Page numbers followed by f denotes a figure and the letter t denotes a table
A
Abacavir, 331, 331f
Absorption, distribution, metabolism, and elimination (ADME), 17
SARs and, 320–323, 321f, 322f, 324t
Acetaminophen
conjugation of, 283f
glutathione conjugation of, 291–292, 291f
N-oxidation of, 265, 265f
sulfate conjugation of, 287f
Acetazolamide, 337
Acetic acid, 148f
for organic salts, 137t
Acetohexamide, 279f
Acetone, 150
Acetonide, 150, 150f
Acetylation, 292–293, 292f–294f
Acetylcholine, 18–19, 19f
conformational isomers of, 230, 231f
homologation and, 339, 340f
neostigmine and, 170–171, 171f
Acetylcholinesterase
neostigmine and, 170–171, 171f
phosphorylation of, 172, 172f
Acidic functional groups, 26–27, 27f
in amino acids, 177–178, 177f
ARBs and, 328f
drug interactions and, 326
in enzymes, 177–178, 177f
Henderson-Hasselbalch equation for, 88–90, 89f
identification of, 52–61
ionization of, 110, 174–175, 175t
pKa of, 71–72, 72f, 86–87
in proteins, 177–178, 177f
salts from, 75–76, 75f, 136–137, 137t
therapeutic significance of, 72–76, 73f–75f
Active conformation, 233
Acylation, 168–171, 169f–171f
Acyl chloride, 271f
Acyl group, covalent bonds and, 168–171, 169f–171f
Adenine, 12, 13t
Adenosine, 288f
Adenosine diphosphate (ADP), 173
Adenosine monophosphate (AMP), 335, 336f
α adrenergic receptors, 31, 31f
diastereomers of, 225, 225f
homologation and, 338
β adrenergic receptors, 31, 317, 372–375
diastereomers of, 225, 225f
homologation and, 338
Adverse drug reactions
with acidic functional groups, 75
of heparin, 115–116
SARs and, 323–326, 325f, 326f
Alanine, 16, 38, 217
binding interactions of, 196t
Albumin, 73
Albuterol, 31, 31f
aliphatic amines and, 63–64, 64f
enantiomers of, 216, 221, 221f
hydroxyl group and, 266–268, 266f–268f
oxidation of, 266–267, 266f
Alcohol dehydrogenase (ADH), 248–249, 266–268, 266f, 267f
Aldehyde
carbonyl group of, 20
charge transfer reactions of, 195f
electron withdrawing functional groups of, 23, 24f
ketone reduction and, 272f
oxidative deamination of, 258
reduction of, 272–273, 272f, 273f
sugars and, 5
Aldehyde dehydrogenase (ALDH), 248–249, 266–268, 266f–268f, 272f
Aldoses, 5
Alendronate sodium, 74f
Alendronic acid, 140, 141f
Alicyclic amines, 62–64, 63f, 64f, 175t
Alicyclic carbon, 256–257, 256f, 257f
Alicyclic rings, 140f
geometric isomers of, 226–227, 227f
lipophilic functional groups and, 30, 30f
numbering of, 4
Aliphatic amines, 62–64, 63f, 64f
ionization of, 175t
pKa of, 71t
Aliphatic carbon, 253–257, 254t, 255f–257f
Aliphatic chains, 189f, 190–192, 190f
Aliphatic hydroxyl groups, 60
Aliphatic rings, 226–227
Aliskiren, 359–362
Alkenes, 252, 252ff, 253f
Alkylation, 168, 168f
Alkyl chains, 30, 30f, 140f
Alkyl group
charge transfer interactions of, 194f
electron donating functional groups and, 23
nitrogen and, 62
Alpha/beta (α/β) designation, 7, 8
Alpha (α) designation, 6–9, 7f
for glycosidic bonds, 9, 9f
Alprostadil, 52–53, 53f
Amantadine, 263, 263f
Amide group, 140f
carbonyl group of, 20
charge transfer reactions of, 195f
electron withdrawing functional groups of, 23, 24f
as hydrogen bond acceptor, 183f, 186f
as hydrogen bond acceptor/donor, 183f
hydrolysis of, 278–279
nitrogen and, 69, 70
oxidation of, 258–265, 259f, 260f, 262f–265f
Amidine group, 66–67, 66f, 140f
ionization of, 175t
pKa of, 71t
resonance delocalization of, 67
Amines, 140f. See also Aromatic amines
biological target selectivity and, 31
charge transfer interactions of, 194f
in gentamicin, 135
ion-dipole interaction with, 131
methylation of, 294, 295
oxidation of, 258–265, 259f, 260f, 262f–265f
pKa and pH of, 99
Amino acids
acidic functional groups in, 177–178, 177f
basic functional groups in, 176, 176f
binding interactions of, 196t
conjugation of, 281t, 288–290, 288f, 289f
enantiomers of, 217
functional groups on, 36–40, 37f
ionic bonds of, 176, 176f
peptides from, 10–12, 10f
Amino terminus, 10, 11f
Amiodarone, 136f
Amitriptyline, 227–228, 227f, 261, 262f
Amlodipine, 361
Amoxicillin, 19, 19f, 150–151, 151f
Amphetamine, 259f
Ampicillin, 7f, 19, 19f, 150–151, 151f
Amrinone lactate, 132f
Angiotensin converting enzyme (ACE)
aliskiren and, 359–360
complexation and, 199, 199f
enalaprilat and, 12
inhibitors, 319–320, 320f
tripeptides and, 11
Angiotensin I, 11, 12f
Angiotensin II, 11
Angiotensin II receptor blockers (ARBs), 327–329, 328f, 335–336
Aniline group, 140f, 194f. See also Aromatic amines
Anomeric carbon, 7
Anomers, 7
Antacids, 117
Antihistamines, 325f
Antivirals, 18
Arginine, 40
binding interactions of, 196t
cation–π interaction of, 193
guanidine group and, 67, 67f, 116
ionic bonds of, 176, 176f
Aripiprazole, 362–364
Aromatic amines, 64–65, 64f, 65f
of bimatoprost, 143
as hydrogen bond acceptor/donor, 183f
ionization of, 175t
pKa of, 71t, 92
sulfate conjugation and, 286, 287f
Aromatic heterocycles
ionization of, 175t
nitrogen in, 68–69, 68f, 69f
pKa of, 71t
Aromatic hydroxylation, 250–252, 251f, 252f
Aromatic nitrogen, 258–265, 259f, 260f, 262f–265f
Aromatic rings, 140f
aryl-aryl stacking interactions of, 192–193, 192f, 193f
charge transfer interactions of, 193–195, 194f, 195f
electron donating functional groups and, 23, 23f
homologation and, 339
for hydroxyl group, 58–60, 58f, 59f
lipophilic functional groups and, 30, 30f
of methylsalicylate, 114
mixed-function oxidases of, 246
of nitrile group, 20, 21f
oxidation of, 250–252, 251f, 252f
of phenolic group, 20
pKa and pH of, 99
position designation for, 4–5
van der Waals interactions of, 189, 189f, 190–192, 190f
Aryl-aryl stacking interactions, 192–193, 192f, 193f
Asparagine, 40
binding interactions of, 196t
dipole-dipole interactions of, 181
Aspartic acid, 39
binding interactions of, 196t
histidine and, 177, 177f
Aspirin
acylation of, 170, 170f
covalent bonds of, 166, 167f
hydrolysis of, 275
Asthma, 17–18, 31, 317, 338
Atenolol
oxidative N-dealkylation of, 260, 261
SARs of, 318f
Atomoxetine
cation–π interaction of, 193, 193f
conjugation of, 283f
oxidative deamination of, 259f
Atorvastatin, 138t, 299–300
ATP, methylation of, 295, 295f
Azide, 186f, 187
Azo group, 273–274, 274f
B
Baclofen, 259f
