Patrick An Introduction to Medicinal Chemistry 3/e Chapter

Patrick An Introduction to Medicinal Chemistry 3/e Chapter

Patrick An Introduction to Medicinal Chemistry 3/e Chapter 13 QUANTITATIVE STRUCTUREACTIVITY RELATIONSHIPS (QSAR) 1 Contents 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. Introduction Hydrophobicity of the Molecule (4 slides) Hydrophobicity of Substituents (2 slides) Electronic Effects 4.1. Hammett Substituent Constant (s) (7 slides) 4.2. Electronic Factors R & F 4.3.

Aliphatic electronic substituents Steric Factors (3 slides) Hansch Equation (4 slides) Craig Plot (2 slides) Topliss Scheme (5 slides) Bio-isosteres Free-Wilson Approach (3 slides) Case Study (10 slides) 3D-QSAR (10 slides) 3D-QSAR Case Study(7 slides) [62 slides] 1 1. Introduction Aims To relate the biological activity of a series of compounds to their physicochemical parameters in a quantitative fashion using a mathematical formula Requirements Quantitative measurements for biological and physicochemical properties Physicochemical Properties Hydrophobicity of the molecule Hydrophobicity of substituents Most common

Electronic properties of substituents properties studied Steric properties of substituents 1 2. Hydrophobicity of the Molecule in octanol] Partition Coefficient P = [Drug [Drug in water] High P High hydrophobicity 1 2. Hydrophobicity of the Molecule Activity of drugs is often related to P e.g. binding of drugs to serum albumin (straight line - limited range of log P) Log (1/C) . . . . . . .. . 0.78

3.82 Log1C 0.75 logP + 2.30 Log P Binding increases as log P increases Binding is greater for hydrophobic drugs 1 2. Hydrophobicity of the Molecule Example 2 General anaesthetic activity of ethers (parabolic curve - larger range of log P values) Log (1/C) 1 2 Log C - 0.22(logP) + 1.04 logP + 2.16 Log P o Log P Optimum value of log P for anaesthetic activity = log Po 1

2. Hydrophobicity of the Molecule QSAR equations are only applicable to compounds in the same structural class (e.g. ethers) However, log Po is similar for anaesthetics of different structural classes (ca. 2.3) Structures with log P ca. 2.3 enter the CNS easily (e.g. potent barbiturates have a log P of approximately 2.0) Can alter log P value of drugs away from 2.0 to avoid CNS side effects 1 3.. Hydrophobicity of Substituents - the substituent hydrophobicity constant (p) A measure of a substituents hydrophobicity relative to hydrogen Tabulated values exist for aliphatic and aromatic substituents Measured experimentally by comparison of log Ps with parent structure Cl

CONH2 Example : Benzene (Log P = 2.13) Chlorobenzene (Log P = 2.84) Cl = 0.71 Benzamide (Log P = 0.64) CONH = -1.49 2 Positive values imply substituents are more hydrophobic than H Negative values imply substituents are less 1 hydrophobic than H 3.. Hydrophobicity of Substituents - the substituent hydrophobicity constant (p) The value of is only valid for parent structures It is possible to calculate log P using values

Example : Cl CONH2 meta-Chlorobenzamide Log P(theory) = log P(benzene) + Cl + CONH Log P (observed) = 2.13 + 0.71 - 1.49 = 1.35 = 1.51 A QSAR equation may include both P and . P measures the importance of a molecules overall hydrophobicity (relevant to absorption, binding etc) identifies specific regions of the molecule which might interact with hydrophobic regions in the binding site 1 2 4. Electronic Effects

