Effect of substituents and functions on drug structure activity relationships
- 1. Substituents and Functions: Qualitative and Quantitative Aspects of Structure–Activity Relationships Substituent Groups
- 2. I. INTRODUCTION The replacement, in an active molecule, of a hydrogen atom by a substituent (alkyl, halogen, hydroxyl, nitro, cyano, alkoxy, amino, carboxylate, etc.) or a functional group can deeply modify The potency, The duration, Perhaps even the nature of the pharmacological effect.
- 3. II. METHYL GROUPS • In this section, we show how a methyl group, so often considered as chemically inert, is able to alter deeply the pharmacological properties of a molecule. We will envisage successively effects on the solubility, conformational effects, electronic effects and effects on the bioavailability and the pharmacokinetics. In the last paragraph, we will present some replacement possibilities of the methyl groups by related groups and extend the study to some larger alkyl groups.
- 4. A. Effects on solubility 1. Increase in lipophilicity CH3 gives place to a positive log (P) increment of 0.52 • The increase in lipophilicity due to methylation can drastically modify the bioavailability of the drug, and thus its efficacy i.e increased affinity for the receptor.
- 5. 2. Hydrophobic interactions • As stated above, the usual result of the methyl group addition to a given molecule is to augment its lipophilicity: • There are, however, exceptions to this rule, especially when the grafting of one or several methyl groups can render the molecule more compact (more “ globular ” ). A good illustration of this effect is provided by aliphatic alcohols. 5+ A lesser amount of structured water molecules is needed to wrap a compact molecule (2,2,3-trimethylbutane) than to wrap an extended one ( n -heptane).
- 6. 3 .Crystal lattice cohesion Greater water solubility can also result from a decrease of the crystal lattice energy, the methyl groups hindering the various intermolecular interactions (hydrogen bonds, dipole–dipole bonds, etc.). In the antibacterial sulfonamide series, The substitution of the pyrimidine ring of sulfadiazine by one, then two, methyl groups causes an increase in solubility. one would expect why the methyl substituted derivatives are less soluble. This for the double reason that they show increased lipophilicity and that they are less dissociated than the parent molecule. N N NH2 SO2NH CH3 CH3 N N NH2 SO2NH Sulfamidine Sulfadiazine
- 7. Indeed the inductive character of the methyl groups disfavors ionization and the non- ionized form of a molecule is always less soluble than the corresponding ionized form. Despite this unfavorable electronic effect, sulfamidine is approximately five times more soluble than sulfadiazine. N N NH2 SO2NH CH3 CH3 N N NH2 SO2NH Sulfamidine Sulfadiazine
- 8. B. Conformational effects The steric hindrance generated by a methyl group can create constraints and impose particular conformations that may be favorable or unfavorable for ligand–receptor interactions.
- 9. C. Electronics effects The methyl group and, more generally all alkyl groups, are the only substituents acting by an inductive electron-donating effect. All the other groups are electron donors by mesomeric effects. This means that the methyl and the alkyls are electron donors in any environment while a basic group, dimethylaminoethyl for example, will be a mesomeric donor in basic or neutral medium, but will become strongly electron attracting by protonation in gastric medium (pH 2).
- 10. D. Effects on metabolism Seen from the metabolic point of view the methyl group plays a particularly important role. Three possibilities are currently met: (a) the methyl group is oxidized, (b) the methyl group is shifted and (c) the methyl group is not (or only slightly) attacked and can then serve as blocking group.
- 11. 1.Oxidation of the methyl group The oxidation of the methyl group begins generally with the formation of the hydroxymethyl analog and continues usually until the carboxyl step. This is observed for simple compounds like camphor or 2- methyl-pyridine but also for drugs like tolbutamide, explaining the relatively short half-life of these latter compounds. Sometimes the oxidation of the methyl group gives rise to an active metabolite, contributing thus to a reasonable half-life to the drug. The grafting of a methyl group, especially on aromatic rings, represents often a good mean of detoxification.
