Vitamins-Medicinal Chemistry MANIK

and
PHARM 3127: Medicinal Chemistry
Vitamin
Md. Imran Nur Manik
Lecturer
Department of Pharmacy
Northern University Bangladesh

Natural Products and Secondary Metabolites: VITAMINS
Prepared By: Md. Imran Nur Manik; B.Pharm; M.Pharm Page 1
manikrupharmacy@gmail.com; Lecturer; Department of Pharmacy; Northern University Bangladesh.
Vitamins
Syllabus for Vitamins: clinical aspects of vitamins, and effects of free
radicals, synthesis of vitamins: vit-c, nicotinamide, and mechanism of action
of vitamins.
Definition:
Vitamins are organic chemical compounds/substances which cannot be synthesized
(in sufficient quantities) in the body but are essential for normal metabolic
functions/reactions.
Vitamins do not furnish energy and they aren’t used as building units for cellular
structures. Lack of specific vitamins leads to distinctive deficiency states such as
Beriberi, Rickets, and Scurvy etc.
Classification:
It is convenient for a number of purposes to classify the vitamins as-
(1) Fat soluble and
(2) Water soluble.
Fat soluble vitamins:
The vitamins which are soluble in fat solvents (dietary and body fat) but relatively
insoluble in water, their absorption from the intestinal tract is associated with that of
lipids and are stored in the body in same fashion as fat are known as fat soluble
vitamins. Fat soluble vitamins are vitamin A, D, E & K.
It can be noted that fat soluble vitamins might be toxic in large doses and are
stored in the body for a long period. Their deficiency state may be caused by conditions
that impair fat absorption.
Water soluble vitamins:
These vitamins are soluble in water but generally not soluble in lipid (however
some are slightly soluble in certain organic solvents) and therefore easily eliminated
from the body.
The water soluble vitamins are vitamin B complex (including vitamin H also
known as vitamin B7) and vitamin C. Our discussion will be confined within the
water-soluble vitamins.
It should be noted that since water-soluble vitamins are easily excreted, they
have greater chance of being deficit than being overabundant.
Md.
Imran
Nur
Manik

Vitamin C:
Introduction:
Vitamin C or Ascorbic acid (toxic to viruses, bacteria and some malignant tumor
cells) is a naturally occurring vitamin which prevents scurvy and has antioxidant
properties. It is a water soluble vitamin.
O
HO
HO
O
OH
OH
O
C
CH2OH
HO H
O
OHHO
Ascorbic acid
Deficiency symptoms:
Scurvy: It consists of the degeneration of collagen and intracellular ground
substances resulting in disturbances of bone growth, hemorrhage of the gums and other
part of the body, loosening of the teeth, capillary fragility with consequent cutaneous
hemorrhages and other abnormalities.
Synthesis:
The synthesis of vitamin C is done from D-glucose. It is a semi-synthesis.
In this process D-glucose is hydrogenated to D-sorbitol which by oxidation with
Acetobactor suboxydans (fermentation) yields L-sorbose. When L-sorbose is treated
with acetone in the presence of conc. H2SO4 and the catalyst (used in dehydrogenation)
diacetone sorbose is formed. When it is oxidized with KMnO4 in strong alkaline medium
diacetone sorburonic acid is formed which upon heating with conc.
HCl gives 2-keto-L-gulonic acid. This when treated with a solution of aqueous HCl in
ethanol-chloroform solvent leads to ascorbic acid.
Uses:
1. Prevention and treatment of scurvy
2. Facilitation of healing and recovery from extensive burns and severe trauma
3. Treatment of some types of anemia (associated with scurvy)
4. Maintenance of an acidic urine
Md.
Imran
Nur
Manik