4.1 Hammett Substituent Constant (s) The constant () a measure of the e-withdrawing or edonating influence of substituents It can be measured experimentally and tabulated (e.g. for aromatic substituents is measured by comparing the dissociation constants of substituted benzoic acids with benzoic acid) X X CO2H X=H CO2 + H [PhCO 2-] KH = Dissociation constant= [PhCO2H] 1 4.1 Hammett Substituent Constant (s) X= electron withdrawing group (e.g. NO2) X = electron

withdrawing X group X CO2H CO2 + H Charge is stabilised by X Equilibrium shifts to right KX > KH K X = log X = logKX - logKH KH Positive value 1 4.1 Hammett Substituent Constant (s) X= electron donating group (e.g. CH3) X = electron withdrawing X group X CO2H CO2

+ H Charge destabilised Equilibrium shifts to left KX < K H K X = log X = logKX - logKH KH Negative value 1 4.1 Hammett Substituent Constant (s) value depends on inductive and resonance effects value depends on whether the substituent is meta or para ortho values are invalid due to steric factors 1 4.1 Hammett Substituent Constant (s) EXAMPLES: p (NO2) meta-Substitution m (NO2) O N O

e-withdrawing (inductive effect only) DRUG para-Substitution O N O DRUG O N O DRUG O N O DRUG O

N O e-withdrawing (inductive + resonance effects) DRUG 1 4.1 Hammett Substituent Constant (s) EXAMPLES: m (OH) p (OH) meta-Substitution OH e-withdrawing (inductive effect only) DRUG para-Substitution OH OH OH

OH e-donating by resonance more important than inductive effect DRUG DRUG DRUG DRUG 1 4.1 Hammett Substituent Constant (s) QSAR Equation: O O X P OEt OEt log1C 2.282 - 0.348 Diethylphenylphosphates (Insecticides)

Conclusion : e-withdrawing substituents increase activity 1 4.2 Electronic Factors R & F R - Quantifies a substituents resonance effects F - Quantifies a substituents inductive effects 1 4.3 Aliphatic electronic substituents Defined by I Purely inductive effects Obtained experimentally by measuring the rates of hydrolyses of aliphatic esters Hydrolysis rates measured under basic and acidic conditions O O

Hydrolysis C X CH2 C OMe X CH2 OH + HOMe X= electron donating Rate I = -ve X= electron withdrawing Rate I = +ve

Basic conditions: Acidic conditions: Rate affected by steric + electronic factors Gives I after correction for steric effect Rate affected by steric factors only (see Es) 1 5. Steric Factors Tafts Steric Factor (Es) Measured by comparing the rates of hydrolysis of substituted aliphatic esters against a standard ester under acidic conditions Es = log kx - log ko k x represents the rate of hydrolysis of a substituted ester ko represents the rate of hydrolysis of the parent ester Limited to substituents which interact sterically with the tetrahedral transition state for the reaction Cannot be used for substituents which interact with the transition state by resonance or hydrogen bonding May undervalue the steric effect of groups in an intermolecular process (i.e. a drug binding to a receptor) 1

5. Steric Factors Molar Refractivity (MR) - a measure of a substituents volume MR = (n 2 - 1) (n 2 - 2) x mol. wt. density Correction factor Defines volume for polarisation (n=index of refraction) 1 5. Steric Factors Verloop Steric Parameter - calculated by software (STERIMOL) - gives dimensions of a substituent - can be used for any substituent Example - Carboxylic acid B4 O B

B3 3 B2 C O H B O C O B1 4 H L 1 6. Hansch Equation A QSAR equation relating various physicochemical properties to the biological activity of a series of compounds

Usually includes log P, electronic and steric factors Start with simple equations and elaborate as more structures are synthesised Typical equation for a wide range of log P is parabolic 2 + k logP + k + k Es + k Log1C k (log P ) 1 2 3 4 5 1 6. Hansch Equation Example: Adrenergic blocking activity of -halo--arylamines Y X

