RATIONAL AND OBJECTIVE

3.1 RATIONAL AND OBJECTIVE:

Gastric acid has been known to play an important role in many physiological processes,
such as digestion, sterilization of food and absorption of calcium and iron. The awareness of
its central role in the etiology of peptic ulcer disease (PUD) and gastroesophagal reflux
disease (GERD) has grown over the years. Peptic ulcer disease (PUD) occurs when gastric
acid and other digestive juices erode the inner lining of the stomach or the first part of the
small intestine. This inner lining is a complex mucous barrier that protects the
gastrointestinal (GI) lining from the corrosive acids and other chemicals that the stomach
produces to digest food. When the barrier breaks down, the lining is exposed to the
destructive potential of the digestive juices. For many years, scientists believed that acidic
foods and stress caused peptic ulcers and treated the ulcers with surgery and medications to
lessen the symptoms. However, research conducted in the 1980s revealed that the most
common cause of peptic ulcers is infection by bacteria called Helicobacter pylori, which
can survive in the acidic environment of the stomach. Such bacteria can produce a change in
the mucous barrier, which results in ulcers. Several other risk factors associated with
recurrence of PUD includes cigarette smoking, chronic consumption of ulcerogenic drugs
like NSAID, consumption of alcohol for prolonged periods, age, emotional stress and
family history.

Potential complications of peptic ulcers include Haemorrhage, Penetration, Perforation,

Obstruction. Different types of peptic ulcers include Duodenal ulcers Gastric ulcers
Esophageal ulcers Stress ulcers Marginal ulcers. pharmacotherapeutic management with
medications which included antacids, anticholinergics and sucralfate. Although these
techniques provided a degree of relief from the symptoms of GERD, the healing of erosions
was very difficult to achieve except with high and frequent doses of antacids. However,
common side effects like alkalosis, abdominal distension, flatulence, diarrhoea and
constipation were associated with the use of antacids. Similarly, use of anticholinergics
resulted in inhibitions of muscarinic M1 receptors at locations outside the stomach, and led
to anticholinergic side effects which limited their use.
With the discovery of benzimidazole sulfoxide class as proton pump inhibitors (PPIs),
significant progress has been made in this field in the recent years. In 1974, timoprazole
was reported as the first prototype proton pump inhibitor. This was followed by picoprazole
in 1976, but these were associated with safety problems in long-term toxicity studies. The
breakthrough came with the synthesis of omeprazole in 1979. This compound was the most
potent of a series of candidate drugs synthesized and tested, and it did not show any
significant effects in the initial repeat-dose toxicity studies in animals. Omeprazole has been
recognized as a major breakthrough in the treatment of GERD and PUD. Moreover, it has
also been effective in the treatment of Zollinger–Ellison syndrome, which was previously
difficult to treat and often required surgical intervention. Further modification of the
pyridine nucleus led to rabeprazole, lansoprazole, pantoprazole etc.

The most common side effects of PPIs are headaches, nausea, abdominal pain, constipation,
flatulence, and diarrhoea. Extreme acid suppression sometimes leads to achlorohydria at
recommended doses and that may produce enteric infections like typhoid, cholera and
dysentery. Clinically, the onset of PPIs is relatively slow and, because they are effective
only in actively secreting parietal cells, acid can be secreted from cells that were inactive
during the relatively short period when they were exposed to PPIs in the plasma. In
addition, new proton pumps are synthesized and inserted into the secretory canalicular
membrane after clearance of the sulphenamides from the secretory canaliculus, thus acid
secretion returns. Therefore, there is a need for PPIs with a more rapid onset of action and
longer half lives resulting in extended acid suppression with an improved control of 24-hour
intragastric acidity, thus improving the clinical efficacy.

Significant drug interactions can lead to decreased absorption of some drugs like
griseofulvin, ketoconazole, vit.B12, iron salts, etc. Unpredictable action and variation in
individual responsiveness can cause hypergastrinemia, gastric polyps and carcinoma. Acute
interstitial nephritis progressing to acute renal failure has also been reported to be associated
with the use of PPIs. Recently there have been reports of an increase in community-acquired
respiratory infections and hospital-acquired Clostridium difficile colitis with the long-term
use of PPIs. Present study is of great importance from pharmaceutical field and will serve
human life by reducing such drug interaction, infections and will reduce the chances of
gastric carcinoma.

Synthesis of Acid Pump Antagonist compounds targeting the H+/K+-ATPase tries to

combine the advantages of both PPIs and H2RAs. They are active in absence of acid
secretion and bind to specific sites in the membrane domain of the H+/K+-ATPase. Study
will help to understand the further prolongation of the acid suppressing effect might be
caused by high affinity of the drug to the enzyme, and tolerance is not to be expected.
Synthesis of imidazopyridine analogues by designing the pharmacophore with repect to
target H+/K+-ATPase will show excellent control of intragastric pH, hence faster symptom
remission and perhaps better clinical results in gastric acid related diseases, symptom relief
and in combination therapy for Helicobacter pylori eradication. Study will help to
understand biochemical characterization of compound in vitro against both the purified
gastric proton pump enzyme, H+/K+-ATPase, and the intact gastric gland. A good
correlation can exists between the inhibitory potency of the PPI and Acid Pump Antagonist.
New compounds may show excellent physicochemical and pharmacological properties that
represent interesting candidates or further development as potassium-competitive acid
blockers.

That’s why we decided to conduct molecular modeling studies for design and development
of lead molecules considering the target of H+/K+-ATPase and synthesis of a series of novel
imidazopyridine analogues. Also characterization of the synthesized compounds by FTIR,
CHN, NMR, Mass spectral analysis etc. Finally to evaluate the novel synthesized
compounds for antiulcer activity as Proton Pump ATPase inhibitors.
3.2 Plan of Work:

A brief outline of the research work carried out is summarized as follows:

Molecular docking studies

• Docking studies of imidazopyridine analogues.

Synthesis

1. Methyl 2-((8-((3-aminophenyl)carbamoyl)-2-(substituted phenyl)imidazo[1,2-

a]pyridine-3-yl)amino)acetate
2. Methyl 2-((8-((3-aminomethyl)benzyl)carbamoyl)-2-(substituted
phenyl)imidazo[1,2-a]pyridine-3-yl)amino)acetate
3. Ethyl -2-((8-((3-(aminomethyl)benzyl)carbamoyl-2-(substituted phenyl)imidazo[1,2-
a]pyridine-3-yl)amino)acetate
4. N-(3-(aminomethyl)benzyl)-3-(substituted benzylamino)-2-(substituted
phenyl)imidazo[1,2-a]pyridine-8-carboxamide
5. N-(3-aminophenyl)-3-(benzylamino)-2-(substitutedphenyl)imidazo[1,2-a]pyridine-
8-carboxamideN-(3-aminophenyl)-2-(substitutedphenyl)-3-((3-methyl benzyl)
amino) imidazo[1,2-a]pyridine-8-carboxamideN-(3-aminophenyl)-2-
(substitutedphenyl)-3-((3-methoxybenzyl)amino)imidazo[1,2-a]pyridine-8-
carboxamide
Characterization of synthesized compounds

• Physicochemical characterization including solubility, melting point and TLC

analysis.
• Structural confirmation by FTIR, 1H NMR and Elemental (CHN) analysis and mass
spectral studies.
Biological evaluation:

In-vitro studies Biological assays: Proton Pump ATPase assay