Phenolics

• Also known as “carbolic acid”. An aromatic organic compound with molecular formula
C6H5OH. Phenols are white crystalline solid that is volatile in nature and its molecule
consist of phenyl group bonded to a hydroxyl group. Phenol is mildly acidic and requires
careful handling due to it propensity to cause chemical burns.
Phenolics can be mainly classified into 2 groups:
a. The FLAVONOIDS
b. The NON-FLAVONOIDS

FLAVONOIDS CLASSES:
1. FLAVONOL
2. FLAVANONE
3. ISOFLAVONE
4. FLAVANOL
5. FLAVONE
6. ANTHOCYANIN

Quercetin
IUPAC NAME:
2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxychromen-4-one
USES: antioxidant and anti-inflammatory effects that might help reduce swelling, kill cancer cells,
control blood sugar, and help prevent heart disease

SAR:
Kaempferol
IUPAC NAME:
3,5,7-trihydroxy-2-(4-hydroxyphenyl)chromen-4-one
USES: used for the therapy of hormone-regulated cancers such as ovarian, breast, cervical,
hepatocellular carcinoma, and leukemia

SAR:
Hesperetin
IUPAC NAME:
(2S)-5,7-Dihydroxy-2-(3-hydroxy-4-methoxyphenyl)-2,3-dihydro-4H-1-benzopyran-4-one
USES: antioxidant, anti-inflammatory, anti-allergic, hypolipidemic, vasoprotective and
anticarcinogenic actions

SAR:
Naringenin
IUPAC NAME:
(2S)-5,7-Dihydroxy-2-(4-hydroxyphenyl)-2,3-dihydro-4H-1-benzopyran-4-one
USES: hepatoprotective, anti-atherogenic, anti-inflammatory, anti-mutagenic, anticancer,
antimicrobial agent
SAR:

Daidzein
IUPAC NAME:
7-Hydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one
USES: protect against chronic diseases that are common in Western societies, such as cancer,
osteoporosis, and ischemic heart disease

SAR:

• fits well into the active site of ERs and its two hydroxyl groups are involved in an important
hydrogen bonding network
• less favorable for the hydrophobic interaction
Epigallocatechin
IUPAC NAME:
(2R,3R)-5,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-1-benzopyran-3-yl 3,4,5-
trihydroxybenzoate
USES: reducing inflammation, aiding weight loss, and preventing certain chronic diseases

SAR:

Apigenin
IUPAC NAME:
5,7-Dihydroxy-2-(4-hydroxyphenyl)-4H-1-benzopyran-4-one
USES: anti-inflammatory compound can improve testosterone, boost sleep quality, protect
against cancer
SAR:

Luteolin
IUPAC NAME:
2-(3,4-Dihydroxyphenyl)-5,7-dihydroxy-4H-1-benzopyran-4-one
USES: medicine for treating various diseases such as hypertension, inflammatory disorders, and
cancer
SAR:

Delphinidin
IUPAC NAME:
3,5,7-Trihydroxy-2-(3,4,5-trihydroxyphenyl)-1λ4-1-benzopyran-1-ylium
USES: treatment of psoriasis
SAR:

Cyanidin
IUPAC NAME:
2-(3,4-Dihydroxyphenyl)-3,5,7-trihydroxy-1λ4-benzopyran-1-ylium
USES: reduce the chance of cancer

SAR:
NON FLAVONOIDS CLASSES:
1. HYDROXYCINNAMIC ACIDS
2. STILBENES
3. HYDROXYBENZOIC ACIDS

Hydroxycinnamic Acid:

- Derived from cinnamic acid, present in foods often as simple esters with quinic acid or glucose.
- Act as powerful antioxidants and protect biologically important molecules from oxidation.
- Biological effects being reported to reduce or even prevent cardiovascular disorders, cancer,
neurological disorders such as Alzheimer's and Parkinson's diseases.
CAFFEIC ACID
IUPAC NAME:
(2E)-3-(3,4-Dihydroxyphenyl)prop-2-enoic acid
USES: used in supplements for boosting athletic performance, exercise-related fatigue, weight
loss, cancer, HIV/AIDS, herpes, and other conditions