C
C
C
C
CH2OH
H OH
HO H
H OH
H OH
H O
H2, CuCl
CH2OH
C
C
C
C
CH2OH
H OH
HO H
H OH
H OH
D-SorbitolD-Glucose
Bacteria
Acetobactor
suboxydans
Oxidation
CH2OH
C
C
C
C
CH2OH
H OH
HO H
H OH
O
CH2OH
C
C
C
C
CH2OH
HO H
H OH
HO H
O
CH2OH
C
C
C
C
CH2OH
HO H
H OH
H
HO
O
L-Sorbose
Inverted formula Furanose form
Acetone, CuSO4
CH2OH
C
C
C
C
H2C
H
H
H
O
O
O
C
H3C
H3C
O
O
C
CH3
CH3
Diacetone sorbose
KMnO4
Strong alkaline
medium
COOH
C
C
C
C
H2C
H
H
H
O
O
O
C
H3C
H3C
O
O
C
CH3
CH3
COOH
C
C
C
C
CH2OH
HO H
H OH
HO H
O
Diacetone sorburonic acid
2-keto-L-gulonic acid
Conc. HClHeat
Aqueous HCl
CHCl3-ethanol
solution
O
HO
HO
O
OH
OH
Ascorbic acid
Dosage:
1. Prophylactic dose → 45-60 mg/per day via oral or IM routes, during pregnancy and
lactation an additional 20-40 mg is required.
2. Therapeutic dose:
a. Treatment of scurvy → 100 mg three times daily for several weeks
b. For severe burns → 200-500 mg daily
Md.
Imran
Nur
Manik

Mechanism of action
Vitamin C plays a role in many oxidative and other metabolic reactions, e.g.
Hydroxylation of proline and lysine residues of protocollagen—essential for formation
and stabilization of collagen triple helix;
Hydroxylation of carnitine,
Conversion of folic acid to folinic acid,
Biosynthesis of adrenal steroids, catecholamines, oxytocin and vasopressin and
metabolism of cyclic nucleotides & prostaglandins.
It directly stimulates collagen synthesis and is very important for maintenance of
intercellular connective tissue. A number of ill-defined actions have been ascribed to
ascorbic acid in mega doses, but none is proven.
Vitamin C also acts
As an antioxidant (reacting directly with aqueous free radicals), which is important in
the protection of cellular function; and
To enhance the intestinal absorption of nonhaem iron.
Fig. Collagen structure
Md.
Imran
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Manik

Vitamin B-complex
B-complex group of vitamins comprise a large number of water soluble vitamins which
are nutritional essentials for all forms of life, from the lowest form of yeast and bacteria
to the highest form, the man.
Apart from being important nutritionally, they form essential co enzymes to certain
important intracellular enzyme systems. There are about individual components, most of
them are synthesized by the microbial flora.
Components of vitamin B complex are:-
1. Thiamine – Vit B1
2. Riboflavin – Vit B2
3. Niacin – Vit B3
4. Pantothenic acid – Vit B5
5. Pyridoxine – Vit B6
6. Biotin – Vit B7
7. Folic acid group
8. Cyanocobalamin – Vit B12
Vitamin B1 (thiamine):
Introduction:
Vitamin B1 known as thiamine is a water-soluble vitamin that occurs in moderate
to rich quantity in dried yeast, nuts, rice, egg yolks, brans and some other vegetable. It is
biotransformed inside the body and function as co-enzyme in several metabolic
processes.
N
N
H
H3C
N
S
CH3
OH
NH2
Thiamine
Beriberi. It is manifested in mainly two forms-
1. Dry beriberi → main symptom is polyneuropathy (affect the nervous system)
2. Acute wet beriberi → Affect the CVS. Predominant symptoms are edema and
serous effusions
3. Infantile beriberi affects the children of malnourished mothers
4. Gastrointestinal beriberi affects the digestive system and other bodily systems
Md.
Imran
Nur
Manik

Synthesis:
N
N
H
H3C
N
S
CH3
OH
NH2
N
N
H3C
Cl
NH2
N
S
CH3
OH+
Condensation
2-methyl-4-amino-5-
chloromethylpyrimidine
hydrochloride
4-methyl-5-
( -hydroxyethyl)
thiazole