Balsalazide, 273, 273f
Basic functional groups, 26–27, 27f
in amino acids, 176, 176f
drug interactions and, 326
Henderson-Hasselbalch equation for, 88–90, 89f
identification of, 52–72
ionization of, 110, 174–175, 175t
pKa of, 71–72, 74f, 86–87
resonance delocalization, 67
salts from, 75–76, 75f, 136–137, 137t
therapeutic significance of, 72–76, 73f–75f
thioridazone and, 128
Beclomethasone dipropionate, 149, 149f, 324t
Benign prostatic hyperplasia (BPH), 319
Benzimidazole rings, charge transfer interactions of, 194f
Benzodiazepines, 65, 65f
Benzoic acid, 148f
Benzothiazole rings, 194
Benzoxazole rings, 194f
Benztropine, 187, 187f
Benzylic carbon, 253–256, 255f
Berg, J. M., 13
Beta (β) designation, 6–9, 7f
Bethanechol, 98
Bimatoprost, 139, 143, 143f
Binding interactions, 3–4. See also specific bond types
of biological targets, 195–196, 196t
SARs and, 316–320, 317f, 318f, 320f
Bioisoteres, 331–337
Bioisoteric replacement, 334
Biological targets
active conformation of, 233
acylation of, 170–171, 171f
binding interactions of, 195–196, 196t
covalent bonds and, 167
functional groups and, 31, 31f, 36
pharmacodynamic effects and, 17
pKa and pH and, 114
stereochemistry with, 175
steric effects with, 175
Biopolymers, 17
Bisphosphonate, 186f
Boat conformation, 232, 232f
Bonds. See Binding interactions
Brentuximab vedotin, 344, 345f
Brimonidine, 67, 67f
Brimonidine tartrate, 132f
Bromine, 22, 22f, 179t, 180
Busulfan, 24
Butorphanol tartrate, 75f
C
Cahn, Robert, 217
Calcium hydroxide, 129, 137t
Candesartan, 147, 147f
Candesartan cilexetil, 147, 147f, 276, 277f
Captopril, 60, 60f
complexation of, 199, 199f
Henderson-Hasselbalch equation for, 95, 96
methylation of, 296f
oxidation of, 268–270
pH and pKa of, 91, 92, 95, 96
SARs of, 319–320, 320f
Carbamates
as hydrogen bond acceptor, 183f
as hydrogen bond acceptor/donor, 183f
hydrolysis of, 279f
isavuconazole and, 344, 344f
nitrogen and, 69–70
Carbidopa, 52–53, 296f
Carbinolamine
isavuconazole and, 344, 344f
oxidative deamination of, 258
Carbon
chirality of, 210–213, 211f
electronegativity of, 179, 179t, 180
mixed-function oxidases of, 246
oxidation of, 253–257, 254f–257f
van der Waals interactions of, 189f, 190–192, 190f
Carbonic anhydrase
sulfonamide group and, 335, 337f
thiazides and, 116, 116f
Carbonyl group
chirality of carbon and, 211
mixed-function oxidases of, 246
nitrogen and, 70
oxidation of, 254–255, 255f
pH and pKa of, 107
resonance of, 20, 21f
Carboprost tromethamine, 137t
Carboxylic acid
as acidic functional group, 27f, 52–53, 53f
amino acid conjugation and, 288, 290
ARBs and, 329
in cefepime, 135
complexation of, 199, 199f
electron donating functional groups and, 23, 23f
esters of, 147, 147f
as functional group, 18
of furosemide, 185, 185f
Henderson-Hasselbalch equation for, 88–90, 89f
hydrolysis and, 277
hydroxyl group and, 74, 266–268, 266f–268f
ionic bonds of, 32, 114
ionization of, 175t
ketone reduction and, 272f
for lipid solubility, 148, 148f
methylene group and, 177
nonclassical isosteres of, 337t
noncovalent bonds of, 174
oxidation of, 266–267, 266f
oxidative dehalogenation and, 271f
PABA and, 115, 115f
in peptides, 10
pH and pKa of, 71t, 101, 103, 114
prodrug conversion of, 341
resonance delocalization of, 67
resonance of, 20
tetrazole rings and, 58, 58f
Carboxyl terminus, 10–11, 11f
Catechol-O-methyltransferase (COMT), 294, 296
Catechol rings, 251–252, 252f
Catechols, 295, 296
nonclassical isosteres of, 337t
Cation–π interaction, 193, 193f
Cefepime, 134–135, 135f
Cefoxitin, 33, 33f
acylation of, 169, 169f
covalent bonds of, 167, 167f
Cefprozil, 364–367
Celecoxib, 56, 56f
Cephalexin, 33, 33f, 275, 276f
Cephalosporins, 33, 33f
covalent bonds of, 167
drug interactions with, 325
Ceritnib, 69, 69f
Cetirizine, 52–53, 53f, 325f
Chain branching, 339–341, 341f
Chair-chair inversion, 232, 232f
Chair conformation, 232, 232f
Charge transfer interactions, 193–195, 194f, 195f
Chelation, 197–199, 197f, 198f
drug interactions and, 325, 325f
Chemical antagonism, ionization and, 115–116, 116f
Chiral centers
designations for, 216–220, 218f, 218t
of diastereomers, 224–225
of geometric isomers, 226
Chirality, 210–213, 211f
Chlorambucil, 167f, 168, 168f
Chloramphenicol, 271f, 274f
Chloramphenicol sodium succinate, 147, 147f
Chlorine
aliphatic amines and, 64
electronegativity of, 21, 22, 22t, 179t, 180
SARs of, 318
Chlorpheniramine, 180–181
Chlorpromazine, 328, 328f, 340f
Chlorpropamide, 329–330, 329f, 334
Cholesterol, 18–19
steroid nomenclature for, 9, 10f
Chronic obstructive pulmonary disease (COPD), 17–18, 31, 317
homologation and, 338
Ciclopirox olamine, 137t
Cimetidine, 337
pH and pKa of, 106
Ciprofloxacin, 72, 72f
drug interactions of, 198–199
Cis isomers, 226–227, 227f, 228, 228f
Classical isosteres, 334–335, 334t, 335f
Clavulanate potassium, 137t
Clindamycin
hydrogen bonds of, 187–188, 187f
molecular modification of, 330, 330f
prodrug conversion of, 342, 343f
Clomipramine hydrochloride, 137t
Clonidine, 72, 72f
Clonidine hydrochloride, 130f
Clopidogrel
covalent bonds of, 167f
CYP2C19 and, 298
rearrangement reactions of, 173, 173f
Cocaine, 278
Complexation, 199, 199f
Conformational isomers, 228–236, 229f–232f, 234f, 235f
Conformational restriction, 2
benefits of, 234–236, 234f, 235f
molecular modification and, 327–328, 327f
SARs and, 317–318
Conjugate base, 62
Conjugation, 280–297
acetylation, 292–293, 292f–294f
of amino acids, 288–290, 288f, 289f
of glucuronic acid, 281–285, 281t, 283f–285f
of glutathione, 290–292, 290f, 291f
methylation, 294–296, 295f, 296f
of sulfates, 285–287, 286f, 287f, 292
Copper, chelation of, 197, 197f
Covalent bonds, 166–173, 166t, 167f–173f
acylation and, 168–171, 169f–171f
alkylation and, 168, 168f
concerns with, 166–167, 167f
electrophilic functional groups and, 24
of inorganic salts, 129
ionization with, 174
phosphorylation and, 171–172, 172f
rearrangement reactions and, 173, 173f
types of, 167–173, 168f–173f
C-terminus, 177, 177f
Cyclizine, 325f
Cyclohexane, 4
chair-chair inversions of, 232
conformational isomers of, 232, 232f, 233
oxidation of, 257f
Cyclooxygenase, 32, 32f