CH CH2 1 Log C NRR' 1.22 - 1.59 + 7.89 Conclusions: Activity increases if is +ve (i.e. hydrophobic substituents) Activity increases if is negative (i.e. e-donating substituents) 1 6. Hansch Equation Example: Antimalarial activity of phenanthrene aminocarbinols CH2NHR'R" (HO)HC X Y 1 2 Log C - 0.015 (logP) + 0.14 logP + 0.27 X + 0.40 Y + 0.65 X + 0.88 Y + 2.34 Conclusions: Activity increases slightly as log P (hydrophobicity) increases (note that the constant is only 0.14) Parabolic equation implies an optimum log Po value for activity

Activity increases for hydrophobic substituents (esp. ring Y) Activity increases for e-withdrawing substituents (esp. ring Y) 1 6. Hansch Equation Choosing suitable substituents Substituents must be chosen to satisfy the following criteria: A range of values for each physicochemical property studied values must not be correlated for different properties (i.e. they must be orthogonal in value) at least 5 structures are required for each parameter studied Substituent H Me Et n-Pr 0.00 0.56 1.02 1.50 MR 0.10 0.56 1.03 1.55 Substituent H Me 0.00 0.56 MR 0.10 0.56 n-Bu 2.13 1.96 Correlated values.

Are any differences due to or MR? OMe NHCONH2 I CN -0.02 -1.30 1.12 -0.57 0.79 1.37 1.39 0.63 No correlation in values Valid for analysing effects of and MR. 1 7. Craig Plot Craig plot shows values for 2 different physicochemical properties for various substituents Example: . . . . . .. . . . . . .. . . .

. . . . . . + 1.0 + - CF3SO 2 .75 CN CH3SO2 SO 2NH2 NO2 .50 OCF3 .25 CO2H -2.0

- -1.6 -1.2 -.8 -.4 SF5 CF3 CH3CO CONH2 .4 I Br Cl F .8 1.2

1.6 CH3CONH -.25 Me 2.0 + Et t-Butyl OCH3 OH + + -.50 NMe 2 NH2 -.75 - - -1.0

- - + 1 7. Craig Plot Allows an easy identification of suitable substituents for a QSAR analysis which includes both relevant properties Choose a substituent from each quadrant to ensure orthogonality Choose substituents with a range of values for each property 1 8. Topliss Scheme Used to decide which substituents to use if optimising compounds one by one (where synthesis is complex and slow) Example: Aromatic substituents H 4-Cl L 4-OMe

L M E E 4-CH3 L M E M 3,4-Cl2 L E 4-But 3-Cl L 3-CH3 2-Cl

4-NMe2 E E 3-NMe2 See Central Branch L 3-Cl M 3-Me-4-NMe2 4-NO2 M 3-CF3 3,5-Cl2 M 3-CF3-4-Cl 4-CF3 3-CF3-4-NO2 2,4-Cl2

4-NO2 3-NO2 4-F 4-NH2 1 8. Topliss Scheme Rationale Replace H with para-Cl (+ and +) Act. + and/or + advantageous add second Cl to increase and further Little change favourable unfavourable replace with Me (+ and -) Act.

+ and/or + disadvantageous replace with OMe (- and -) Further changes suggested based on arguments of and steric strain 1 8. Topliss Scheme Aliphatic substituents CH3 L E H; CH2OCH3 ; CH2SO2CH3 i-Pr M Et L E L

M Cyclopentyl E END CHCl2 ; CF3 ; CH2CF3 ; CH2SCH3 Ph ; CH2Ph M Cyclohexyl Cyclobutyl; cyclopropyl t-Bu CH2Ph CH2CH2Ph 1 8. Topliss Scheme Example Order of Synthesis SO2NH2 R 1 2 3

4 5 R H 4-Cl 3,4-Cl2 4-Br 4-NO2 Biological Activity High Potency M L E M * M= More Activity L= Less Activity E = Equal Activity 1 8. Topliss Scheme Example R

N N N N Order of Synthesis CH2CH2CO2H 1 2 3 4 5 6 7 8 R H 4-Cl 4-MeO 3-Cl 3-CF3 3-Br 3-I 3,5-Cl2