- 12. 2.The methyl group is shifted • A methyl group, when grafted on a nitrogen or sulfur atom, can transform this latter in an “ onium, ” able to act as methyl donor. In living organisms the usual suppliers of methyl rests are choline and methionine. • More generally, any S - or N -methylated drug can constitute a methyl donor. • On the other hand, when the methyl (or alkyl) rest is linked to a good leaving group, as found for alkyl sulfates or sulfonates such as methyl sulfate or busulfan, alkylating reagents are produced and there exists a huge risk of carcinogenicity.
- 13. 3.The methyl serves to block a reactive function A reactive function, such as an active hydrogen belonging to a hydroxyl, thiol or amino, can be masked by methylation. Methyl groups can thus serve to protect sensitive functionalities from metabolic hydroxylation. The ene-diol function is essential to the antioxidant properties of vitamin C, it is therefore not surprising that its methylation leads to an inactive compound
- 14. • In steroids the 6α-position (e.g. prednisolone is a position that is normally hydroxylated. Grafting a methyl in this place prevents its hydroxylation. • Halogens (particularly fluorine) suit even better because they are not sensitive at all to oxidative attacks. O O OH CH3 OH CH3 OH O O OH CH3 OH CH3 OH CH3 Prednisolone Methylprednisolone
- 15. E. Extensions to other small alkyl groups • The methyl group is the prototype of a saturated aliphatic substituent with lipophilic and electron-donor inductive effect. • In some instances, it can advantageously be replaced by related groups bringing either symmetry, or more lipophilicity, or an increased inductive effect.
- 16. bulkiness ( E s ) of the isopropyl and cyclopentyl groups, while the tert-butyl group is far more voluminous. Furthermore, it is remarkable to observe that the electron-donor effect of the cyclopentyl group is superior to that of the cyclohexyl group.
- 17. 2.Gem -dimethyl and spiro- cyclopropyl • Gem -dimethyl and spiro-cyclopropyl are useful to render a carbon atom quaternary and therefore resistant to metabolic attacks. O O OH O OH CH3 CH3 CH3 CH3 Gemeprost (abortifacient)
- 18. Gem -dimethyl can also constitute solutions to introduce symmetry into a chiral center, or to protect a close and sensitive function, as in the case of gemeprost, an analog of prostaglandin E1 used in medical abortion, where the gem - dimethyl groups at C-16 protect the alcohol moiety at C-15 from rapid metabolic oxidation.
- 19. 3.Isopropyl and cyclopropyl The cyclopropyl rest is less bulky than the isopropyl group for a maximal electron-donor effect. This electronic effect is involved when the cyclopropyl group of efavirenz, a nonnucleoside reverse transcriptase inhibitor, interacts with the aromatic ring of tyr181 via a π-aryl interaction which is presumably favorable to binding. The lipophilic effect of cyclopropyl explains why abacavir, a nucleoside reverse transcriptase inhibitor, has an improved absorption in the CNS compared to diaminopurine dioxolane (DAPD).
- 20. 4. The cyclopentyl group The cyclopentyl group creates the maximal inductive effect for a relatively reasonable bulkiness. It is often a good filling of a hydrophobic pocket as illustrated for the cAMP. Phosphodiesterase inhibitor rolipram . The inhibitory activity toward type IV cAMP phosphodiesterase is increased 10 times when the meta -methoxy group is replaced by a meta -cyclopentyl group (rolipram). N H O O O CH3 N H O O O CH3 CH3 Rolipram
- 21. III. EFFECTS OF UNSATURATED GROUPS 1. Existence of electronic effects : the unsaturated rests behave as electron attractors through inductive effects. Furthermore, direct interactions of donor–acceptor type are possible thanks to the π electron cloud surrounds present in multiple bonds. 2. Possibility of existence of a geometrical isomery (e.g. cis – trans geometric isomery). 3. Possibility of activation through conjugation : the association of several unsaturated functions in conjugated position (dienes, enynes, enones, enolides, polyunsaturated derivatives) renders the corresponding molecules very reactive. It facilitates especially the addition of biological nucleophiles and notably of thiols.