acylation of, 170, 170f
conformational isomers of, 235, 235f
covalent bonds and, 166
enantiomers of, 222
ionic bonds on, 114
Cyclopentane, 4
Cyclopentylpropionic acid, 148f
Cyclophosphamide, 345–346, 345f
CYP2C9, 297–298, 298f
CYP2C19, 298, 300
CYP2D6, 298, 299f, 300, 300f
CYP3A4, 299–300, 361
Cysteine, 39
binding interactions of, 196t
glutathione conjugation and, 290–291
omeprazole and, 347, 347f
Cytochrome P450 (CYP450), 246–248, 247f, 248t, 249f
for alkene oxidation, 252f
for aromatic hydroxylation, 252f
for carbonyl group oxidation, 254–255, 255f
for hydroxyl group oxidation, 266–268, 266f–268f
ketone reduction and, 272f
metabolism and, 297–300
N-oxidation by, 263f, 264f, 265f
for O-dealkylation, 278
oxidative deamination by, 259f
for oxidative dehalogenation, 270–271, 271f
for sulfur oxidation, 268–270, 269f, 270f
Cytosine, 12, 13t
D
Debye forces, 188
Deconjugation, 279, 280f
Deoxyribofuranose sugars, 6, 6f
Deoxyribonucleic acid (DNA), 12
covalent bonds and, 166
electrophilic functional groups and, 24
functional groups on, 40–41, 41f
hydrogen bonds of, 184, 184f
molecular modification and, 330–331
sulfate conjugation and, 286
Dewick, P. M., 5, 13
Dexamethasone, 98
Diastereomers, 224–228, 224f–228f
enantiomers and, 224–225, 224f
geometric isomers and, 228, 228f
Diazepam, 65, 65f
aromatic hydroxylation of, 251f
conjugation of, 285
heparin and, 136f
oxidative N-dealkylation of, 259, 260f
β-dicarbonyl groups, 53–54, 55f, 140f
enantiomers of, 215
pKa of, 71t
Diclofenac, 32, 32f
amino acid conjugation of, 289f
conformational isomers of, 235, 235f
enantiomers of, 223f
SARs of, 318
Dicyclomine, 257f, 338, 339
Diethylstilbestrol, 228, 228f
1,4-dihydropyridine (1,4-DHP), 318–319, 318f
5α-dihydrotestosterone, steroid nomenclature for, 9, 10f
Dipeptides, 10
Diphenhydramine, 325f
Diphenoxylate, hydrolysis of, 277f, 278
Dipole-dipole interactions, 27, 180–181. See also Hydrogen bonds
charge transfer interactions as, 193–195, 194f, 195f
Dipole-induced dipole interaction, 188–190, 189f, 190f
Dipole interactions, 179–188, 179t, 183f–187f. See also Hydrogen bonds
van der Waals interactions, 188–190, 189f, 190f
Disopyramide, 221, 221f
Disopyramide phosphate, 137t
Disulfide bond
of cysteines, 39
reductions of, 274
D/l designation, 8, 216–220, 218f, 218t
Dopamine
alpha/beta (α/β) designation of, 7f
methylation of, 294
Double bonds, 3–4
for conformational restriction, 327–328
Doxepin, 227–228, 227f
Doxycycline, 35, 35f, 322–323, 322f
DrugBank, 13
Drug interactions
chelation and, 198–199
of organic salts, 134–135, 135f, 136f
pH and, 326
pKa and pH and, 116–117
SARs and, 323–326, 325f, 326f
Duloxetine, 272, 273f
Duration of action
of pharmacodynamic effects, 17
pKa and pH and, 112–113, 113f
E
Easson, Leslie, 222–223
E isomers, 227–228, 227f
Electrolytes, 59
Electron donating functional groups, 23, 24f
sulfonamides and, 56
Electronegativity, 21–22, 22t
Electron withdrawing functional groups, 23, 24f
penicillin G and V and, 25–26, 25f, 26f
phenols and, 59–60
sulfonamides and, 56
Electrophilic functional groups, 24–26, 24f–26f
glutathione conjugation and, 291–292
sulfate conjugation and, 287f
Enalaprilat, 11, 12f, 18
enantiomers of, 213–215, 215f
SARs of, 319–320, 320f
Enantiomers, 8, 213–224, 214f, 215f, 218t, 221f–223f
designations for, 216–220, 218f, 218t
diastereomers and, 224–225, 224f
pharmacological and therapeutic differences between, 220–224, 221f–223f
steric hindrance of, 223–224, 223f
Encainide, 264, 264f
Enflurane, 271f
Enol form, of β-dicarbonyl groups, 54
Enterohepatic circulation/recycling, 285
Enzymes. See also specific types
acidic functional groups in, 177–178, 177f
as biological targets, 17, 36
enantiomers and, 224
ionic bonds of, 176, 176f
metabolism and, 245
for oxidation, 246–249, 247f, 248t, 249f
sulfate conjugation and, 286
Epinephrine, 31, 31f
enantiomers of, 222–223, 222f
homologation of, 338
methylation of, 294
SARs of, 316–317, 317f
Epirubicin, 279f
Eplerenone, 72, 72f
Eprosartan, 328, 328f
Erythromycin, 133, 134f
Erythromycin stearate, 133
Esmolol, 275, 276f
Essentials of Foye’s Principles, 13
Ester group, 140f
carbonyl group of, 20
of carboxylic acid, 147, 147f
electron withdrawing functional groups of, 23, 24f
as electrophilic, 24
as hydrogen bond acceptor, 183f
hydrolysis of, 276, 277f
lipophilic functional groups and, 28–29
organic salts and, 134
prodrug conversion of, 341–342, 342t
for water and lipid solubility, 146–149, 147f–149f
Estradiol, 59–60, 59f
SARs of, 321, 321f
steroid nomenclature for, 9, 10f
Estradiol valerate, 148, 148f
Estrone, 141, 141f, 287f
Estrone sodium sulfate, 61f
Estrone sulfate, 280f
Ether group, 140f
Ethers
charge transfer interactions of, 194f
CYP450 and, 268f
as hydrogen bond acceptor, 183f
oxygen of, 139
Ethinyl estradiol, 321f, 322
Ethylenediaminetetraacetic acid (EDTA), chelation of, 197, 197f
Ethyl group, 277
Excitable membranes, 17
Ezetimibe
dipole-dipole interactions of, 181
hydrogen bonds of, 187, 187f
F
Fβ adrenergic receptors, 31
Fenofibrate, 147f, 148
hydrolysis of, 276, 277f
SARs of, 324t
Fenofibric acid, 147f, 148, 324t
Fenoprofen, 32, 32f
aromatic hydroxylation of, 251f
conformational isomers of, 235, 235f
Fexofenadine, 325f
First-pass metabolism, 299
Fischer, Hermann Emil, 216
Fischer projections, 216–217
Flavin monooxygenase (FMO), 248, 250f
N-oxidation by, 264f
for sulfur oxidation, 268–270, 268f, 269f
Fluconazole, 326, 326f
Fluocinolone acetonide, 150f
Fluorine
electronegativity of, 21, 22, 22t, 179t, 180
as hydrogen bond acceptor, 139, 183f
lipophilic functional groups and, 28
Fluoroquinolones, drug interactions with, 198–199, 325, 325f
Fluoxetine, 18
Flurbiprofen
enantiomers of, 221, 223f
pH and pKa of, 103
Fluvastatin, 138t, 378–380
Fluvoxamine, 283f
Formaldehyde
methenamine and, 117
prodrug conversion of, 346–347, 346f
Fosamprenavir, 279f
Fosamprenavir calcium, 61f
Fosphenytoin, 342, 343f
Fosphenytoin sodium, 137t
Free acid, 129
Free base, 110, 133
Frovatriptan, 68, 68f
Fructofuranose sugars, 6, 6f
Fructose, 6, 6f
Fumarate, 226, 226f
Fumaric acid, 137t
Functional groups. See also specific types