Thiamine
Thiamine is rather synthesized than being isolated/ extracted from the food sources. It is
synthesized by the direct condensation of 2-methyl-4amino-5-chloromethylpyrimidine
hydrochloride and 4-methyl-5-(β-hydroxymethyl) thiazole.
Uses:
1. In thiamine deficiency situations e.g. beriberi, neuritis associated with pregnancy
and neuritis of pellagra
2. Chronic alcoholism
3. Wernicke’s encephalopathy
Dosage:
5 -10 mg three times daily via oral, IM or IV route.
Biochemical functions (general):
Thiamine functions as a coenzyme in the oxidative decarboxylation of alpha-ketoacids
(involved in energy production) and in the transketolase reaction of the pentose
phosphate pathway (involved in carbohydrate metabolism).
The enzyme thiamine pyrophosphate (TPP) or co-carboxylase is intimately connected
with the energy releasing reactions in the carbohydrate metabolism.
TPP also plays an important role in the transmission of nerve impulse. This is because
TPP is required for acetylcholine synthesis and the ion translocation of neural tissue.
Functions of B1 (Specific examples):
1. Enzyme cofactor: (Thiamine pyrophosphate TPP or TDP)
A. Decarboxylation reactions
a) Pyruvate dehydrogenase
b) α-ketoglutarate dehydrogenase
c) α-keto acid dehydrogenase – branched chain amino acid metabolim.
B. Transketolation reactions
a) Transketolase – Pentose Phosphate pathway
Md.
Imran
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Manik

A. Decarboxylation
reactions
a) Pyruvate
dehydrogenase complexes
to TPP:
It catalyzes the breakdown
of pyruvate, to acetyl CoA,
and carbon dioxide.
b) Alpha ketoglutarate
dehydrogenase:
Requires TPP in the
decarboxylation of alpha
ketoglutarate to succinyl
CoA and CO2.
c) α-keto acid
dehydrogenase
– branched
chain amino
acid metabolim.
B. Transketolation reactions
Transketolase: The second group of enzymes that use TPP as co-enzyme are the
transketolases, in the Pentose phosphate pathway ( PPP ) of glucose.
Md.
Imran
Nur
Manik

Vitamin B2 (Riboflavin):
Introduction:
Riboflavin, also known as vitamin B2 is a
water-soluble vitamin occurring widely in animal and
plant foodstuff. It is converted into FAD (flavin adenosine
dinucleotide) and necessary for metabolic processes.
1. Well defined deficiency syndrome consists of
Cheilosis, glossitis, Seborrheic follicular keratosis of
nose and forehead, burning feet etc.
2. Loss of hair (alopecia)
3. Lesions of the skin, eyes, lips, mouth and genitalia.
Synthesis:
H3C
H3C
NH
(CHOCOCH3)3
OCOCH3
O2N N NCl
H3C
H3C
NH
(CHOCOCH3)3
OCOCH3
N N NO2
NH
H
N OO
O
H3C
H3C
N
1
2
3
4
N
N
NH
O
O
OH
HO
OH
5
OH
+
Barbituric acid
4, 5-dimethyl-N-(1'-ribityl) aniline
tetraacetate
4-nitro-phenyldiazonium chloride
Azoderivative Riboflavin
Reaction between 4, 5-dimethyl-N-(1’-ribityl) aniline tetraacetate and 4-nitro-
phenyldiazonium chloride yields an azoderivative which upon reaction with barbituric
acid yield riboflavin.
N
N
NH
NH3C
H3C
O
O
OH
HO
OH
OH
Riboflavin
Md.
Imran
Nur
Manik