- 22. 4. Facilitation of the metabolism : The unsaturated element constitutes often the vulnerable site of the molecule, that will be attacked first (e.g. by formation of an epoxide that evolves into a diol that, on its turn, can undergo oxidative cleaving), but this is not always the case. Therefore, one should pay attention to the problems posed by the formation of these metabolites (aldehydes, carboxylic acids … ): they can also be biologically active. 5. Increase of the narcotic power and the toxicity in comparison with the corresponding saturated compound. Ethylene, acetylene, trichlorethylene, divinyl oxide and, by extension, cyclopropane are examples of unsaturated narcotics
- 23. Classification of unsaturated groups • A. Vinyl series • B. Allylic series • C. Acetylenic series • D. Cyclenic equivalents of the phenyl ring
- 24. Classification of unsaturated groups A. Vinyl series • It may take part to a beneficial electronic interaction. B. Allylic series • All allylic derivatives are relatively hepatotoxic and irritant. • Allylic alcohol itself serves to create experimental hepatic lesions that allow testing hepatoprotecting drugs. We will envisage three categories of allylic derivatives: C –allyl derivatives, N -allyl derivatives, and O -and S -allyl derivatives which often possess alkylating properties.
- 25. 1- C -allyl derivatives They present the double advantage to be lipophilic (rapid onset) and to give place to fast biodegradation (short duration of action). However, they often conserve the intrinsic hepatotoxicity of the allyl group. • Allobarbital is a sedative hypnotic that is no longer used; allylestrenol acts as a pure progestative hormone and alprenolol is a β -blocker
- 26. 2.N -allyl derivatives The replacement in morphine, and in some of its simplified analogs, of the N -methyl group by a N -allyl group (and, later on, by some related groups) has constituted a decisive step in the study of opiate analgesics. Indeed this modification had for the first time achieved the passage of morphinic receptor agonists to the corresponding antagonists
- 27. O - and S -allyl derivatives • Alkylating allyl derivatives: When the allyl rest bears • a good leaving group, it generates easily the allylic cation. • This cation is stabilized by mesomery, and is an excellent electrophile. • Many natural compounds can release allylic alcohols. A first example is found in allicine, the antibacterial principle of garlic, which results from the action of alliinase on alliine. • Penicillin O and penicillin S are both S -allyl derivatives.
- 28. C. Acetylenic series 1. Electronic effects • The acetylene function exerts an electron-attracting effect. This effect can be reinforced by substitution of the acetylenic hydrogen. • The acetylenic CH can act as an hydrogen bond donor
- 29. 2. Aromatic ring equivalents Thanks to their π electron clouds and to their small volume, ethynyl groups can sometimes function as bioisosteres of aromatic rings and give similar donor– acceptor interactions. • Acetylenic group has the rapid metabolization of ethynyl groups
- 30. 3.Structural constraints • In inserting an acetylenic function between two carbon atoms, one achieves a structure with four “ on-line” atoms representing a rigid entity with a distance of 4.2 Å between the two extreme atoms
- 31. D. Cyclenic equivalents of the phenyl ring The cyclohexenyl ring and, to a lesser extent the cyclopentenyl and cycloheptenyl rings can possibly replace a phenyl ring. This is the case for the barbiturics cyclobarbital and heptabarbital which are entirely comparable to phenobarbital. From the metabolic point of view, the cyclohexenyl ring is oxidized in position α to the double bond to produce the corresponding cyclohexenone
- 32. IV. EFFECTS OF HALOGENATION A. The importance of the halogens in the structure–activity relationship 1. Steric effects The obstruction of a molecule by means of halogen substitution can impose certain conformations or mask certain functions. In the case of clonidine the bulky halogen atoms prevent the free rotation and maintain the planes of the aromatic rings in a perpendicular position to each other.
- 33. 2. Electronic effects • Halogens have negative inductive effect which is in the following order: F > Cl > Br > I • The mesomeric donor effect of the halogen atoms is usually not involved in biological medias.
