Sar of Penicillin and cephalosporin

These are the slides of sar of penicillin and sar of cephalosporin of medicinal chemistry 3.

1. P R E S E NTATION O N S A R O F P E N I CILLIN & C E P HALOSPORIN P r e s e n t e d b y - - RANJANA G V M C OLLEGE OF PHARMACY

2. SAR O F P E N ICILLIN T h e r e a r e 2 r i n g s i n Penicillin s t r u cture : - 1 . T h i a z o l i d i n e r i n g 2 . B e t a - l a c t a m r i n g

3. ◆ S u b s t itut ion o n t h i a z o lidine r i n g W h e n t h e s u r f ace a t o m o f t h i a z o l i d i n e r i n g i s oxidised t o a s u l f o n e ( S O 2 ) o r s u l f o x i de ( S O ) I t i m p r o ves a c i d s t a b i lity & d e c r e ase t h e a n t i b a c terial a c t ivity o f t h e a g e nt . T h e r e fore s u l p h u r a t o m i s p l a c e d a t po s i t ion 1 t o r e t a i n d e s i r ed a c t i vity . N o s u b s t i t ution a r e a l l o wed a t t h i s p o s i tion A n y c h a n ge w i l l l o w e r t h e antibacterial activity . M e t h y l g r oup a r e n e c e ssary a t t h i s position . P E N I CILLIN 1 . SUBSTITUTION O N P O S I T ION 1 2 . SUBSTITUTION A T P O S I TION 2 3 . S U B S TITUTION O N P O S I T ION 3 C a r b o x y lic acid i s r e quired f o r a n t i b acterial a c tivity , i f it's c h a n g e t o a l c o h ol o r e s t e r , a c t ivity w i l l d e c r e ase .

4. S U B S T ITUTION O N T H I A Z O L I D I N E R I N G 4 . S U B S T ITUTION O N POSITION 4 5 . S U B S T ITUTION O N P O S I T ION 5 N i t r o g e n i s r e quired w i t h out a n y s u b s t i t ution f o r a n t i b a c terial activity . P o s i t ion 5 m u s t b e u n s u b s t ituted b e c a use h y d r o gen o f C - 5 i s r e quired t o m a i n tain c h i r a l i t y & C i s - f o r m a t i o n o f t h e c o m p o u n d f o r a n t i b a c terial a c tivity .

5. S U B S T ITUTION O N A B E T A L A C T A M R I N G 1 . S U B S T ITUTION O N P O S ITION 6 I t c a n b e e x p l a ined u s i n g P e n i cillin -G ( B e n z y l P e n i cillin ) . Stability o f Benzyl Penicillin c a n f u r ther b e i n c r e ased b y s u b s t ituti o n u s i n g a n electron w i t h drawing g r o up ( N H 2 , C l , F , B r ) . A l p h a s u b s titut e d Benzyl Penicillin i s m o r e s t a b l e t h e n Benzyl Penicillin Towards a c i d catalysed h y d r o l ysis .

6. S U B STITUTION O N BETA L A C T AM RING I n c r e a s i ng s t e r i c hindrance a t a l p h a c a r b o n , i n c r e ase P r o t ection a g a inst -L a c t a m a s e r e s i s tance . T h u s increase s t h e antibacterial activity . S t e r i c hindrance , s l o w t h e r e a c tion b e c a use o f p r e s e n ce o f b u l k y g r o u ps . T h u s i n c r e a s e d stearic hindrance w i l l increase a n t i b a cterial a ctivity , a s i t w i l l p r o t e c t m o r e a g a inst b e t a - l a c t a m a s e r e s i s tance . C a r b o n y l o n b e t a - l a c t a m r i n g i s m u s t . S U B S T ITUTION O N P O S I TION 7 I n c r eas ed s t e r i c hindrance b y this s u b s t i tution & a l s o p r o t e c t d r u g f r o m l a c t a m a s e r e s i s tance . E g : - 1 . M e t h a c i l l i n ( Ortho s u b s t itution ) 2 . N a f c i l l i n ( m e t a s u b s titution ) S U B S T ITUTION O N O R T H O O R M E T A P O S ITION O F B E N Z Y L R I N G C o n t inue ( S U B S TITUTION O N P O S I TION 6 )

7. S A R O F C E P H A LOSPORIN T h e r e a r e 2 r i n g i n CEPHALOSPORIN : - 1 . B e t a l a c t am ring 2 . D i h y d r o t h i a z i n e r i n g

8. A c y l a t i o n o f a m i n o g r oup increas e s t h e p o t e n c y a g a inst g r a m - positive bacteria , b u t i t d e c reas es g r a m - n egative p o t e ncy . H i g h a n t i b a c t erial a c tivity i s o b s e r ved o n l y w h e n n e w a c y l g r o u p s a r e d e r i v ed f r o m c a r b o xylic a c i ds f o r gram-positive bacteria . S u b s titu e n ts o n a r o m a t ic r i n g t h a t i n c r e ases l i p o p h ilicity p r o v i de h i g h er g r a m - positive a c tivity a n d l o w er g r a m - negative a c tivity . P h e n y l r i n g i n s i d e - c h a i n c a n b e r e p l a c e d w i t h o t h e r h e t e r o c y cles ( l i k e - minded t h i o p h ene , f u r a n , p y r i m i dine e t c . ) W h i c h s h o w s i m p r o v e d s p e c t rum o f a c t i vity & P h a r m a c o k inetic p r o p erties . 1 . S U B S TITUTION O N 7 - ACYLAMINO

9. 2 . SUBSTITUTION O N C - 3 N a t u r e o f C - 3 s u b s t itu e n ts i n f l uenc es p h a r m a c o k inetic & p h a r m a c o l ogical properties a s w e l l a s a n t i b a c terial a c tivity M o d i f i cation a t C - 3 p o s i t i on h a s b e e n m a d e t o r e d u ce t h e d e g r a d ation o f c e p h a losporin . 3 . 3 . D I S P L A C E M ENT O F A C E T O X Y G R O U P B Y A Z I D E I O N Y I E L D D E R I V A T IVES W H I C H R E L A T I V ELY L O W G R A M - NEGATIVE A C T IVITY .

10. D i s p l a c ement o f 3 - a c e t o x y g r o u p w i t h a r o m a tic t h i o l s w i l l e n h a n ce t h e activity a g a inst g r a m - negative bacteria w i t h i m p r oved p h a r m a cokinetic properties . R e p l a c ement o f ACETOXY g r oup a t p o s i tion C - 3 w i t h -C H 3 , C l h a s r e s u lted i n o r a l l y a c t i v e c o m p oun d s . C a r b o x y l group o f p o s i tion - 4 h a s b e e n c o n v e r ted i n t o e s t e r p r o d r u g s t o increase b i o a v ailability o f c e p h a losporin & t h e s e c a n b e g i v e n o r a l l y . O x i d a tion o f r i n g s u l p h ur t o s u l p h o x i d e o r sulphone g r e a t ly d e s t r oy t h e antibacterial activity . R e p l a cement o f s u l p hur w i t h o x y gen l e a d s t o o x a c e p h a m w i t h i n c reas ed a n t i b a c terial a c t ivity . R e p l a cement o f s u l p hur w i t h m e t h y l e ne g r o u p h a s greater c h e m i cal s t a bility & a l o n g er h a l f - l i f e . 3 4 5

11. T h a t ' s a l l