Uses:
1. In well-defined vitamin B2 deficiency syndrome
2. It may also help in deficiency syndromes of other vitamin-B-complex.
Usually after the age of 40-45 vitamin deficiency becomes more pronounced. For example
deficiency of vitamin B-complex will lead to lesions of the mouth (and other types of
wounds of the mouth). Then vitamin B administration becomes necessary. Usually
riboflavin is given with other B-complex vitamins as multivitamin preparations.
Dose:
5-25 mg daily via oral route preferably in a preparation containing other B-complex
vitamins.
Functions of B2:
Riboflavin functions as a component of two flavin coenzymes – flavin mononucleotide
(FMN) and flavin adenine dinucleotide (FAD). Riboflavin through its coenzymes Flavin
mononucleotide (FMN) and Flavin adenine dinucleotide (FAD) takes part in a variety of
cellular oxidation-reduction reactions and in energy production. Examples include the
oxidation of glucose, certain amino acids and fatty acids; reactions with several
intermediaries of the Krebs cycle; conversion of pyridoxine to its active coenzyme; and
conversion of tryptophan to niacin.
Riboflavin has a role as an antioxidant. It may be involved in maintaining the integrity of
erythrocytes.
Some of the specified roles are as follows:
Integral component of electron transport chain ATP Synthesis ----NADFMNCoQ
Component of several enzymes in the metabolic pathway
• TCA cycle  succinate dehydrogenase
• Fatty Acid Oxidation  acyl CoA dehydrogenase
• Amino acid oxidation As a part of alpha ketoglutarate
• Isocitrate dehydrogenase complex ( dihydrolipoate dehydrogenase)
 FMN-dependent Enzymes
During the amino acid oxidation, FMN
is reduced. It is re-oxidized by
molecular oxygen to produce
hydrogen peroxide.
Md.
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 FAD-dependent enzymes
a) Conversion of Succinate to fumarate by succinate dehydrogenase in TCA requires
FAD.
b) Conversion of Pyruvate to acetyl CoA requires FAD,NAD as part of the Pyruvate
dehydrogenase.
c) NAD is also required in the a-Ketoglutarate dehydrogenase (Alpha ketoglutarate
to succinyl) CoA by alpha in TCA cycle.
Vitamin B3:
Introduction:
Niacin (nicotinic acid) and
niacinamide (nicotinamide) are
known as vitamin B3.
But niacin show hypocholesterolemic properties not shown by niacinamide and
excessive dosage of niacin causes flushing.
Both of these are water soluble vitamins.
Md.
Imran
Nur
Manik

Deficiency syndrome:
The well defined deficiency syndrome is pellagra (which is associated with skin
lesions, diarrhea and other symptoms). It is characterized by 3D () or 4D symptoms
(Diarrhea, Dermatitis, Dementia and Death).
Synthesis:
O
O
O
N N
CH3
H3C CH3
CH2CH3
H3C
COOH
5-Ethyl-2-methyl-pyridineParaldehyde
(trimer of acetaldehyde)
Nicotinic acid
NH3,
P
HNO3
Oxidation

N
OH
O
N
O
O
C2H5
EtOH
NH3
N
NH2
O
Esterification
EtOH
Nicotinic acid Niacinamide
Esterification of nicotinic acid affords ethyl nicotinate. Amidation of that with
ammonia in ethanol results in niacinamide (nicotinamide).
Use:
1. Prevention and treatment of pellagra.
Dosage:
For pellagra initially 300-500 mg daily in divided doses preferably in oral route. For
maintenance multivitamin preparation is used. In the intravenous route 25-100 mg.
Physiological role and actions
Nicotinic acid is readily converted to its amide which is acomponent of the coenzyme
Nicotinamideadenine- dinucleotide (NAD) and its phosphate (NADP) involved in
oxidation-reduction reactions.
These pyridine nucleotides act as hydrogen acceptors in the electron transport chain in
tissue respiration, glycolysis and fat synthesis. Flavoproteins regenerate them by
oxidizing NADH and NADPH.
Nicotinic acid (but not nicotinamide) in large doses is a vasodilator, particularly of
cutaneous vessels. It also lowers plasma lipids.
Md.
Imran
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Manik

Some of the specified roles are as follows:
Coenzymes are active participants in oxidation-reduction reactions – Dehydrogenases
B3 function in at least 200 reactions in cellular metabolic pathways
NAD+
• Participates in catabolic reactions
• Electron and hydrogen ion acceptor
NADP+
• Anabolic reactions
• Important in biochemical pathway for fatty-acid synthesis, steroid and bile
acid synthesis.
NAD+
dependent enzymes
• Lactate dehydrogenase
(lactate → pyruvate)
NADPH utilizing reactions
• HMG CoA reductase (HMG CoA → mevalonate) in
Fatty acid metabolism
Md.
Imran
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Manik