Biological Activity High Potency L L M L M L M * * * M= More Activity L= Less Activity E = Equal Activity 1 9. Bio-isosteres NC Substituent p m MR

CN O C C C CH3 -0.55 0.50 0.38 11.2 O CH3 0.40 0.84 0.66 21.5 S CH3 -1.58

0.49 0.52 13.7 O O O S CH3 S NHCH3 C NMe2 O O -1.63 0.72 0.60 13.5 -1.82 0.57 0.46 16.9 -1.51 0.36 0.35 19.2

Choose substituents with similar physicochemical properties (e.g. CN, NO2 and COMe could be bio-isosteres) Choose bio-isosteres based on most important physicochemical property (e.g. COMe & SOMe are similar in p; SOMe and SO2Me are similar in ) 1 10. Free-Wilson Approach Method The biological activity of the parent structure is measured and compared with the activity of analogues bearing different substituents An equation is derived relating biological activity to the presence or absence of particular substituents Activity = k1X1 + k2X2 +.knXn + Z Xn is an indicator variable which is given the value 0 or 1 depending on whether the substituent (n) is present or not The contribution of each substituent (n) to activity is determined by the value of kn Z is a constant representing the overall activity of the structures studied 1 10. Free-Wilson Approach

Advantages No need for physicochemical constants or tables Useful for structures with unusual substituents Useful for quantifying the biological effects of molecular features that cannot be quantified or tabulated by the Hansch method Disadvantages A large number of analogues need to be synthesised to represent each different substituent and each different position of a substituent It is difficult to rationalise why specific substituents are good or bad for activity The effects of different substituents may not be additive (e.g. intramolecular interactions) 1 0. Free-Wilson / Hansch Approach Advantages It is possible to use indicator variables as part of a Hansch equation - see following Case Study

1 11. Case Study QSAR analysis of pyranenamines (SK & F) (Anti-allergy compounds) O OH OH X 3 Y 4 NH O O O 5 Z 1 11. Case Study

O OH X 4 NH O O 19 structures were synthesised to study and 1 Log C 3 Y O Stage 1 OH - 0.14 - 1.35( )2 0.72 and = total values for and for all substituents

Conclusions: Activity drops as increases Hydrophobic substituents are bad for activity - unusual Any value of results in a drop in activity Substituents should not be e-donating or e-withdrawing (activity falls if is +ve or -ve) 1 5 Z 11. Case Study O OH OH X 3 Y 4 NH O O O

5 Stage 2 61 structures were synthesised, concentrating on hydrophilic substituents to test the first equation Anomalies a) 3-NHCOMe, 3-NHCOEt, 3-NHCOPr. Activity should drop as alkyl group becomes bigger and more hydrophobic, but the activity is similar for all three substituents b) OH, SH, NH2 and NHCOR at position 5 : Activity is greater than expected c) NHSO2R : Activity is worse than expected d) 3,5-(CF3)2 and 3,5(NHMe)2 : Activity is greater than expected e) 4-Acyloxy : Activity is 5 x greater than expected 1 Z 11. Case Study Theories O OH OH X 3 Y 4

NH O O O 5 Z a) 3-NHCOMe, 3-NHCOEt, 3-NHCOPr. Possible steric factor at work. Increasing the size of R may be good for activity and balances out the detrimental effect of increasing hydrophobicity b) OH, SH, NH2, and NHCOR at position 5 Possibly involved in H-bonding c) NHSO2R Exception to H-bonding theory - perhaps bad for steric or electronic reasons d) 3,5-(CF3)2 and 3,5-(NHMe)2 The only disubstituted structures where a substituent at position 5 was electron withdrawing e) 4-Acyloxy Presumably acts as a prodrug allowing easier crossing of cell membranes. The group is hydrolysed once across the membrane. 1 11. Case Study O OH

OH X 3 Y 4 NH O O O 5 Z Stage 3 Alter the QSAR equation to take account of new results 1 2 + 2.0(F- 5) + 0.39(345 -HBD) - 0.63(NHSO ) Log C 0.30 1.35( )

