Med chem unit2

Med chem unit2

1. * Medicinal chemistry is a chemistry-based discipline, also involving aspects of biological, medical and pharmaceutical sciences. It is concerned with the invention , discovery , design , identification and preparation of biologically active compounds , the study of their metabolism , the interpretation of their mode of action at the molecular level and the construction of structure-activity relationships (SAR). Drugs are strictly defined as chemical substances that are used to prevent or cure diseases in human, animals and plants.

2. * The word drug , therefore, imposes an action-effect context within which the properties of a substance are described. For example when a drug is defined as an analgesic, it means that it is used to treat pain ….. Thus a drug may described as having analgesic, vasodepressor, anticonvulsant, antibacterial, …….…etc properties.

3. * Drugs activity, solubility in plasma and distribution to various tissues is dependent on their physicochemical properties. Even the interaction of a drug with a receptor or an enzyme is dependent on characteristics of a drug molecule, such as ionization , electron distribution , polarity and electronegativity . To understand drug action, the physicochemical parameters that make this action possible should be also understood.

4. * Drug names: (nomenclature) Chemical 6-Chloro-3,4-dihydro-7-sulfamoyl-2H-1,2,4-benzothiadiazine 1,1-dioxide Trade Hydrodiuril ® , Hydroaquil ® , Esidrex ® , Urozide ® , Novohydrazide ® etc. Many others Generic Hydrochlorothiazide

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6. * Pharmaceutical Phase Pharmacokinetic Phase Pharmacodynamic Phase Dosage form Tablet, etc. Absorption Distribution Metabolism Excretion etc Drug action Drug-receptor Interaction

7. * The pH-Partition Hypothesis on Drug Absorption This theory provides a basic framework for understanding of drug absorption from the GIT and drug transport across the biological membrane. The principle points of this theory are: The GIT and other biological membranes act as lipid barriers. The un-ionized form of the acidic or basic drug is preferentially absorbed. Most drugs are absorbed by passive diffusion. The rate of drug absorption and the amount of drug absorbed are related to its oil-water partition coefficient, the more lipophilic the drug, the faster is its absorption. Weak acidic and neutral drugs may be absorbed from stomach but basic drugs are not.

8. * Ionization and pH at Absorption site The fraction of the drug existing in its un-ionized form in a solution is a function of both the dissociation constant and the pH of the solution at the absorption site. IONIZATION (pKa)

9. * It is a means of expressing a drug's solubility is lipid versus water. A drug is added to a two-phase solution of oil (or other organic solvent like 1-octanol) and water, mixed, and the concentration of drug in the organic and water phases determined. The ratio of the two phases reflects the relative lipid/water solubility. Partition Coefficient (Lipid/Water Partition Coefficient)

10. Lipid-Water Partition Coefficient The ratio of the concentration of the drug in two immiscible phases: a nonpolar liquid or organic solvent (representing the membrane); and an aqueous buffer, pH 7.4 (representing the plasma) *

11. Lipid-Water Partition Coefficient The higher the lipid/water p.c. the greater the rate of transfer across the membrane polarity of a drug, by increasing ionization will the lipid/ water p.c. polarity of a drug, suppression of ionization will the lipid/ water p.c. *

12. Lipid-Water Partition Coefficient The higher the lipid/water p.c. the greater the rate of transfer across the membrane polarity of a drug, by increasing ionization will the lipid/ water p.c. polarity of a drug, suppression of ionization will the lipid/ water p.c. *

13. * A drug’s partition coefficient, K org/aqu is an index of the drug’s lipophilicity. Log P = 1 means 10:1 Organic:Aqueous Log P = 0 means 1:1 Organic:Aqueous Log P = -1 means 1:10 Organic:Aqueous In general, assuming passive absorption Optimum CNS penetration around Log P = 2 +/- 0.7 Optimum Oral absorption around Log P = 1.8 Optimum Intestinal absorption Log P =1.35 Optimum Colonic absorption Log P = 1.32 Optimum Sub lingual absorption Log P = 5.5 Optimum Percutaneous Log P = 2.6 (& low mw )

14. * The partition ratio of a given drug will determine its solubility in plasma, its ability to traverse cell membranes, and which tissues it will reach. Drugs must have some aqueous solubility since this is essential for absorption through membranes, and for the production of an adequate concentration at the site-of-action. A balance between hydrophilicity and lipohilicity is necessary.  This must be taken into account when chemically modifying a drug for optimal activity.

15. * The relationship between physicochemical properties and drug action “Theoretical representations” Overton-Meyer Hypothesis The hypothesis states that, the higher the partition ratio P, the higher the pharmacological effect. The Ferguson Principle The concentration of a drug in plasma is directly proportional to its activity. Ferguson Constant is represented by X where:

16. * High thermodynamic activity means that the activity of the drug is based on its physicochemical properties only, such as in a gaseous anesthetic. Such drugs are known as non-specific agents .