on amino acids, 36–40, 37f
biological targets and, 31, 31f, 36
characteristics and roles of, 15–50
chemical properties of, 19–33
for COPD and asthma, 17–18
defined, 15–17
on DNA, 40–41, 41f
versus drug molecules, 72, 72f
electron donating, 23, 24f, 56
electronic effects of, 20–26, 21f–26f, 22t
electron withdrawing, 23, 24f, 25–26, 25f, 26f, 56, 59–60
electrophilic, 24–26, 24f–27f
hydrogen bonds of, 27–28, 28f
ionization of, 73–74, 109–110
molecular modification and, 328–331, 328f–331f
with nitrogen, 70–72, 71t, 72f
noncovalent bonds and, 174
nucleophilic, 24–26, 24f–27f, 29f, 30f, 60
on ribonucleic acid (RNA), 40–41
on RNA, 41f
solubility effects in, 26–30, 27f–30f
steric effects of, 30–33, 31f–33f
for water and lipid solubility, 149–151, 150f, 151f
Furanose rings, 6
Furan rings, 194f
Furosemide, 185, 185f
G
Gabapentin, 52–53, 53f, 63–64, 64f
Gauche conformation, 231, 231f
Gemfibrozil, 72, 72f
Gentamicin, 74f
cefepime and, 134–135, 135f
pH and pKa of, 110, 110f
Geometric isomers, 226–228, 227f
diastereomers and, 228f
Glucocorticoids
hydrolysis of, 276, 277f
lipid solubility of, 148, 149f, 150, 150f
Glucopyranose sugars, 6, 6f, 7–8
Glucose, 6, 6f
alpha/beta (α/β) designation of, 7–8
Glucuronic acid, 281–285, 283f–285f
conjugation of, 281t
Glucuronide, 281t, 282–285, 283f–285f
Glutamic acid, 39
acidic functional groups in, 177, 177f
binding interactions of, 196t
ionization of, 178, 178f
Glutamine, 40
amino acid conjugation of, 288f, 289f
binding interactions of, 196t
Glutathione, 24
aromatic hydroxylation of, 251, 252f
conjugation of, 281, 281t, 290–292, 290f, 291f
sulfate conjugation and, 286
Glyburide
molecular modification of, 329–330, 329f
pH and pKa of, 107
Glyceraldehyde, 216
Glycine, 37
amino acid conjugation of, 288f, 289f
binding interactions of, 196t
Glycosides, 279f
Glycosidic bonds, 9, 9f
Gout, 75, 111–112
Graham Solomons, T. W., 5, 13
Grimm’s Hydride Replacement Law, 331–334, 331f, 332t
Guanabenz acetate, 137t
Guanidine group, 66–67, 67f, 140f
in arginine, 116
ionization of, 175t
pKa of, 71t, 116
resonance delocalization of, 67
Guanine, 12, 13t
Guanosine monophosphate (GMP), 335, 336f
H
H2 receptor antagonists, 117, 326, 336–337, 337f
Halcinonide, 150f
Halogens, 140f
charge transfer reactions of, 195f
electronegativity of, 22, 22t
electron withdrawing functional groups of, 23, 24f
as electrophilic, 24
nonclassical isosteres of, 337t
oxidative dehalogenation of, 270–271, 271f
Haloperidol, 136f
Haloperidol decanoate, 148, 148f, 149–150
Hemiacetal sugars, 6, 6f
Hemiketal sugars, 6, 6f
Henderson-Hasselbalch equation, 85–86, 88–92, 89f, 100–108
for captopril, 95, 96
SARs and, 312
for tamoxifen, 96
Heparin
chemical antagonism of, 115–116, 116f
drug interactions with, 135, 136f
Heterocyclic nitrogens, 183f
Heterocyclic rings
charge transfer interactions of, 193–195, 194f, 195f
numbering of, 5
pH and pKa of, 102
Histidine, 40
angiotensin I and, 11
aryl-aryl stacking interactions of, 192–193
aspartic acid and, 177, 177f
binding interactions of, 196t
cation–π interaction of, 193
ionic bonds of, 176–177, 176f
ionization of, 177, 177f
HMG-CoA reductase inhibitors, 138, 138t
Homocysteine, 39
Homologation, 338–341, 339f–341f
Human immunodeficiency virus (HIV) protease inhibitors, 383–385
Human immunodeficiency virus (HIV) reverse transcriptase inhibitors, 331
Hydralazine, 65, 65f, 66
acetylation of, 292, 292f
conjugation of, 283f
Hydrazide group, 68, 175t
Hydrazine group, 65–66, 65f, 66
carbidopa and, 51
as hydrogen bond acceptor/donor, 186f
Hydrobromic acid, 129
Hydrocarbon chains, 338
Hydrocarbon rings, 188–190, 189f, 190f
Hydrochloric acid, 128, 129, 137t
Hydrocortisone, 148, 149f
Hydrocortisone butyrate, 149, 149f
Hydrogen
chirality of carbon and, 212
electronegativity of, 179, 179t, 180
Hydrogen bond acceptor, 28, 29f, 182–183, 183f, 186f
fluorine as, 139
Hydrogen bond donors, 28, 29f, 182–183, 183f, 186f
Hydrogen bonds, 181–187, 183f–187f
doxycycline and tetracycline and, 35, 35f
of functional groups, 27–28, 28f
hydrophilic functional groups and, 139
of hydroxyl group, 20, 131
lactones and, 142
metabolism and, 244, 245f
Hydrolysis, 275–279, 276f, 277f, 279f, 280f
prodrug conversion and, 343
Hydrophilic functional groups, 26–28, 27f, 28f
of bimatoprost, 143, 143f
drug molecule analysis for, 139, 140f
hydrogen bonds and, 139
organic salts in, 131, 132f
with ortho designation, 141
for penicillin G, 150–151, 151f
Hydrophobic functional groups, 28–30, 29f, 30
drug molecule analysis for, 139, 140f
ionic bonds of, 114, 114f
van der Waals interactions of, 190–192, 191f
3-hydroxy-3-methylglutaryl CoA (HMG-CoA), 315, 316f
Hydroxylamine
N-oxidation of, 263, 263f, 264
reduction of, 274f
sulfate conjugation of, 287f, 292
Hydroxyl group, 140f
in alendronic acid, 140, 141f
aliphatic amines and, 64–65
alpha/beta (α/β) designation of, 7–8
aromatic rings for, 58–60, 58f, 59f
carboxylic acid and, 74
charge transfer interactions of, 194f
chirality of carbon and, 211
conjugation of, 284
doxycycline and tetracycline and, 35, 35f
electron withdrawing functional groups of, 23, 24f
erythromycin and, 133, 134f
as hydrogen bond acceptor/donor, 183f
hydrogen bonds of, 20, 131
ketone reduction and, 272f
methylation of, 294
noncovalent bonds of, 174
as nucleophilic, 24
oxidation of, 266–268, 266f–268f
of phenol, 139
phenyl rings and, 22–23, 22f
of pravastatin, 142, 142f
prodrug conversion in, 341
resonance of, 20, 21f
SARs of, 321, 321f, 322–323, 322f
sulfate conjugation of, 287f
Hypertension, 319, 359–362
Hyperuricemia, 75
Hypoxanthine, 335
I
Ibandronate sodium, 74f
Ibuprofen, 1
alpha/beta (α/β) designation of, 7f
enantiomers of, 221
Imidazole ring
charge transfer interactions of, 194f
of histidine, 176–177
ketoconazole and, 117
Imide group
as acidic functional group, 27f
β-dicarbonyl groups and, 53, 55f
nitrogen and, 70
pH and pKa of, 71t, 102
Imine group, 65–66, 65f
ionization of, 175t
pKa of, 71t
Imipramine, 65f
Indole rings
aromatic heterocycles and, 68
charge transfer interactions of, 194f
Indomethacin, 285
Induced dipole-induced dipole interactions, 10f, 188–190, 189f