2 + 0.78(M - V) + 0.72(4- OCO) - 0.75 Conclusions (F-5) (3,4,5-HBD) (NHSO2) (M-V) 4-O-CO e-withdrawing group at position 5 increases activity (based on only 2 compounds though) H-bond donor group at positions 3, 4,or 5 is good for activity Term = 1 if a HBD group is at any of these positions Term = 2 if HBD groups are at two of these positions Term = 0 if no HBD group is present at these positions Each HBD group increases activity by 0.39 Equals 1 if NHSO2 is present (bad for activity by -0.63). Equals zero if group is absent. Volume of any meta substituent. Large substituents at meta position increase activity Equals 1 if acyloxy group is present (activity increases by 0.72). Equals 0 if group absent 1 11. Case Study O OH

OH X 3 Y 4 NH O O O 5 Z Stage 3 Alter the QSAR equation to take account of new results 1 2 + 2.0(F- 5) + 0.39(345 -HBD) - 0.63(NHSO ) Log C 0.30 1.35( )

2 + 0.78(M - V) + 0.72(4- OCO) - 0.75 The terms (3,4,5-HBD), (NHSO2), and 4-O-CO are examples of indicator variables used in the free-Wilson approach and included in a Hansch equation 1 11. Case Study O OH OH X 3 Y 4 NH O O O 5

Z Stage 4 37 Structures were synthesised to test steric and F-5 parameters, as well as the effects of hydrophilic, H-bonding groups Anomalies Two H-bonding groups are bad if they are ortho to each other Explanation Possibly groups at the ortho position bond with each other rather than with the receptor - an intramolecular interaction 1 11. Case Study O OH X 3 Y 4 NH O Stage 5 OH

O O 5 Z Revise Equation 1 2 2 Log 0.034( ) 0.33 + 4.3( F 5) + 1.3 ( R 5) 1.7( ) + 0.73(345- HBD)

C - 0.86 (HB- INTRA) - 0.69(NHSO2) + 0.72(4- OCO) - 0.59 a) Increasing the hydrophilicity of substituents allows the identification of an optimum value for ( = -5). The equation is now parabolic (-0.034 ( )2) b) The optimum value of is very low and implies a hydrophilic binding site c) R-5 implies that resonance effects are important at position 5 d) HB-INTRA equals 1 for H-bonding groups ortho to each other (act. drops -086) equals 0 if H-bonding groups are not ortho to each other e) The steric parameter is no longer significant and is not present 1 11. Case Study Stage 6 Optimum Structure and binding theory XH NH RHN X O OH C

CH CH2 OH C CH CH2 OH O OH X 3 5 NH X NH3 1 11. Case Study NOTES on the optimum structure It has unusual NHCOCH(OH)CH2OH groups at positions 3 and 5

It is 1000 times more active than the lead compound The substituents at positions 3 and 5 are highly polar, are capable of H-bonding, are at the meta positions and are not ortho to each other allow a favourable F-5 parameter for the substituent at position 5 The structure has a negligible (2 value 1 12. 3D-QSAR Physical properties are measured for the molecule as a whole Properties are calculated using computer software No experimental constants or measurements are involved Properties are known as Fields Steric field - defines the size and shape of the molecule

Electrostatic field - defines electron rich/poor regions of molecule Hydrophobic properties are relatively unimportant Advantages over QSAR No reliance on experimental values Can be applied to molecules with unusual substituents Not restricted to molecules of the same structural class Predictive capability 1 12. 3D-QSAR Method Comparative molecular field analysis (CoMFA) - Tripos Build each molecule using modelling software Identify the active conformation for each molecule Identify the pharmacophore OH HO NHCH3 HO Build 3D model Active conformation

Define pharmacophore 1 12. 3D-QSAR Method Comparative molecular field analysis (CoMFA) - Tripos Build each molecule using modelling software Identify the active conformation for each molecule Identify the pharmacophore OH HO NHCH3 HO Build 3D model Active conformation Define pharmacophore 1 12. 3D-QSAR Method