FERULIC ACID
IUPAC NAME:
(E)-3-(4-hydroxy-3-methoxyphenyl)prop-2-enoic acid
USES: helps to protect overall skin integrity by reducing the development of fine lines, spots, and
wrinkles

SAR:
• Antibacterial activity of phenolic acid increases at lower pH
• The decreasing number of hydroxyl groups with methoxy groups increases the activity of
hydroxybenzoic acid but have minor effects with hydroxycinnamic acid.
• The substitution of hydroxyl group increases the activity of hydroxybenzoic acid but not the
hydroxycinnamic acid
Hydroxybenzoic Acid:

- is a white crystalline solid that is widely used in organic synthesis.

- are used as preservatives in cosmetics and pharmaceuticals.
Mechanism of Action:

• They are postulated to act by disrupting membrane transport processes or by inhibiting

synthesis of DNA and RNA or of some key enzymes, such as ATPases and
phosphotransferases in some bacterial species.

VANILLIC ACID
IUPAC NAME:
4-Hydroxy-3-methoxybenzoic acid
USES: used as a flavoring agent
SAR:

SYRINGIC ACID
IUPAC NAME:
4-Hydroxy-3,5-dimethoxybenzoic acid
USES: used as a therapeutic agent in various diseases (diabetes, CVDs, cancer, cerebral
ischemia, neuro and liver damage)

STILBENES:

- Natural stilbenes are a group of polyphenols characterized by the presence of a 1,2-diphenyl

ethylene nucleus
- Stilbenes contain two benzene rings joined by a molecule of ethanol or ethylene.
- Stilbenes are principally found in grapes and berries as cis and trans isomeric forms of
resveratrol.
Mechanism of Action:
• Stilbenes have an extraordinary potential for the prevention and treatment of different diseases,
including cancer, due to their antioxidant, cell death activation, and anti-inflammatory properties.
• Stilbenes have shown ability to reduce the incidence of tumorigenesis by interfering with
molecular events at all steps, that is, initiation, promotion, and progression stages of
carcinogenesis.
SAR:

Pinosylvin: differs from Resveratrol in lacking one hydroxyl at C4’, which makes it more lipophilic
but losing its antioxidant activity,
Resveratrol: inhibits endothelin-1, a vascular tension group. The addition of 2 hydroxyl groups in
the 4 and 4’ position led to a significant decrease in total endothelin-1 secretion and in endothelin-
1 messenger RNA (mRNA) levels in human endothelial cells.
Polyphenols
• Polyphenols are plant-derived micronutrients. They're in many supplements, but you can
also get them from foods like fruits, vegetables, teas, and spices.
• Polyphenols are extremely potent antioxidants. They help to prevent or reverse cell
damage caused by aging, the environment, and your lifestyle. This damage has been
linked to an increased risk of many chronic diseases over time.
• Polyphenols are classified on the basis of the number of phenol rings that they contain
and of the structural elements that bind these rings to one another.

They are broadly dived in four classes;

▪ Phenolic acids
▪ Flavonoids
▪ Stilbenes
▪ Lignans

Flavonoid- compounds are products extracted from plants and they are found in several parts of
the plant. Flavonoids are used by vegetables for their growth and defence against plaques.

Rutin
IUPAC Name:
2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-3-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-
[[(2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxymethyl]oxan-2-yl]oxychromen-4-one

Uses: strengthen and increase flexibility in blood vessels, such as arteries and capillaries.
 SAR:

• Addition of thiosemicarbazide group showed the XO inhibition moderately

• Incorporation of hydrazide groupsremarkably increased the XO inhibitory action
• Addition of phenylthiosemicarbazide group significantly increased the XO Inhibition
• Presence of glcosidic 3-O rutinoside linkage is essential for the xanthine oxidase inhibitory
potential as detachment of group diminished theXO inhibitory activity

Quercetin
IUPAC Name:
2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxychromen-4-one
Uses: help reduce swelling, kill cancer cells, control blood sugar, and help prevent heart disease.