Inductive effect, 22–23
electron withdrawing functional groups and, 23
Influenza, 18
Ingold, Christopher, 217
Inorganic salts, 129–131, 130f
for lipid solubility, 146
Intensity, of pharmacodynamic effects, 17
Interferon-alpha, 343–344
Intrinsic induction, 21
Iodine, 22, 22t, 179t, 180
Ion-dipole interactions, 180–181
with amine, 131
with hydrophilic functional groups, 26
ionic bonds and, 175
Ionic bonds, 175–179, 176f–178f
of carboxylic acid, 32
of inorganic salts, 129
ion-dipole interactions and, 175
pKa and pH and, 114–115
Ionization
of acidic functional groups, 110, 174–175, 175t
of basic functional groups, 110, 174–175, 175t
chemical antagonism and, 115–116, 116f
with covalent bonds, 174
of functional groups, 73–74, 109–110
of glutamic acid, 178, 178f
of histidine, 177, 177f
lipid bilayers and, 110
of lipophilic functional groups, 113
of penicillin V, 129
of phenols, 113
of thioridazine, 129
Irbesartan, 328f
conjugation of, 283f
enantiomers of, 213, 214f
Isavuconazole, 344, 344f
Isavuconazonium sulfate, 344, 344f
Isoleucine, 38
binding interactions of, 196t
Isomeric sugars, 7
Isoniazid, 69f, 293, 293f
Isopropyl group
biological target selectivity and, 31
homologation and, 338
prodrugs, 147f, 148
Isoproterenol, 31, 31f
hydrogen bonds of, 183, 184f
methylation of, 294
SARs of, 317, 317f, 318f
Isosteres, 331–337, 331f, 332t, 333t, 334t, 335f–337, 337t
Isoxazole rings, 23, 24f
Itraconazole, 299–300
K
Keesom forces, 188
Ketoconazole, 117, 326, 326f
Keto form, of β-dicarbonyl groups, 54, 55f
Ketones
charge transfer reactions of, 195f
as hydrogen bond acceptor, 183f
hydroxyl group and, 266–268, 266f–268f
oxidative deamination of, 258
reduction of, 272–273, 272f, 273f
sugars and, 5–6
Ketoprofen
aromatic hydroxylation of, 251f
enantiomers of, 221, 222f
Ketose, 5–6
L
Labetalol
diastereomers of, 225, 225f
sulfate conjugation of, 287f
β-lactams, 33, 33f. See also specific drugs
acylation of, 169, 169f
covalent bonds of, 167
hydrolysis of, 278–279
SARs of, 314–315, 314f, 315f, 320–321
Lactones, 142, 261, 262f
Lamivudine, 331, 331f
Langmuir, Irving, 331–332
Lansoprazole, 117
Lead. See Molecular modification
Lemke, 5
Leucine, 38
binding interactions of, 196t
Levonorgestrel, 367–370
Levothyroxine, 59–60, 59f, 113, 113f
Lidocaine, 74f
chain branching of, 341, 341f
hydrolysis of, 275, 276f
metabolism of, 245–246, 245f
Lincomycin, 330, 330f
Liothyronine, 59–60, 59f, 113, 113f
Lipid bilayers, ionization and, 110
Lipid solubility. See also Lipophilic functional groups
drug interactions and, 326
enhancement benefits to, 154
metabolism and, 152–154, 152f, 153f, 244
optimizing, 146–152, 147f–151f
prodrug conversion and, 342t, 343
SARs and, 312, 323
water solubility and, 144–145, 145f
Lipophilic functional groups, 28–30, 29f, 30f
drug molecule analysis for, 139
homologation and, 338
ionization of, 113
organic salts in, 132–133, 132f
pH and pKa of, 113
of simvastatin, 142, 142f
Lomustine, 213
London dispersion forces, 188
Losartan, 188–190, 189f, 256f
Lovastatin, 18–19, 19f, 138t
Lysine, 40
binding interactions of, 196t
cation–π interaction of, 193
ionic bonds of, 176, 176f
M
Maleate, 226, 226f
Mechanism of action
of busulfan, 24
of pharmacodynamic effects, 17
of thiazides, 117
Mechlorethamine, 345–346, 345f
Medicinal chemistry, 1
Mefenamic acid, 318
Meperidine, 74f
oxidative N-dealkylation of, 259, 260f
van der Waals interactions of, 189, 189f, 191, 192f
Meprobamate, 283f
6-mercaptopurine, 335, 336f
Metabolism, 243–310. See also Conjugation; Oxidation
affecting factors on, 297–300, 298f–300f
chirality of carbon and, 211
cytochrome P450 (CYP450) and, 297–300
enzymes and, 245
general concepts of, 244–246, 245f
hydrolysis, 275–279, 276f, 277f, 279f, 280f
lipid solubility in, 244
phase II of, 280–297
phase I of, 246–280
of prodrugs, 246
reduction, 272–275, 272f–275f
solubility and, 152–154, 152f, 153f
steric hindrance on, 33, 33f
water solubility in, 244
meta designation, 4–5
aromatic hydroxylation and, 250–251
SARs and, 319
Metaproterenol, SARs of, 317, 317f
Metformin, 67f
Metformin, guanidine group and, 67
Methacholine, 18–19, 19f
enantiomers of, 221, 221f
Methadone, reduction of, 272, 273f
Methdilazine, 340f
Methenamine
formaldehyde and, 117
prodrug conversion of, 346–347, 346f
Methionine, 39
binding interactions of, 196t
methylation of, 295f
Methotrexate, 111
Methotrexate, pH and pKa of, 111
Methoxy group
electron donating functional groups and, 23, 23f
electron withdrawing functional groups of, 23, 24f
quinidine and, 68
α-methyl acetic acids, enantiomers of, 223–224, 223f
Methylation, 294–296, 295f, 296f
conjugation of, 281t
Methyldopa, methylation of, 294
Methyldopamine, enantiomers of, 222f, 223
α-methyldopamine, alpha/beta (α/β) designation of, 7f
Methylene group, 177
chirality of carbon and, 212
homologation with, 338–341, 339f–341f
van der Waals interactions of, 192
Methyl group, 18–19, 19f
amino acid conjugation of, 290
biological target selectivity and, 31
charge transfer interactions of, 194f
methylation of, 295
morphine and, 34, 34f
SARs of, 318
in simvastatin, 142, 142f
testosterone and, 34, 34f
Methylsalicylate, 114
Methyltestosterone, 321f, 322
Methyl-tetrazole-thiomethyl (MTT) group, 323–324
Metiamide, 336, 337
Metoclopramide, hydrogen bonds of, 185–186, 185f
Metoprolol
chirality of carbon of, 210–212, 211f
CYP2D6, 298, 299f
Metoprolol tartrate, 137t
Metronidazole, reduction of, 274f
Minoxidil, sulfate conjugation of, 287f
Mitoxantrone, 193
Mixed-function oxidases, 246
Molecular modification, 326–347
conformational restriction and, 327–328, 327f
functional groups and, 328–331, 328f–331f
homologation, 338–341, 339f–341f
of isosteres, 331–337, 331f, 332t, 334t, 335f–337f, 337t
prodrug conversion from active drugs, 341–347, 342t, 343f–347f
of sulfonylureas, 329–330, 329f
Monoethylglycinexylidide, 341, 341f
Monomethylauristatin E (MMAE), 344, 345f
Montelukast, 370–372
Morphine
conjugation of, 284, 285
deconjugation of, 280f
homologation of, 339, 339f
hydrogen bonds of, 182
methyl group and, 34, 34f
Morphine sulfate, 130f
Mutarotation, 7
N