Place the pharmacophore into a lattice of grid points . . . . . Grid points Each grid point defines a point in space 1 12. 3D-QSAR Method Position molecule to match the pharmacophore . . . . . Grid points

Each grid point defines a point in space 1 12. 3D-QSAR Method A probe atom is placed at each grid point in turn . . . Probe atom . . Probe atom = a proton or sp3 hybridised carbocation 1 12. 3D-QSAR Method A probe atom is placed at each grid point in turn .

. . Probe atom . . Measure the steric or electrostatic interaction of the probe atom with the molecule at each grid point 1 12. 3D-QSAR Method The closer the probe atom to the molecule, the higher the steric energy Can define the shape of the molecule by identifying grid points of equal steric energy (contour line) Favourable electrostatic interactions with the positively charged probe indicate molecular regions which are negative in nature Unfavourable electrostatic interactions with the positively charged

probe indicate molecular regions which are positive in nature Can define electrostatic fields by identifying grid points of equal energy (contour line) Repeat the procedure for each molecule in turn Compare the fields of each molecule with their biological activity Can then identify steric and electrostatic fields which are favourable or unfavourable for activity 1 12. 3D-QSAR Method . . . .. Tabulate fields for each compound at each grid point Compound Biological Steric fields (S) Electrostatic fields (E) activity at grid points (001-998) at grid points (001-098) S001 S002 S003 S004 S005 etc E001 E002 E003 E004 E005 etc 1 5.1 2 6.8 3 5.3 4 6.4 5

6.1 Partial least squares analysis (PLS) QSAR equation Activity = aS001 + bS002 +..mS998 + nE001 +.+yE998 + z 1 12. 3D-QSAR Method Define fields using contour maps round a representative molecule 1 3. 3D-QSAR - CASE STUDY 13. Tacrine Anticholinesterase used in the treatment of Alzheimers disease NH2 N 1 3. 3D-QSAR - CASE STUDY 13. Conventional QSAR Study 12 analogues were synthesised to relate their activity with the

hydrophobic, steric and electronic properties of substituents at NH positions 6 and 7 9 2 R1 7 R2 6 N Substituents: CH3, Cl, NO2, OCH3, NH2, F (Spread of values with no correlation) 1 1 2 1 pIC = 3.09 MR(R ) + 1.43F(R , R ) + 7.00 Log C 50

Conclusions Large groups at position 7 are detrimental Groups at positions 6 & 7 should be electron withdrawing No hydrophobic effect 1 13. 3D-QSAR - CASE STUDY CoMFA Study Analysis includes tetracyclic anticholinesterase inhibitors (II) NH2 R1 8 R3 1 R2 2 N 7 R4 3 II

R5 Not possible to include above structures in a conventional QSAR analysis since they are a different structural class Molecules belonging to different structural classes must be aligned properly according to a shared pharmacophore 1 13. 3D-QSAR - CASE STUDY Possible Alignment Good overlay but assumes similar binding modes Overlay 1 13. 3D-QSAR - CASE STUDY X-Ray Crystallography A tacrine / enzyme complex was crystallised and analysed Results revealed the mode of binding for tacrine Molecular modelling was used to modify tacrine to structure (II) whilst still bound to the binding site (in silico) The complex was minimised to find the most stable binding mode for structure II The binding mode for (II) proved to be different from tacrine

1 13. 3D-QSAR - CASE STUDY Alignment Analogues of each type of structure were aligned according to the parent structure Analysis shows the steric factor is solely responsible for activity 7 6 Blue areas - addition of steric bulk increases activity Red areas - addition of steric bulk decreases activity 1 13. 3D-QSAR - CASE STUDY Prediction 6-Bromo analogue of tacrine predicted to be active (pIC50 = 7.40) Actual pIC50 = 7.18 NH2 Br N 1

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