- 34. 3-Hydrophobic effects • Halogen have lipophilic effect. π of F = 0.14, Cl = 0.71, Br = 0.86, and CF3 = 0.88 4- Reactivity of the halogens • In terms of bond strength, all C-halogen bonds are weaker than the C — H bond except for the C — F bond, due to the high electronegativity of the fluorine and an orbital size similar to that of carbon.
- 35. B. Usefulness of the halogens and of cognate functions 1- Fluorine It induces an increase in lipophilicity and its electronegativity is the highest in the periodic classification. The difference in electronegativity between fluorine and carbon creates a large dipole moment in this bond. This dipole may contribute to the molecule’s ability to be engaged in intermolecular interactions.
- 36. • Fluorine is able to participate to hydrogen bonds with the hydrogen of water. These bonds are weaker than those obtained with oxygen, but they are still strong enough to contribute to the binding of fluoroaromatic compounds to active site and/or receptor • The importance of electrostatics in the interaction of aromatics fluorine with cations and hydrogen bond donors can be visualized using electrostatic potential surfaces
- 37. In monofluorobenzene, the potential of the fluorine is concentrated on the unique fluorine present, whereas in polyfluorobenzene the negative charge is spread over several fluorine atoms. For this reason, monofluorobenzene may give stronger interactions. • Fluorine is also used to block metabolically sensitive positions of a molecule. When the fluorine is placed in an activated position.
- 38. 2-Chlorine A chlorine substituent produces simultaneously an increase in lipophilicity, an electron-attracting effect and a metabolic obstruction. 3- Bromine Bromine is the less used halogen, and when it serves, it is usually incorporated as a bromo- aryl. The reproach against bromine is to generate reactive alkylating intermediates, more easily than chlorine or fluorine.
- 39. 4-Iodine • Although even lesser tolerated than bromine, iodine is used to the treatment of certain thyroidal deficiencies. Administrated by internal route, iodine and iodine derivatives • trigger either acute hypersensitivity reactions (larynx oedema, cutaneous hemorrhages, fever, arthralgies, etc.). chronic reactions (iodism). • In addition to its use in certain dysfunctions of the thyroid gland, iodine presents to specific uses: covalent iodine derivatives serve as radiological contrast substances and 131 iodine (half-life: 8 days) is used as radioactive tracing agent.
- 40. 5-Extensions-cognate groups • Chlorine, trifluoromethyl, cyano or azido groups are more or less bioisosteres. • Other possible candidates are: SCN, SCF3 , -SO2CF3 and CH =CF2
- 41. V. EFFECTS OF HYDROXYLATION A. Effects on solubility • The introduction of an alcoholic or a phenolic hydroxy group into an active molecule changes the partition coefficient toward more hydrophilicity and renders the molecule more water soluble.
- 42. B. Effects on the ligand–receptor interaction • The hydroxy group is an essential element for hydrogen bonding with the receptor. For others the attachment of a hydroxy group can result in potency changes. Beta receptor agonistic activity of epinephrine and desoxyepinephrine.
- 43. C. Hydroxylation and metabolism As a rule metabolic hydroxylation of an active compound represents a detoxication (phase I) mechanism. It results generally from a first-pass effect and can be followed or not by a conjugation reaction.
- 44. VI. EFFECTS OF THIOLS AND OTHER SULFUR-CONTAINING GROUPS A. Drugs containing thiol: They are able to coordinate Zn(II) and act as free radical scavenger. Their lipophilicity allows them to attain high lever in heart tissue and then they can be used as cardioprotective drugs The heavy-metal chelating properties of thiols were taken advantage of in the design of dimercaprol ( “ British Anti- Lewisite, ” BAL) as counter poison of the arsenical war gas Lewisite. Methylthio substitution on aromatic rings is practiced, but even then, the obtained thioethers are very reactive. They are easily converted to sulfoxides and vice versa
- 45. B. Drugs containing oxidized sulfides The sulfoxide (S=O) and the sulfone (O=S=O) functions are very polar and usually confer mediocre CNS bioavailability.