Nabumetone, 346, 346f
N-acetyltransferase (NAT), 292–293, 292f
Nadolol, 372–375
Naphazoline, 66, 66f
Naproxen, 1
alpha/beta (α/β) designation of, 7f
enantiomers of, 221, 222f
SARs of, 324t
Naproxen sodium, 130f
SARs of, 324t
Nateglinide
conjugation of, 283f
ionic bonds of, 176, 176f
N-dealkylation, 289–290
Nefazodone, 195, 195f
Neostigmine
acylation of, 170–171, 171f
hydrolysis of, 279f
Neostigmine bromide, 72, 72f
conformational isomers of, 234, 235f
Newman projections, 230, 231f
Niacin, oxidative N-dealkylation of, 261, 262f
Nicardipine, oxidative N-dealkylation of, 260, 260f
Nifedipine, SARs of, 318, 318f
Nimodipine, acetylation of, 293, 294f
Nitrile group
aromatic rings of, 20, 21f
charge transfer reactions of, 195f
electron withdrawing functional groups of, 23, 24f
nonclassical isosteres of, 337t
pKa and pH of, 99
resonance of, 20, 21f
Nitrofurantoin, 274, 274f
Nitrogen, 70
alkyl group and, 62
amidine group and, 66–67
in aromatic heterocycles, 68–69, 68f, 69f
chelation and, 197
β-dicarbonyl groups and, 53, 54
electronegativity of, 21, 22, 22t, 179, 179t
guanidine group and, 67, 67f
as hydrogen bond acceptor, 183
N-oxidation and, 262–265, 263f–265f
resonance delocalization of, 67
Nitro group
charge transfer reactions of, 195f
electron withdrawing functional groups of, 23, 24f
reduction of, 273–274, 274f
SARs of, 318
Nitrone, N-oxidation of, 264, 264f
Nitroso, N-oxidation of, 263, 263f
Nitroso group, nitro group reduction and, 274, 274f
Nizatidine, 336
N-methyltransferase, 294
Nonclassical isosteres, 334, 335–336, 338
Noncovalent bonds, 166t, 173–200. See also Dipole interactions; Ionic bonds
functional groups and, 174
Nonelectrolytes, 59
Nonsteroidal anti-inflammatory drugs (NSAIDs)
acylation of, 170, 170f
conformational isomers of, 235, 235f
drug interactions with, 326
enantiomers of, 221–224, 223f
prodrug conversion of, 346, 346f
reductions of, 275
SARs of, 318, 318f, 319
Norethindrone, sulfate conjugation of, 287f
N-oxidation, 262–265, 263f–265f
NPH insulin
for lipid solubility, 148
as lipid-soluble, 133
N-terminus, ionic bonds of, 176, 176f, 177
Nucleic acids
binding interactions of, 196t
as biological targets, 17
nomenclature for, 12, 13t
Nucleophilic functional groups, 24–26, 24f–26f
alkylation of, 168, 168f
glutathione conjugation and, 291
methylation of, 296
thiols and, 60
Nucleosides, 12
O
Octapeptides, 10, 11f
O-dealkylation, 277f, 278
Ofloxacin, 376–378
Olamine, 137t
Omega (ω) designation, 6–8, 7f
Omeprazole, 117
chirality of carbon of, 210, 211f
prodrug conversion of, 347, 347f
Orbital hybridization, 3–4
Organic salts, 131–135
drug interactions of, 134–135, 135f, 136f
esters and, 134
in hydrophilic functional groups, 131, 132f
for lipid solubility, 146
in lipophilic functional groups, 132–133, 132f
Organophosphates, 171
Orphenadrine, 64, 64f
ortho designation, 4
aromatic hydroxylation and, 251–252
hydrophilic functional groups with, 141
SARs and, 317–318, 318f
Oseltamivir, 18, 277f, 388–390
Oxazole rings, 194f
Oxidation
of alicyclic carbon, 256–257, 256f, 257f
of aliphatic carbon, 253–256, 254t, 255f–257f, 256–257
of alkenes, 252, 252f, 253f
of amides, 258–265, 259f, 260f, 262f–265f
of amines, 258–265, 259f, 260f, 262f–265f
of aromatic nitrogen, 258–265, 259f, 260f, 262f–265f
of aromatic rings, 250–252, 251f, 252f
of benzylic carbon, 253–256, 254t, 255f
of carbon, 253–257, 254f–257f
of carbonyl group, 254–255, 255f
CPY450 for, 246–248, 247f, 248t, 249f
enzymes for, 246–249, 247f, 248t, 249f
of hydroxyl group, 266–268, 266f–268f
in metabolism, 246–271
of sp2 hybridized centers, 253–256, 254t, 255f
of sulfur, 268–270, 269f, 270f
Oxidative deamination, 258, 259f
Oxidative dehalogenation, 270–271, 271f
Oxidative N-dealkylation, 258–262, 259f, 260f, 262f
Oxime, 186f
2-oxoclopidogrel, 173, 173f
Oxygen
chelation and, 197
β-dicarbonyl groups and, 54
electronegativity of, 22, 22t, 179, 179t
of ethers, 139
as hydrogen bond donor, 183
inductive effect of, 23
Oxyphenbutazone, 54
P
Pamidronate disodium, 61f
para-aminobenzoic acid (PABA), 115, 115f
HIV reverse transcriptase inhibitors and, 331
SAR of, 313, 314, 314f
para designation, 4
Paroxetine, 251f
Partition coefficients
for HMG-CoA reductase inhibitors, 138, 138t
solubility and, 137–145, 138f, 140f–143f, 145f
Penicillamine, 60, 60f
chelation for, 197, 197f
Penicillin G, 25–26, 25f, 26f
alpha/beta (α/β) designation of, 7f
hydrophilic functional groups for, 150–151, 151f
SARs of, 324t
Penicillin G benzathine, 75f, 76
for lipid solubility, 148
as lipid-soluble, 132
SARs of, 324t
Penicillin V, 25–26, 25f, 26f
ionization of, 129
salt form of, 128
Pentazocine, 285, 296f
Pentobarbital, 256f, 267f, 270f
Peptides
designations for, 9–12, 10f–12f
functional groups and, 36–40, 37f
Perindopril, 277f
Peroxide group, 197
pH
antacids and, 117
biological targets and, 114
defined, 86–88
drug interactions and, 116–117, 326
drug therapy and, 108–118, 109f–111f, 113f–116f
duration of action and, 112–113, 113f
enantiomers and, 215
Henderson-Hasselbalch equation for, 85–86, 88–92, 89f, 100–108
ionic bonds and, 114–115, 175
ionization and, 174–175
partition coefficients and, 138
pKa and, 92–98
plasma proteins and, 113
quantitative problems for, 98–108
Rule of Nines for, 103–108
SARs and, 312
solubility effects of, 109–112, 109f–111f
solving problems of, 85–125
steric effects on, 86
Pharmacodynamics effects, 17
Pharmacogenomics, 297
Pharmacokinetic effects, defined, 17
Phase II metabolic transformations, 244
Phase I metabolic transformations, 243
Phenobarbital, 54, 55f, 73f
pKa and pH of, 101–102, 112
Phenolic group, 58–60, 58f, 59f, 140f
as acidic functional group, 27f
aromatic hydroxylation of, 251–252
aromatic rings of, 20
charge transfer interactions of, 194f
CYP450 and, 268f
as hydrogen bond acceptor/donor, 183f
hydroxyl group of, 139
ionization of, 113, 175t
pKa of, 71t
sulfate conjugation of, 287f
Phenolic hydroxyl group, 30
methylation of, 294–295
sulfate conjugation of, 287f
Phenol-O-methyltransferase (POMT), 294
Phenothiazines
chain branching of, 340–341, 341f
conformational restriction of, 327–328