17. * Low thermodynamic activity means that the activity of the drug is based on its structure rather than physicochemical properties. Agents in this category are called specific agents , and their activity at low concentrations infers that they have a specific receptor.

18. * Electronic Effects Hammett Substituent Constant ( σ ) The constant ( σ ) a measure of the e-withdrawing or e-donating influence of substituents It can be measured experimentally and tabulated (e.g. s for aromatic substituents is measured by comparing the dissociation constants of substituted benzoic acids with benzoic acid) X=H K H = Dissociation constant = [PhCO 2 - ] [PhCO 2 H]

19. * X= electron withdrawing group (e.g. NO 2 ) σ X = log K X K H = logK X - logK H Charge is stabilized by X Equilibrium shifts to right K X > K H Positive value Hammett Substituent Constant ( σ )

20. * X= electron donating group (e.g. CH 3 ) σ X = log K X K H = logK X - logK H Charge destabilized Equilibrium shifts to left K X < K H Negative value Hammett Substituent Constant ( σ ) X = electron donating group

21. * Hammett Substituent Coefficient

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23. * σ value depends on inductive and resonance effects σ value depends on whether the substituent is meta or para ortho values are invalid due to steric factors

24. * Linear free energy relationship

25. * ρ the slope of the line, is a proportionality constant pertaining to a given equilibrium. σ is a descriptor of the substituents ( Hammett constant ). The magnitude of σ gives the relative strength of the electron-withdrawing or -donating properties of the substituents. σ is positive if the substituent is electron-withdrawing and negative if it is electron-donating .

26. * Some illustrative values of ρ Some illustrative values of σ

27. * Applications of the Hammett Equation 1. Prediction of the pKa of ionization equilibria. For benzoic acid derivatives:

28. * Given σ meta = 0.71 for nitro groups and σ para = - 0.13 for methyl groups, the calculated pKa=2.91 , which compares favorably with the experimental value of 2.97.

29. * 2. Selection of the substituents for optimum biological activity. e.g. QSAR relating the inhibition of bacterial growth by a series of sulfonamides A QSAR was developed based on the σ values of the substituents where C is the minimum concentration of compound that inhibited growth of E. coli . It was found that electron-withdrawing substituents favor inhibition of growth.

30. * Hansch derived constants for the contributions of substituents to the partition coefficient. The lipophilicity constant, π , is defined as:   π = log Px - log PH = log (Px/PH) where Px is partition constant for the compound with X as substituent and PH is the partition constant for the parent. Tables of values of π for other substituents are available. Hansch Constant ( π )

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

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

33. * The following are the π values for various substituents on an aromatic ring: -CF3 (1.07), -Br (0.94), -OCH3 (-0.02), -CH2OH (-1.03). Which functional group listed above will increase the water solubility of the following drug the most (ie. we replace the R- group with one of the substituents). A) -CF 3 (1.07) B) -Br (0.94) C) -OCH 3 (-0.02) D) -CH 2 OH (-1.03) E) They will all make the drug equally lipophilic

34. * Steric Effects The third major factor that often must be considered in QSAR involves steric effects. For studies involving reactivity of organic compounds, a steric parameter, Es, was defined by Taft as : where k is the rate constant for the acid hydrolysis of esters of the type

35. * Assuming the electronic effects of substituent X can be ignored, the size of X will affect the transition state and hence the rate of reaction. By definition Es = 0 for X=H. Tables of values of Es for other substituents are available.

36. * 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 Steric Effects

37. * A drug's activity was really a function of two processes: its transportation from point of entry to receptor site(s) ( pharmacokinetics ). its interaction with the receptor ( pharmacodynamics ). Hansch proposed that the ability of a drug to get through a membrane might be modeled by its partition coefficient between a lipid-type solvent and water Hansch Approach

38. * The suggested model for a drug traveling through the body to its receptor site might be: log 1/C = - k(log P) 2 + k'(log P) + k" where potency is expressed as log (1/C) and C is the concentration of a drug that provides some standard biological effect. This equation has the format for a parabola The significance of this observation is that an optimum hydrophobicity may exist.

39. * Optimum value of log P for anaesthetic activity = log P o Log P o Log P Log (1/C)

40. * Accordingly several membranes may have to be traversed for compounds to get to the target site, and compounds with the greatest hydrophobicity will become localized in the membranes they encounter initially, thereby slowing their transit to the target site. Hansch proposed also that there should be a linear free energy relationship (like the Hammett equation) between lipophilicity and drug activity and that this might be indicated by the partition coefficient

41. * Hansch Linear Free Energy Model Hansch has derived a general equation based on linear free-energy considerations. In this equation is the ability to incorporate parameters which encompass the full range of known biological requirements for drug activity. Among theses terms for biological transport , drug/enzyme binding energies and substituent effects (both electronic and steric ). The most general form of Hansch equation is:

42. * log 1/C = - aπ 2 + bπ + ρσ + c Where activity expressed as 1/C , C = concentration, π is the Hansch constant (measure of lipophilicty ), ρ is constant related to the given molecule, σ is the Hammett substituent constant which is a measure of the electronic effect. Es Taft’s constant Log 1/C = k 1 P - k 2 P 2 + k 3 σ + k 4 Es + k 5

43. * Look at size and sign for each component of the equation. Values of r <<0.9 indicate equation not reliable Accuracy depends on using enough analogs, accuracy of data, & choice of parameters. Hansch Analysis

44. * Examples for Hansch equations log 1/C = 1.22 π – 1.59 σ + 7.89 (n = 22; r = 0.918 ) log 1/C = 0.398 π + 1.089 σ + 1.03 Es + 4.541 (n = 9; r = 0.955 )

45. * Log 1 C ⎛ ⎝ ⎞ ⎠ = 1.22 π - 1.59 σ + 7.89 Conclusions: Activity increases if π is + (i.e. hydrophobic substituents) Activity increases if σ is negative (i.e. e-donating substituents ) Examples: Adrenergic blocking activity of β -halo- β -arylamines

46. * For the antibacterial activity of substituted phenols log 1/C = 0.684 log P – 0.921σ + 0.268

47. * For a series of phosphonate esters, cholinesterase inhibitors log K = -0.152 π – 1.68 σ + 4.053 Es + 7.212 Where K is the inhibition constant, σ is the Hammett substituent constant for aliphatic systems Es is the Taft steric constant. In this example steric effect of the substituents plays an important role. The bulkier groups cause a decrease in cholinesterase inhibition.

48. * For the antibacterial effects on gram-negative bacteria of a series of diguanidines: log 1/C = -0.081 π 2 + 1.483 π – 1.578

49. * Conclusions: Activity increases slightly as log P (hydrophobicity) increases (note that the constant is only 0.14) Parabolic equation implies an optimum log P o value for activity Activity increases for hydrophobic substituents (esp. ring Y) Activity increases for e-withdrawing substituents (esp. ring Y) Log 1 C ⎛ ⎝ ⎞ ⎠ = - 0.015 (log P ) 2 + 0.14 log P + 0.27 Σ π X + 0.40 Σ π Y + 0.65 Σ σ X + 0.88 Σ σ Y + 2.34 Example: Antimalarial activity of phenanthrene aminocarbinols

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52. * Quantitative Structure-Activity Relationship ( QSAR ) Models Set of Compounds Activity Data (Y) Molecular Descriptors (X i ) ∝ QSAR Y = f (X i ) Interpretation Prediction

53. * Free-Wilson Analysis log (1/C) = Σ a i x i + μ x i : presence of group i (0 or 1) a i : activity group contribution of group i μ : activity value of unsubstituted compound

54. * Dipole-Dipole : Here a partially positive atom in a dipole is attracted to a partially negative atom in another dipole. Hydrogen Bonding : A dipole-dipole interaction where on of the constituents is a hydrogen attached to a heteroatom.

55. * Hydrogen bonds Vary in strength Weaker than electrostatic interactions but stronger than van der Waals interactions A hydrogen bond takes place between an electron deficient hydrogen and an electron rich heteroatom ( N or O ) The electron deficient hydrogen is usually attached to a heteroatom ( O or N ) The electron deficient hydrogen is called a hydrogen bond donor ( HBD ) The electron rich heteroatom is called a hydrogen bond acceptor ( HBA )

56. * Hydrogen bonds HBA HBD The interaction involves orbitals and is directional Optimum orientation is where the X-H bond points directly to the lone pair on Y such that the angle between X, H and Y is 180 o

57. * Hydrogen bonds Examples of strong hydrogen bond acceptors - carboxylate ion, phosphate ion, tertiary amine Examples of moderate hydrogen bond acceptors - carboxylic acid, amide oxygen, ketone, ester, ether, alcohol Examples of poor hydrogen bond acceptors - sulfur, fluorine, chlorine, aromatic ring, amide nitrogen, aromatic amine Example of good hydrogen bond donors - Quaternary ammonium ion

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59. Lone pair electrons Water can act as an H -bond Donor or Acceptor Donates H Accepts H *

60. * Examples of H-bonding interactions

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62. * The Hydrophobic Effect : when two alkyl chains approach one another, water is extruded from the space in between them, resulting in an increase in entropy, and thus a decrease in energy.

63. * Charge-Transfer Complexes : a lone pair of electrons is "shared" with a neighboring group that has considerable π character.

64. * Van der Waals Forces : one carbon in a chain approaches another carbon on a neighboring chain, causing a perturbation known as an induced dipole . These opposite partial charges then attract one another.

65. * Drugs may also bind to receptors using covalent bonding . This may be a permanent bond, in which case the receptor or enzyme target is "killed", or it may be transient.