- 46. VII. ACIDIC FUNCTIONS The prototypical representatives of the group are the carboxylic acids. However, a huge number of bioisosteres such as sulfonic or phosphonic acids, tetrazoles or 3-hydroxyisoxazoles are available R PO OH OH N O OH R S OO OH NH N N N R O OHR
- 47. A. Effects on solubility • Carboxylic acids are often highly ionized at the physiological pH values and this is even more the case for sulfonic acids and poorly cross membranes. • They are subject to a rapid clearance from the animal body. • However, once absorbed, they can establish strong ionic interactions with the basic amino acids, especially with lysine, contained in the blood serum albumin, or the enzyme and receptor proteins.
- 48. • The second generation of antihistaminic compounds are less lipophilic, thanks to the replacement of the hydroxy group by a carboxylic acid. They are also P-gp substrate, which limits CNS exposure. N N Cl OH O N N Cl O COOH Hydroxyzine Cetirizine
- 49. B. Effects on biological activity • The sulfonic acids as a class are generally not biologically active. • For carboxylic acids the situation depends on whether the carboxylic function is introduced in small or large molecules. 1. In small molecules • The introduction of a carboxylic group changes fundamentally the biological activity. Very often the initial biological activity is destroyed and the toxicity of the parent compound is reduced.
- 50. . NH2 NH2 COOH OH OH COOH Phenethylamine Phenylalanine (inactive as sympathomimetic) Phenol (no antiinflammatory) 2. In large molecules: High pharmacological activity is maintained despite the presence of the carboxylic group.
- 51. 3-Isosteric substititution of carboxylic group • A good example is losartan. • Activity increases dramatically by substituting carboxylic group by tetrazole. R pKa IC50(nM) COOH 5 0.23 COONHSO2P h 8.44 0.14 NHCOCF3 9.5 6.3 NHSO2CF3 4.5 0.083 Tetrazole 5–6 0.019 N N nBu Cl OH R
- 52. VIII. BASIC GROUPS The basic groups met in medicinal chemistry are the amines, the amidines, the guanidines and practically all nitrogen containing heterocycles. Basic groups are polar and one would expect that highly ionized bases (especially quaternary ammonium salts) would resemble the sulfonic acids and show limited activity due to their mediocre membrane permeability. In practice bases with p K a values superior to 10 have very limited chance to reach the CNS.
- 53. • As seen for the acidic groups, the introduction of a basic group into a biologically active compound which contains no such group already has as consequence essentially a solubilizing effect. This effect can also be enhanced through salt formation. • In drug–protein interactions the classical counter- anions of organic bases are the aspartic and the glutamic carboxylates.
- 54. • Acylation deactivates the amines strongly as does the introduction in some other place of the molecule of a carboxylic or sulfonic group (formation of zwitter ions: bipolar ions). • Aromatic amines are always more hazardous than aliphatic amines and form toxic metabolites
- 55. IX. ATTACHMENT OF ADDITIONAL BINDING SITES A. To increase lipophilicity Cyclic amino acids such as nipecotic acid and guvacine have been shown to inhibit GABA uptake (anticonvulsant). However, these small amino acids do not readily cross the BBB and thus limit their potential clinical usefulness. A considerable improvement has been the discovery of compound SKF 89976A COOH NH COOH N COOH NH Nipeconic acid Guvacine SKF 89976A
- 56. B. To achieve additional interactions • The fixation of large aromatic substituents such as 2-naphtyl and 3,3-diphenylpropyl to the low-efficacy partial agonist 4-PIOL transform this series in powerful GABA A receptor antagonists.
- 57. Instead of ensuring high lipophilicity, these aralkyl groups serve to achieve additional interactions with the target macromolecule. This is typically the case for the angiotensin converting enzyme inhibitor enalaprilat. The exchange in captopril of the thiol function for a carboxylic group as ligand for the enzyme zinc atom entails an important decrease in activity. This decrease could be compensated by the attachment of a phenethyl moiety. N O O OH SH CH3 H N NH O O O OH O CH3 CH3 H H
- 58. For further readings: Camille Wermuth David Aldous Pierre Raboisson Didier Rognan “The practice of Medicinal Chemistry” Academic press