Phenylalanine, 38
angiotensin I and, 11–12, 12f
aryl-aryl stacking interactions of, 192–193
binding interactions of, 196t
cation–π interaction of, 193
van der Waals interactions on, 189, 189f
Phenylephrine, aromatic hydroxylation of, 252, 252f
Phenylethyl group, 19–20, 22–23, 22f
Phenylpropanolamine, 296f
Phenyl rings, 20
charge transfer interactions of, 194–195, 194f, 195f
electron donating functional groups and, 23, 23f
hydroxyl group and, 22–23, 22f
Phenytoin, 54, 55f
chirality of carbon of, 211, 211f
drug interactions with, 326
prodrug conversion of, 342, 343f
Phenytoin sodium, 130f
Phosphates, 60–61, 61f
binding interactions of, 196t
hydrolysis of, 279f
ionization of, 175t
pKa of, 71t
3′-phosphoadenosine-5′-phosphosulfate (PAPS), 285, 286f
Phosphonates, 60–61, 61f
ionization of, 175t
pKa of, 71t
Phosphonic acid, 27f
5-phosphoribosyl 1-pyrophosphate (PRPP), 335, 336f
Phosphoric acid, 129, 137t
Phosphorus, 179t, 180
Phosphorylation, 171–172, 172f
Phosphoserine, 38–39
Phytonadione (vitamin K), 140–141, 141f
Pindolol, 74f
Pioglitazone, 283f
Piperidine rings, 192
Pitavastatin, 138t
Pitavastatin calcium, 137t
Pivalic acid, 148f
pKa
of acidic functional groups, 71–72, 72f
of basic functional groups, 71–72, 72f, 86–87
biological targets and, 114
defined, 86–88
drug interactions and, 116–117
drug therapy and, 108–118, 109f–111f, 113f–116f
duration of action and, 112–113, 113f
Henderson-Hasselbalch equation for, 85–86, 88–92, 89f, 100–108
ionic bonds and, 114–115, 175
ionization and, 174–175
pH and, 92–98
plasma proteins and, 113
quantitative problems for, 98–108
Rule of Nines for, 103–108
SARs and, 312
solubility effects of, 109–112, 109f–111f
solving problems of, 85–125
steric effects on, 86
structure activity relationships (SARs) and, 117
Plasma proteins
drug interactions and, 326
pKa and pH and, 113
(+)/(-) Designation, 8
Polyethylene glycol (PEG), 343–344
Potassium hydroxide, 129, 137t
Potassium penicillin V, 128, 129
Pravastatin, 138t, 378–380
hydroxyl group of, 142, 142f
partition coefficients of, 142, 142f
SARs of, 324t
Pravastatin calcium, 130f
Prazosin, 69, 69f
conformational isomers of, 229–230, 230f
SARs of, 319, 319f
Prednisolone, 324t
Prednisolone sodium phosphate, 146, 147f, 324t
Preferred conformations, 230–231
Prelog, Vladimir, 217
Presystemic metabolism, 299
Primaquine, 263, 263f
Probenecid, 289f
Procainamide, 65f, 334, 335, 341
acetylation of, 293, 293f
hydrolysis of, 278
pKa of, 91–92
Procaine, 334, 335, 341
Prochlorperazine, 264, 265f
Prodrugs
conversion from active drugs, 341–347, 342t, 343f–347f
hydrolysis of, 276, 277f
metabolism of, 246
for water and lipid solubility, 146–149, 147f–149f
Proline, 38
binding interactions of, 196t
Promethazine, 136f, 340f
Prontosil, 110–111, 111f
Propantheline, 338, 339
Propionic acid, 148f
Propranolol, 152–153, 152f
Propylthiouracil, 283f
Prostacyclin (PGI2), 170
Protamine sulfate, 115–116, 116f
Proteins. See also specific types
acidic functional groups in, 177–178, 177f
as biological targets, 17, 36
ionic bonds of, 176, 176f
sulfate conjugation and, 286
Proton pump inhibitors, 117
Protriptyline, 253f
Pteridine rings, 195f
Purine rings, 5
Purines, 12, 13t
Pyranose rings, 6
Pyridine, 68
Pyridine rings, 195f
Pyridostigmine bromide, 234, 235f
Pyrimidine rings, 5
charge transfer reactions of, 195f
Pyrimidines, 12, 13t
Pyrrole rings
aromatic heterocycles and, 68
charge transfer interactions of, 194f
as hydrogen bond acceptor/donor, 183f
Q
Quazepam, 270f
metabolism of, 153, 153f
partition coefficients of, 142–143, 142f
SARs of, 324t
Quetiapine fumarate, 137t
Quinapril, 380–383
Quinazoline rings, 195f
Quinidine, 69f, 225, 225f
Quinine, 225, 225f
Quinoline, 68
Quinoline rings, 195f
R
Raloxifene, 285, 285f
Ramiprilat, 199, 199f
Ranitidine, 269f, 336, 337
Rearrangement reactions, 173, 173f
Reduction, 272–275, 272f–275f
Reinforced ionic bonds, 185, 185f
Resonance
of carbonyl group, 20, 21f
of carboxylic acid, 20
of β-dicarbonyl groups, 54
electron withdrawing functional groups and, 23
of hydroxyl group, 20, 21f
of nitrile group, 20, 21f
sulfonamides and, 56
of thiols, 60
Resonance delocalization, 67
Ribofuranose sugars, 6, 6f, 7–8
Ribonucleic acid (RNA), 12
functional groups on, 40–41, 41f
molecular modification and, 330–331
Ribose, 6, 6f
alpha/beta (α/β) designation of, 7–8
Rizatriptan, 289–290, 289f
Rosuvastatin, 138t
R/S designations, 8, 216–220, 218f
Rule of Nines
of carboxylic acid of PABA, 115
for pKa and pH, 103–108
for uric acid, 112
S
S-adenosylmethionine (SAM), 25, 295f
Salicylic acid, 73f
amino acid conjugation of, 288f
ionic bonds on, 114, 114f
Salmeterol, 189–190, 190f, 339
oxidative N-dealkylation of, 261
Salts, 75–76, 75f. See also Inorganic salts; Organic salts
from acidic functional groups, 136–137, 137t
from basic functional groups, 75–76, 75f, 136–137, 137t
defined, 128–129
solubility and, 127–164
Saquinavir, 383–385
Sawhorse projections, 230, 231f
Schiff bases, 65
Serine, 38–39
binding interactions of, 196t
enantiomers of, 217
hydrogen bonds of, 182
Simvastatin, 18–19, 19f, 138t
hydrolysis of, 275, 276f, 278
lipophilic functional groups of, 142, 142f
methyl group in, 142, 142f
partition coefficients of, 142, 142f
SARs of, 324t
Single bonds, 3–4
S-methyltransferase, 294
Sodium chloride, 128
Sodium hydroxide, 128, 129, 137t
Sodium phosphate, 146–147, 147f
Sodium sulfacetamide, 75, 75f
Solubility. See also Lipid solubility; Water solubility
in functional groups, 26–30, 27f–30f
metabolism and, 152–154, 152f, 153f
partition coefficient and, 137–145, 138f, 140f–143f, 145f
of pH and pKa, 109–112, 109f–111f
Sorafenib, 386–388
sp2 hybridized centers, 253–256, 254t, 255f
Stedman, Edgar, 222–223
Stereochemical center, 7
Stereochemistry
with biological targets, 175
chirality of carbon, 210–213, 211f
conformational isomers, 228–236, 229f–232f, 234f, 235f
diastereomers, 224–228, 224f–228f
drug actions and, 209–242
enantiomers, 213–224, 214f, 215f, 218f, 218t, 221f–223f
Stereoisomers, 213
Steric effects
with biological targets, 175
of functional groups, 30–33, 31f–33f
on pH and pKa, 86
Steric hindrance