SAR:

• Replacement with OMe moiety keep the activity

• Replacement with OMe moiety enhanced the activity
• Both replaced with Ome moiety enhanced activity.
Stilbene - used in manufacture of dyes and optical brighteners, and also as a phosphor
(luminescence) and a scintillator.

Benznidazole
IUPAC name:
N-benzyl-2-(2-nitro-1H-imidazol-1-yl)acetamide

Uses: treat a certain parasitic infection (Chagas disease).

SAR:
▪ Introduction of different polarized substituents at 5-positions affects ythe activity.
▪ Decrease in the length of the alkyl linker reduces anti-HBV activity dramatically.
▪ Introduction of one methyl group on the ethylene chain also decreases the activity

Lignans - a large group of low molecular weight polyphenols found in plants, particularly seeds,
whole grains, and vegetables.
Medioresinol
IUPAC name:
N-benzyl-2-(2-nitro-1H-imidazol-1-yl)acetamide
Uses: reduce the cardiovascular disease risk.

SAR:

• Presence of carbonyl group at C-7' might enhance antitumor effect OMe.

• The hydroxyl group at C-4/4' was substituted by other groups, and H-5/5 was not
substituted, which could improve antitumor activity
• The more methoxy groups were substituted, the worse the antioxidant activity could be
• The type of sugar substituent was related to the inhibition of glucosidase activity enhanced
anti-inflammatory effect
• The antitumor effect could be decreased if the carbonyl was introduced
 • H-5 not substituted for enhanced anti-inflammatory effect OMe

Phenolic acids - one of the main classes of plant phenolic compounds. They are found in the
variety of plant-based foods viz. seeds, skins of fruits and leaves of vegetables contain them in
highest concentrations.

Salicylic acid
IUPAC name: 2-hydroxybenzoic acid
Uses: treat many skin disorders, such as acne, dandruff, psoriasis,seborrheic dermatitis of the
skin and scalp, calluses, corns, common warts, and plantar warts

SAR
• If the position of -OH group is changed to Meta or Para w.r.t-COOH group, the activity
abolish.
• Removing-OH group reduces its activity.
• Acetylation of Salicylic acid will give Aspirin a potent Analgesic compound.
• GIT side effects are associated with -COOH group.
• Substitutions of ring will decrease its activity.
• Substitution of halogen atoms on aromatic ring increases the potency and toxicity of
salicylic acid
Alkaloids

• Alkaloids are important chemical compounds that serve as a rich reservoir for drug
discovery. Several alkaloids isolated from natural herbs exhibit antiproliferation,
antibacterial, antiviral, insecticidal, and antimetastatic effects on various types of cancers
both in vitro and in vivo. Therapeutically, alkaloids are particularly well known as
anaesthetics, cardioprotective, and anti-inflammatory agents. Well-known alkaloids used
in clinical settings include morphine, strychnine, quinine, ephedrine, and nicotine.
Class of Alkaloids
Pyrrolidine
Tropane
Pyridine
Piperidine
Isoquinoline
Imidazole
Indole
Purine
Tropolone
Thiazole
Oxazole derivatives
Isoxazole derivatives
Pyrrolidine
- Alkaloids containing one nitrogen atom as part of a five-membered ring
Nicotine
IUPAC NAME:
3-(1-methyl-2-pyrrolidinyl)pyridine
Uses:
Used to help treat addiction to or dependence on smoking cigarettes.

SAR:

• The R1, R2, and R3 position is detrimental to the binding affinity.

• A large substituent at the R2α or R3α position as well as a hydrogen bond accepting
substituent at the R2β position are not beneficial to the binding.
Tropane
- Tropane alkaloids are a class of bicyclic alkaloids and secondary metabolites that contain
a tropane ring in their chemical structure.

