x = log (K x /K benzoic )

19. Electronic Effects: The Hammett Constant  e-withdrawing groups stabilize the carboxylate ion: larger Kx, and have positive  values e.g. Cl, CN, CF 3 e-donating groups (e.g. alkyl) equilibrium shifts left (favoring unprotonated): lower Kx and negative  values

20. Hammett Constants Hammett constant takes into account both resonance and inductive effects; thus, the value depends on whether the substituent is para or meta substituted -- ortho not measured due to steric effects In some positions only inductive effects effect & some both resonance & inductive effects play a part aliphatic electronic substituent constants are also available

21. Uses Only one known example where just Hammett constants effectively predict activity (insecticides, diethyl phenyl phosphates. These drugs do not have to pass into or through a cell membrane to have activity). Log (1/C) = 2.282  – 0.348

22. Steric Effects  much harder to quantitate Examples are:  Taft’s steric factor (Es) (~1956), an experimental value based on rate constants  Molar refractivity (MR)-- measure of the volume occupied by an atom or group--equation includes the MW, density, and the index of refraction--  Verloop steric parameter --computer program uses bond angles, van der Waals radii, bond lengths

27. Hansch equations log 1/C = 1.22  – 1.59  + 7.89 (n=22; s=0.238; r= 0.918 log 1/C = 0.398  + 1.089  + 1.03 Es + 4.541 (n=9; r= 0.955) log C b = 0.765  = 0.540  2 + 1.505 log 1/c = 1.78  – 0.12  + 1.674