of enantiomers, 223–224, 223f
in hydrolysis, 278
on metabolism, 33, 33f
SARs and, 318
Steroids, 9, 10f
Streptomycin sulfate, 137t
Structure activity relationships (SARs), 3, 311–326
absorption, distribution, metabolism, and elimination (ADME) and, 320–323
of ACE inhibitors, 320f
ADME and, 321f, 322f, 324t
adverse drug reactions and, 323–326, 325f, 326f
of angiotensin converting enzyme (ACE) inhibitors, 319–320
of beta-lactams, 314–315, 314f, 315f, 320–321
binding interactions and, 316–320, 317f, 318f, 320f
of doxycycline, 322–323, 322f
drug interactions and, 323–326, 325f, 326f
of HMG-CoA, 316f
of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA), 315
pKa and, 117
of sulfisoxazole, 313, 314, 314f
of tetracycline, 322–323, 322f
"why" or "how" component of, 312–313
Sucralfate, 110, 110f
Sugars
binding interactions of, 196t
isomeric, 7
numbering of, 5–6, 6f
Sulfacetamide, 75, 75f
Sulfamethoxazole, 68, 68f
acetylation of, 293, 293f
pH and pKa of, 110–111, 111f, 115, 115f
SAR of, 313
sulfate conjugation of, 287f
Sulfanilamide
pH and pKa of, 110–111, 111f
SAR of, 313
Sulfates, 60–61, 61f
conjugation of, 281t, 285–287, 286f, 287f, 292
ionization of, 175t
pKa of, 71t
Sulfhydryl group, 60, 60f
complexation of, 199, 199f
electron withdrawing functional groups of, 23, 24f
glutathione conjugation and, 290–291
methylation of, 295
as nucleophilic, 24
Sulfisoxazole
conjugation of, 283f
SAR of, 313, 314, 314f
Sulfisoxazole diolamine, 131, 132f
Sulfonamide group, 55–57, 56f, 140f
as acidic functional group, 27f
carbonic anhydrase and, 335, 337f
conjugation of, 283f
electron withdrawing functional groups of, 23, 24f
as hydrogen bond acceptor, 187
as hydrogen bond acceptor/donor, 186f
ionization of, 175t
nitrogen and, 70
nonclassical isosteres of, 337t
pH and pKa of, 71t, 115, 115f
Sulfone, 268, 269f
as hydrogen bond acceptor, 186f, 187
Sulfonic acid, 27f
Sulfonyl group
nitrogen and, 70
pH and pKa of, 107
Sulfonylureas, 55–57, 56f
as acidic functional group, 27f
drug interactions with, 326
as hydrogen bond acceptor/donor, 186f, 187
hydrolysis of, 279f
ionization of, 175t
molecular modification of, 329–330, 329f
pKa of, 71t
Sulfoxide group, 268, 269f
reductions of, 275, 275f
Sulfur
chelation and, 197
chirality of carbon and, 210
electronegativity of, 179t, 180
methylation of, 295
oxidation of, 268–270, 269f, 270f
Sulfuric acid, 129, 137t
Sulindac, 275, 275f
Sumatriptan, 56, 56f
T
Tamoxifen
CYP2D6 and, 300, 300f
Henderson-Hasselbalch equation for, 96
oxidation of, 252, 252f
pKa and pH of, 94–95, 96
van der Waals interactions of, 189, 190f
Z isomer of, 227–228, 227f
Tamsulosin
conformational isomers of, 229, 229f
SARs of, 319, 319f
Tartaric acid, 137t
Tautomeric forms, of β-dicarbonyl groups, 54
t-butylacetic acid, 148f
Telmisartan, 328f, 329
Temazepam
metabolism of, 153, 153f, 245–246, 245f
partition coefficients of, 142–143, 142f
SARs of, 324t
Terbutaline, 18, 19, 317, 317f
Testosterone
methyl group and, 34, 34f
SARs of, 321, 321f
steroid nomenclature for, 9, 10f
Tetracaine, 293, 294f
Tetracycline, 35, 35f
chelation of, 198, 198f
drug interactions with, 325, 325f
metabolism of, 244, 245
SARs of, 322–323, 322f
Tetrahydrozoline, 66, 66f
Tetrazole, 329
ionization of, 175t
nonclassical isosteres of, 337t
pKa of, 71t
Tetrazole rings, 58, 58f
Thiazides, 75
carbonic anhydrase and, 116, 116f
mechanism of action of, 117
Thienopyridine, 167
Thiethylperazine, 268, 269f
Thioamide, 186f
Thiocarbonyl, 270, 270f
Thioesters, 186f
Thioethers
as hydrogen bond acceptor, 183f
oxidation of, 268
Thio-inosine monophosphate (T-IMP), 335, 336f
Thiols, 60, 60f
electron withdrawing functional groups of, 23, 24f
as hydrogen bond acceptor/donor, 183f
ionization of, 175t
pKa of, 71t
Thiopental, 270f
Thiophene rings, 194f
Thiophenol, 60, 60f
Thioridazine, 129
Thioridazine hydrochloride, 128, 129
Thiourea group, 337
as hydrogen bond acceptor/donor, 186f
nonclassical isosteres of, 337t
Threonine, 38–39, 180–181
binding interactions of, 196t
Thromboxane A2 (TXA2), 170
Thymine, 12, 13t
Ticlopidine, 64, 64f
Timolol maleate, 132f
Tirofiban, 56, 56f
Tobramycin, 74f, 140, 141f
Tocainide, 341, 341f
Tolazamide, 257
Tolmetin, 266–267, 266f
Tolterodine, 193
trans conformations, 231, 231f
trans designation, 251
Transfer RNA (tRNA), 198
trans isomers, 226–227, 227f, 228, 228f
Transpeptidase, 169, 169f
Transport proteins, 74–75
enantiomers and, 224
omeprazole and, 347, 347f
Triamcinolone, 150, 150f
acetone and, 150
SARs of, 324t
Triamcinolone acetonide, 150, 324t
Trientine, 197, 197f
Trifluoperazine, 340f
Trifluoroethyl group, 142
Trifluoromethyl group, 139, 143, 270
Trimethadione, 54, 55f
Trimethoprim, 268f
Trimethyllysine, 40
Tripeptides, 10–11, 11f
Triple bonds, 3–4
Tromethamine, 137t
Tryptophan, 38
aryl-aryl stacking interactions of, 192–193
binding interactions of, 196t
cation–π interaction of, 193
Tyrosine, 38–39
aryl-aryl stacking interactions of, 192–193
binding interactions of, 196t
cation–π interaction of, 193
hydrogen bonds of, 183, 184f
U
Uracil, 12, 13t
Urea group
as hydrogen bond acceptor/donor, 183f
nitrogen and, 70
Uric acid, 75
in gout, 111–112
pH and pKa of, 111–112
Rule of Nines for, 112
V
Valacyclovir, 277f
Valeric acid, 148f
Valine, 38
binding interactions of, 196t
Van der Waals interactions, 188–190, 189f, 190f
Verapamil, 98, 109–110, 109f
Vitamin K (phytonadione), 140–141, 141f
W
Warfarin, 73f
drug interactions with, 326
enantiomers of, 213, 214f
metabolism of, 297–298, 298f
reduction of, 272, 273f
Water solubility. See also Hydrophilic functional groups; Hydrophobic functional groups
of catechol rings, 251–252, 252f
drug interactions and, 326
enhancement benefits to, 154
lipid solubility and, 144–145, 145f
in metabolism, 244
metabolism and, 152–154, 152f, 153f
optimizing, 146–152, 147f–151f
prodrug conversion and, 342t, 343
SARs and, 312, 323
Z
Zafirlukast, 56, 56f, 370–372
pH and pKa for, 100
Zaleplon, 264, 265f
Zanamivir, 152, 152f, 388–390
Zidovudine, 331, 331f
Zileuton, 197–198, 198f
Z isomers, 227–228, 227f
Zwitterion form, 151
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