Presented by, Sanjay Gopi, Dept of PHarmacutial Chemistry, SET's College of pharmacy, Dharwad.

1. DEPT. PHARMACEUTICAL CHEMISTRY
1
Presented to,
Dr. S. D. joshi,
Dept of pharmaceutical CHEMISTRY,
SET’s College of Pharmacy,
Dharwad
From,
Sanjay Gopi
Dept of Pharmaceutical Chemistry
SET’s College of pharmacy
Dharwad.

2. CONTENTS :CONTENTS :
 Xanthine oxidase inhibitors
 Cystochrome P-450 inhibitors
 DHFR Inhibitors
 Gastric proton pump inhibitors
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3. XANTHINE OXIDASE :
 The enzyme xanthine oxidase (bovine milk enzyme) catalysis the oxidation of
Hypoxanthine to xanthine & xanthine to uric acid.
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4. Example : 3-mthyl xanthine
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5. Mechanism :
 The active site of XO is composed of a molybdopterin unit with the
molybdenum atom also coordinated by terminal oxygen (oxo), sulfur atoms and a
terminal hydroxide.
 In the reaction with xanthine to form uric acid, an oxygen atom is transferred
from molybdenum to xanthine, whereby several intermediates are assumed to be
involved.
 The reformation of the active molybdenum center occurs by the addition of
water.
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6.  During sever liver damage, XO is released into the blood, so blood assy for XO is
a way to determine if liver damage has happned.
 Xanthinuria is a rare genetic disorder where the lack of xanthine oxidase leads
to high concentration of xanthine in blood can cause health problems such as
renal failure.
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7. XANTHINE OXIDASE INHIBITORS :
 Xanthine oxidase inhibitors is any substance that inhibits the activity of xanthine
oxidase.
 Xanthine oxidase inhibitors reduces the production of uric acid.
Xanthine inhibitors are of two types
 Purine analogues & others
 Purine analogues include allopurinol & oxipurinol.
 Others include febuxostat & inositols.
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8. Examples :
allopurinol Oxipurinol
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9. Mechanism of action of allopurinol
 allopurinol is a purine analog, it is a structural isomer of hypoxanthine & is an a
inhibitor of the enzyme xanthine oxidase.
 In addition to the blocking uric acid production inhibitor of xanthine oxidase
causes an increase in hypoxanthine & xanthine.
 While xanthine can not be converted into purine ribotides, hypoxanthine can be
salvaged to purine ribotides adinosine & guanosine monophosphate.
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10.  Increased level of these ribotides may causes feed back inhibition of amido
phosphoribosyl transferase – rate limiting enzyme of purine biosynthesis.
 Allopurinol therfore decreases uric acid formation may also inhibit the purine
synthesis.
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11. CYTOCHROME P450 INHIBITORS
 Cytochrome p450 belongs to the super family of protiens containing a heme
cofactor & therefore are hemoprotines.
 Many drug interactions are result of inhibition or induction of the CYP450
enzymes.
 Enzyme inhibition usually involves competation with another drug for the
enzyme binding site.
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12. Examples :
Ciprofloxacine Isoniazid
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13. Mechanism of action
Ciprofloxacin is a broad spectrum antibiotic active against both Gram-
positive & Gram-negative bacteria.
It functions by inhibiting DNA gyrase, a type 2 topoisomerase, &
topoisomerase 4 , enzymes necessary to separate bacterial DNA there by
inhibiting cell division.
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14. DHFR Enzyme
DHFR enzyme that reduces dihydrofolic acid to tetradhydrofolic folic acid
using NADPH as electron donor, which can be converted to the kinds of
tetrahydrofolate cofactors.
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15. Mechanism
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16. DHFR Inhibitors :
DHFR inhibitor is molecule that inhibits the function of dihydrofolate reductase
& is the type of antifolate.
Examples
Trimthoprim Iclaprim
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17. Mechanism of action :
 Trimethoprim binds to dihydrofolate reductase & inhibits the reduction of
dihydrofolic acid (DHF) to tetrahydrofolic acid (THF).
 THF is an essential precursor in the thymine synthesis pathway & interference
with this pathway inhibits the bacterial DNA synthesis.
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18.  Trimethoprim’s affinity for bacterial dihydrofolate reductase is several thousand
times greater than its affinity for human dihydrofolate reductase
 Sulfamethoxazole inhibits dihydrofolate synthatase an enzyme involved further
upstream in the same pathway
 Trimethoprim & sulfamethoxazole is commonly used in combination due to
claimed synergistic effect & reduced development of resistance.
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19. GASTRIC ACID SECRETION
 Acid secretion is a physiological process of the stomach this acid production is caused by the
highly specialized cell is fundic mucosa, and gastric parietal cells in the stomach.
 This gastric acid will directly or indirectly helps the physiological functions like it will initiates
the activation of the enzyme pepsinogen which is involved in digestive process, it will also kills
bacteria and microbes.

20. PROTON PUMP( H+
/ K+
-ATPase ENZYME)
1.Structure :
Present in tubulovesicular and canalicular mestric parital cells
Consist of two subunits a114-kDa-α-subunit (10 trance membrane
helix) and 34-kDa-β-subunit (1 trance membrane helix)
α- subunit-catalytic and transport function
β-subunit- required for endocytic retrieval of H+
/ K+
-ATPase
enzyme from the canalicular membrane
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21. DEPT. PHARMACEUTICAL CHEMISTRY 21
STRUCTURE OF PROTON PUMP

22. DEPT. PHARMACEUTICAL CHEMISTRY 22
PROTON PUMP AND ACID SECRETION.

23. GASRTIC PROTON PUMP INHIBITORS :
Proton pump inhibitors (or "PPI"s) are a group of drugs whose main action is
pronounced and long-lasting reduction of gastric acid production. They are the
most potent inhibitors of acid secretion available today.
The group followed and has largely superseded another group of pharmaceuticals
with similar effects, but different mode-of-action, called H2-receptor antagonists.
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This class of compound inhibit gastric proton pump in a
non competitive manner by covalent binding of their
active intermediate to the enzyme.

24. Omeprazole
Pentaprasol
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O
N
N
S
H N OMe
OMe
O
F
F
H
C

25. Mode of action:-
 Physico-chemically PPIs (Omeprazole) represent
a weak base with a pka value of 4.
 It can pass through biological membrane as a result
of its lipid permeable properties.
 At physiological pH it is unionized & this neutral
form passes freely across biological membrane.
 However is an acidic environment with a pH below
4,it is protonated. This result in a limited
permeability. Due to unique structure of parietal cell
with its Secrotory Cannaliculi
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26.  PPIs (Omeprazole) is trapped with in these
Cannaliculi & undergoes chemical transformation
into activated Pyridinium Sulfenamide (active
enzyme inhibitor).
 Which bind covalently to sulphydryl groups of
cysteins of the proton pump (H+
/K+
ATPase)
followed by structural alteration of the enzyme
finally inactivates the catalytic function of the
enzyme.
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27. FAQ’S
1)Eplain the process of gastric cid secretion, write an account of developing drug
from lead the inhibition of gastric acid secretion.
2) Discuss mechanism of action of gastric acid secretion & inhibition what are the
drugs used for controlling acid secretion explain their mechanism.
3) Write account on DHFR enzyme inhibitor.
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28. REFERENCES
 Medicinal chemistry by Burger, 4th
edition Pg.no 103-104
 Principles of drug design by Smith Pg.no 17-19
www.google.com
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