Vitamin B6 (pyridoxine):
Introduction:
Vitamin B6 is actually a mixture of pyridoxine, pyridoxal and pyridoxamine which
are interconverted. The most stable and common analogue used in pharmaceutical
preparations is pyridoxine.
Deficiency syndrome:
1. Seborrheic and desquamative dermatitis of the eyes and mouth
2. Glossitis and stomatitis
3. Intertrigo of breasts and inguinal region of women
Synthesis:
O
O
H3C
HN
CH3
O
N
O
CH3 O
N
O
O
H3C O
H3C
NH3C
HO
N
O
HO
H3C
OH
OH
P2O5
CH3
2, 5-dihydrofurane
Mineral acid
hydroquinone
HCl.
N-formylalaninate
4-methyl-5-ethoxyoxazole
Pyridoxine hydrochloride
H2O
Salification
H3C
Decomposition
Uses:
1. When using isoniazid or other pyridoxine antagonists causes pyridoxine
deficiency. This causes peripheral neuritis. Thus when using pyridoxine
antagonists pyridoxine is given as prophylactic.
2. Used in other pyridoxine deficiency e.g. convulsions in infants, hypochromic
anemia, some types of megaloblastic anemia, homocystinuria etc.
3. It improves symptoms related to thiamine, riboflavin and niacin deficiency.
Md.
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Dose:
1. Prophylactic dose → 25-50 mg daily.
2. In pyridoxine deficiency syndromes → 10-250 mg daily in oral, IM or IV route
3. For drug induced peripheral neuritis → 50-200 mg daily.
Vitamin B5 (pantothenic acid):
Introduction:
Pantothenic acid is a water soluble vitamin widely distributed in nature. It is found
in eggs, liver, dairy products and leafy vegetables. It is included in multiple-vitamin
preparations and not generally used alone.
HO
O
N
H
O
OH
H3C CH3
OH
Pantothenic acid
Deficiency syndromes:
Deficiency of pantothenic acid leads to several discomforts e.g.
- Malaise (a general sense of discomfort)
- Fatigue
- Headache
- Sleep disturbances
- Nausea
- Abdominal cramps (a sudden and irregular pain)
Dose:
Daily 5-10 mg daily.
Vitamin B7/Vitamin H/Biotin:
Introduction:
Biotin is a water soluble vitamin widely distributed in nature. it is normally
synthesized by the intestinal bacteria and therefore supplementation is usually
unnecessary.
Md.
Imran
Nur
Manik

H
N
S
NH
O
COOH
Biotin
Deficiency syndromes:
- Mild dermatitis
- Glossitis (inflammation of the tongue)
- Lethargy
- Abdominal pain
- Anorexia
- Mental depressions etc.
Dose:
It is included in multi-vitamin preparations at 0.15 mg/day for children and 0.30
mg/day for adults.
General References
 KD Tripathi MD: Essentials of Medical Pharmacology, 7th
Edition, Chapter 67:
Vitamins, Jaypee Brothers Medical Publishers (P) Ltd, India (2013) pp 909-918
 Dietary Supplements, 3rd
Edition (Pamela Mason) Pharmaceutical Press, UK, 2007.
 Handbook of vitamins, 4th
Edition, (Janos Zempleni, Robert B. Rucker, Donald B.
McCormick, John W. Suttie) CRC Press,U.S.A. 2007.
 Laurence KM, James N, Miller MH, et al. Doubleblind randomised controlled trial
of folate treatment before conception to prevent recurrence of neural tube defects.
BMJ 1981; 282: 1509–1511.
 National Health Service. National Library for Health.
http://www.clinicalanswers.nhs.uk/index.cfm?question=248 (Page last accessed on
October 31, 2006).
Md.
Imran
Nur
Manik

Vitamins-Medicinal Chemistry MANIK

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