1. BENZIMIDAZOLE DERIVATIVES AS
H+/K+ ATPASE INHIBITORS
- Syed Baseeruddin Alvi
Presented by
Under the guidance of mrs.iffath rizwana

2. INTRODUCTION
 GASTRIC ACID HAS BEEN KNOWN FOR MANY
DECADES TO BE A KEY FACTOR IN NORMAL UPPER
GASTROINTESTINAL FUNCTIONS, INCLUDING
PROTEIN DIGESTION AND CALCIUM ABSORPTION AS
WELL AS PROVIDING SOME PROTECTION AGAINST
BACTERIAL INFECTIONS…..
 INAPPROPRIATE LEVELS OF ACID CAN GIVE RISE TO
SEVERE PATHOLOGICAL CONDITIONS LIKE
 GERD (Gastroesophageal reflux disease)
 PEPTIC ULCERS…etc etc….
 THESE IF LEFT UNTREATED COULD BE LIFE
THREATENING..

3. CIMETIDINE
 IT IS A CLASSICAL DRUG USED IN THE TREATMENT OF ACID
RELATED DISORDERS.
 IT ACTS BY BLOCKING H2 RECEPTORS, THEREBY INHIBITING
GASTRIC ACID RELEASE.
 IT ALSO INHIBITS THE RELEASE OF PENTAGASTRIN,
RESPONSIBLE FOR THE STIMULATION OF ACID RELEASE.
 THE PARENT COMPOUND OF CIMETIDINE IS HISTAMINE.

4. SAR OF CIMETIDINE
 GUANIDINE ANALOGUE OF HISTAMINE POSSESS WEAK ANTAGONIST
ACTIVITY TO THE ACID SECRETORY ACTIVITY OF HISTAMINE.
 INCREASING THE LENGTH OF SIDE CHAIN FROM 2 TO 4 CARBONS
COUPLED WITH REPLACEMENT OF STRONGLY BASIC GUANIDINE
GROUP BY NEUTRAL METHYL THIOUREA FUNCTION LEADS TO
BURIMAMIDE.
Burimamide
Guanidine

5.  INSERTION OF ELECTRONEGATIVE THIOETHER IN THE SIDE
CHAIN OF METHYLENE GROUP FAVOURS
N- TAUTOMER
&
 INTRODUCTION OF 5-METHYL GROUP FAVOURS H2
RECEPTOR SELECTIVITY
 BECAUSE OF INCREASED TOXICITY
REPLACING THIOUREA SULPHUR
WITH CYANO-IMINO FUNCTION
TO GIVE CIMETIDINE. Metiamide
Cyano-imino function

6.  CYANOGUANIDINE GROUP IS A GOOD BIOISOSTERE FOR
THIOUREA GROUP.

7.  NITRO KETENE AMINAL GROUP IS OPTIMUM FOR
ACTIVITY
 PLACING THE SULFUR NEXT TO THE RING LOWERS
ACTIVITY
 2,5-DISUBSTITUTION IS BEST…
 VARIATION ON DIMETHYL AMINO GROUP CAN BE
DONE…

9. MECHANISM OF ACTION
 OMEPRAZOLE – A PRODRUG GETS CONVERTED INTO ITS
ACTIVE FORM IN ACIDIC ENVIRONMENT.
 IT IS ACTIVATED BY PROTON-CATALYSED PROCESS TO
GENERATE A SULFENAMIDE.
 SULFENAMIDE INTERACTS COVALENTLY WITH SULFHYDRYL
GROUPS OF CYSTEINE RESIDUE IN H+/K+ ATPase

10. SAR OF OMEPRAZOLE
 OMEPRAZOLE CONSISTS OF 3 PARTS –
 SUBSTITUTED BENZIMIDAZOLE RING
 SUBSTITUTED PYRIDINE RING
 CH2SO CHAIN
 SUBSTITUTION OF PYRIDINE RING WITH ALKYL OR ALKOXY
GROUPS ( EXCEPT 6- POSITION) GIVES GOOD ANTISECRETORY
ACTIVITY
 METHOXY GROUP AT FOURTH POSITION OF PYRIDINE RING
DONATES ELECTRONS TO PYRIDINE NITROGEN, THEREBY
INCREASING THE % OF CATIONIC PYRIDINE.

11.  THIS ALSO INCREASES THE NUCLEOPHILIC CHARACTER OF
PPI’s.
 CATIONIC PYRIDINE FACILITATES THE INTRAMOLECULAR
NUCLEOPHILIC ATTACK AT C2 OF BENZIMIDAZOLE RING
LEADING TO THE FORMATION OF ACTIVE SULFENAMIDE AND
SULFENIC ACID.
 PRESENCE OF METHYL GROUP AT 3 AND 5 POSITIONS
ENHANCES NUCLEOPHILIC CHARACTER OF UNIONIZED
PYRIDINE NITROGEN.

12. BENZIMIDAZOLE DERIVATIVES
CONTAINING OXYCYCLIC PYRIDINE
 THESE DERIVATIVES ARE SYNTHESISED BY REACTING
2-MERCAPTOBENZIMIDAZOLE WITH CHLOROMETHYL OXYCYCLIC
PYRIDINE COMPOUNDS FOLLOWED BY LOW-TEMPERATURE OXIDATION
WITH m-CHLOROPERBENZOIC ACID.

13.  OXYCYCLIC PYRIDINES WERE CONVERTED TO N-OXIDES BY
CYANATED OXYCYCLIC PYRIDINE WHICH WAS OBTAINED
UNDER TRIMETHYL SILYL CYANIDE CONDITION .UPON FURTHER
TREATMENT CHLOROMETHYL OXYCYCLIC PYRIDINES WAS
OBTAINED.

14.  THE OXYCYCLIC PYRANO AND FUROPYRIDINES ARE
PREPARED BY PALLADIUM CATALYSED CYCLIZATION OF
IODOPYRIDINEALLYL ETHER OR BY THERMAL SIGMATROPIC
REARRANGEMENT OF 4-PYRIDINE PROPARGYL ETHER

15. CONCLUSION
INTRODUCTION OF 5-MEMBERED OR 6-MEMBERED OXYCYCLES
TO PYRIDINE POTENTIATED THE INHIBITORY ACTIVITY OF THE
COMPOUNDS WHERE THE SIZE AND POSITION OF ATTACHMENT
OF OXYCYCLES DID NOT PRODUCE ANY SIGNIFICANT CHANGE.

16. THANK YOU