BENZIMIDAZOLE DERIVATIVES AS H+/K+ ATPASE INHIBITORS

Presented by - Syed Baseeruddin AlviUnder the guidance of mrs.iffath rizwana

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..

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.

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

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

CYANOGUANIDINE GROUP IS A GOOD BIOISOSTERE FOR THIOUREA GROUP.

RANITIDINE

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…

OMEPRAZOLE

IUPAC Name : RS)-5-methoxy-2-((4-methoxy-3,5-dimethylpyridin-2-yl) methylsulfinyl)-1H-benzo[d]imidazole

Mol. Mass

– 345.4 gm/mol

C - 17

N – 03

O – 03

S – 01

H – 19

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

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.

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.

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.

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.

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

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.

THANK YOU