Atropine
IUPAC NAME:
(RS)-(8-Methyl-8-azabicyclo[3.2.1]oct-3-yl) 3-hydroxy-2-phenylpropanoate
Uses:
Used to reduce saliva and fluid in the respiratory tract during surgery.

SAR:

Scopolamine
IUPAC NAME:
(–)-(S)-3-Hydroxy-2-phenylpropionic acid (1R,2R,4S,5S,7α,9S)-9-methyl-3-oxa-9-
azatricyclo[3.3.1.02,4]non-7-yl ester
Uses:
Prevent nausea and vomiting caused by motion sickness or medications used during surgery.
SAR:
N substituent can be quaternary ammonium salt or tertiary amine or both with different alkyl
groups,
Pyridine
- a class of alkaloids, nitrogen-containing chemical compounds widely found in plants, that
contain a pyridine ring.

Isoniazid
IUPAC NAME:
Pyridine-4-carbohydrazide
Uses:
Antibiotic used for the treatment of tuberculosis.

SAR:

• Pyridine ring is essential for activity.

• Substitution of R-1, R-2 at N-2 leads to variable activity.
 • Addition of isopropyl group at position R-2 results in loss of anti-tubercular activity but
exhibit psychomotor stimulant activity, while acetyl isoniazid is inactive.
• Any substitution (Alkyl) at R-3 results in loss of activity
• NH is most active derivative.
Ethionamide
IUPAC NAME:
2-ethylpyridine-4-carbothioamide
Uses:
It is used together with other medicines to treat tuberculosis (TB).

SAR:

• Contains ethyl group at position 2.

• A 2nd line anti TB agent, analogue of isonicotinamide but it is di-substituted and contains
S in place of O.

Piperidine
- This heterocyclic amine consists of a six-membered ring containing five methylene bridges
(–CH2–) and one amine bridge (–NH–).
Piperine
IUPAC NAME:
(2E,4E)-5-(2H-1,3-Benzodioxol-5-yl)-1-(piperidin-1-yl)penta-2,4-dien-1-one
Uses:
Against chronic diseases, such as reduction of insulin-resistance, anti-inflammatory effects, and
improvement of hepatic steatosis.

SAR:

• Essential for MAO-A inhibition

• Short chain derivatives are more selective for hMAO-B than hMAO-A
• Replacement with amine moiety results in increased hMAO-B inhibition then hMAO-A
• Introduction of O at N decrease MAO potential

Isoquinoline
- Isoquinoline is a heterocyclic aromatic organic compound. It is a structural isomer of
quinoline. Isoquinoline and quinoline are benzopyridines, which are composed of a
benzene ring fused to a pyridine ring.
Morphine
IUPAC NAME:
(4R,4aR,7S,7aR,12bS)-3-methyl-2,4,4a,7,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-
e]isoquinoline-7,9-diol
Uses:
to relieve moderate to severe pain.

SAR:
1. Modification on alicyclic ring

• The alcoholic hydroxyl group at C-6 when methylated, esterified, oxidized, removed, or
replaced by halogen analgesic activity as well as toxicity of the compound increased. The
reduction of C-6 keto group to C-6 ẞ hydroxyl in oxymorphone gives Nalbupine, it shows
antagonistic action of µ receptors.
• The saturation of the double bond at C-7 position gives more potent compound. Examples,
Dihydro morphine and Dihydro codeine.
• The 14 ẞ hydroxyl group generally enhances µ agonistic properties and decreases
antitussive activity. However, activity varies with the overall substitution on the structure.
• Bridging of C-6 and C-14 through ethylene linkage gives potent derivatives.
• Reaction of thebaine with dienophile (i.e diel's alder reaction results in 6, 14 endo etheno
tetrahydro thebaine derivatives, which are commonly called oripavines' Some oripavines
are extremely potent u agonist, for example, Etorphine and Buprenorphine are the best
known. These derivatives are about a thousand times more potent than morphine as u
agonist.
2. Modification on phenyl ring

• An aromatic phenyl ring is essential for activity.

• Modification on phenolic hydroxyl group decreases the activity.
 • Any other substitution on phenyl ring diminishes activity.
3. Modification of 3° nitrogen

• A tertiary amine is usually necessary for good opioid activity.

• The size of the N substitution can dictate the compounds potency and its agonists and its
reverse antagonistic property.
• The N-methyl substitution is having good agonistic property, when increased the size of
the substitution by 3-5 carbons results in antagonistic activity. Still larger substituent on N
returns agonistic property of opioids, for example, N-phenyl ethyl substitution is ten times
more potent than N-methyl groups.
• N-allyl and N-cylo alkyl group leads to narcotic antagonistic property.
4. Epoxide Bridge

• Removal of 3,4 epoxide bridge in morphine structure result in the compound that is refered
to as morphinans.
• The morphinans are prepared synthetically. As the synthetic procedure yielded compound
is a racemic mixture, only levo isomer possesses opioid activity while the dextro isomer
has useful antitussive activity, for example, Levorphanol and Butorphanol.
• Levorphanol is a more potent analgesic than morphine.
Codeine
IUPAC NAME:
(5α,6α)-7,8-didehydro-4,5-epoxy- 3-methoxy-17-methylmorphinan-6-ol
Uses:
used to treat pain, coughing, and diarrhea. It is also commonly used as a recreational drug.

SAR:

• Naturally occurring opium

• Replacement of -OCH3 at C3
 • Also known as 3-methyl ether morphine.
• --OCH3 causes weak Mu-agonist activity.
• Analgesic activity reduced to 10%, but antitussive activity is retained.
• --OH at C6 causes histamine release and allergic response if given parentally.
Berberine
IUPAC NAME:
7,8,13,13a-tetradehydro-9,10-dimethoxy-2,3-[methylenebis(oxy)]berbinium
Uses:
Used as an antimicrobial, stomachic, bitter tonic and in the treatment of oriental sores.

SAR:

• Dioxolane ring
• Essential for lipid lowering activity, strong inhibitory effects, essential for anti-diabetic
activity
• C13-Introducing alkyl groups, heteroaromatic ring improves antibacterial and anticancer
activities.
• Substituting with hydroxyl groups shows notable hypoglycemic activity.
• Substitution at N-7, C-13 decreases lipid lowering activity,
• Methoxy group at C-10. C-11 enhances anti-diabetic and lipid lowering activity.
Imidazole
- Imidazole alkaloids contain an imidazole nucleus and are derived from histidine.
Pilocarpine
IUPAC NAME:
(3S,4R)-3-Ethyl-4-((1-methyl-1H-imidazol-5-yl)methyl)dihydrofuran-2(3H)-one
Uses: Used to treat glaucoma and ocular hypertension.

SAR:

• Pilocarpine is a cholinergic parasympathomimetic agent.

• In particular it stimulates muscarinic receptors.
• Therefore, it increases the retention of exocrine glands and produces contraction of the
iris, sphincture muscle and ciliary muscle
Indole
- a class of alkaloids containing a structural moiety of indole.
Indomethacin
IUPAC NAME:
2-[1-(4-chlorobenzoyl)-5-methoxy-2-methylindol-3-yl]acetic acid
Uses:
Used for gouty geoarthritis, osteoarthritis, rheumatoid arthritis, ankylosing spondylitis

SAR:

• Replacement of the carboxyl group with other acidic functionalities decreases the activity.
• As the acidity of the carboxyl group increases, the anti-inflammatory activity of drug also
increases and vice-versa.
• Amide analogues are inactive.
• Acylation of indole nitrogen decreases the activity.
• N-benzoyl derivatives substituted in the para-position with fluoro, chloro, trifluoromethyl or
thiomethyl group are most active.
• Substitution on the indole ring with groups like methoxy, fluoro, dimethylamino, methyl,
allyloxy or acetyl increases the activity of drug.
• Nitrogen atom on the indole ring is not important for the activity of the drug.
• Alkyl substitution at the α-position is more active than the aryl substitutions.
• Only S-(+)-enantiomers shows the anti-inflammatory activity.
Purine
- The purine alkaloids are a distinct form that have a nitrogen containing ring structure
resembling that of purine.
Adenine
IUPAC NAME:
7H-purin-6-amine
Uses:
Used to make one of the building blocks of DNA and RNA

SAR:

• N7 is required for antagonist activity (8-Br-7-Deaza- ADPR is inactive)

• NH2 group at C6 is required for agonist activity (IDPR is very weak agonist)
• Hydrophobic substituents at C8 results in antagonists (8-Br, 8-Ph-, 8-thiophenyl-, 8- (3-
Ac- Ph-) ADPR)
• 2-F-ADPR is an agonist
Xanthine
IUPAC NAME:
3,7-dihydropurine-2,6-dione
Uses:
Derivatives are for relief of bronchospasm caused by asthma or chronic obstructive lung disease.
SAR:

Tropolone
- Tropolones refer to non-benzenoid seven-membered aromatic compounds with a
carbonyl group, which are also called troponoids or tropolonoids.

Colchicine
IUPAC NAME:
N-[(7S)-1,2,3,10-tetramethoxy-9-oxo-6,7-dihydro-5H-benzo[a]heptalen-7-yl]acetamide
Uses:
Used to prevent gout attacks
SAR:
Thiazole
- Thiazole, or 1,3-thiazole, is a heterocyclic compound that contains both sulfur and
nitrogen.

Thiamine
IUPAC NAME:
2-[3-[(4-amino-2-methylpyrimidin-5-yl)methyl]-4-methyl-1,3-thiazol-3-ium-5-yl]ethanol;chloride
Uses:
Used to treat beriberi and to treat and prevent Wernicke-Korsakoff syndrome
SAR:
• Methylene bridge.
• Amino group in the pyrimidine ring.
• Hydroxy ethyl group at the thiazole ring.
Methyl group of pyrimidine ring, when replaced by:
• a-Ethyl or propyl groups gives an active compound.
• b- Butyl group gives inactive compound.
Oxazole
- Oxazole chemicals are a unique class of five-membered monocyclic heteroarenes,
containing a nitrogen atom and an oxygen.

Oxaprozin
IUPAC NAME:
3-(4,5-diphenyl-1,3-oxazol-2-yl)propanoic acid
Uses:
Used to relieve pain, tenderness, swelling, and stiffness caused by osteoarthritis
SAR:

• Substituents on 5-phenyl preferred; similar SAR on 4-phenyl with lower overall potency.
• Replacement by pyrazole leads to ~10 fold loss of potency
• 3,5- disubstitutional favored, -Cl and -CF3 favored.
• Longer chains decrease efficacy towards partial agonism; shorter chains inactive.
• Carboxylic acid is essential.
Isoxazole

Cycloserine
IUPAC NAME:
(4R)-4-amino-1,2-oxazolidin-3-one
Uses:
To treat tuberculosis (TB)
SAR:
• This ring system is also called oxazolidine.
• Naturally obtained as d-isomers (more active)
• Contain Keto group at position 3 (oxo group) and NH2 at position 4
• Investigation shows that replacement of carboxyl group at position 3 with thiocarbonxyl
sulphur (S)-- it increases antibacterial activity.
Sulfamethoxazole
IUPAC NAME:
4-amino-N-(5-methyl-1,2-oxazol-3-yl)benzenesulfonamide
Uses:
to treat infections including urinary tract infections, middle ear infections (otitis media), bronchitis,
traveler's diarrhea, and shigellosis (bacillary dysentery).

SAR:

• Compound having a methyl substituent at the 5-position and a 4-

aminobenzenesulfonamide group at the 3-position.