9 A M I N O A C R I D I N E

I N T R O D U C T I O N :

M a l a r i a i s a d e v a s t a t i n g i n f e c t i o u s d i s e a s e c a u s e d

b y t h e p r o t o z o a n p a r a s i t e P l a s m o d i u m . F o u r s p e c i e s

o f P l a s m o d i u m a r e k n o w n t o i n f e c t h u m a n s : P . v i v a x ,

P . m a l a r i a e . a n d P . t h e l a t t .P . o v a l e . f a l c i p a r u m .

T h e d e v e l o p m e n t o f a n t i m .e r b e i n g t h e m o s t d e a d l y .

a l a r i a l c o m p o u n d s c o n t i n u e s t o b e a m a j o r f o c u s o f .

m a n y l a b o r a t o r i e s , a n d a s s u c h , a v a r i e t y o f c o m p o u

n d s h a v e b e e n e x p l o r e d i n t h e p r o p h y l a x i s a n d t r e a t

m e n t o f t h i s d i s e a s e C a n c e r c h e m o t h e r a p e u t i c s b a s e d

o n t h e 9 a m i n o a c r i d i n e s c a f f o l d h a v e b e e n d e v e l o p e

d ( e . g . L e d a k r i n a n d A m a s c r i n e ) . 9 a m . A d d i t i o n a l l y .

i n o a c r i d i n e s h a v e b e e n e x p l o r e d a s p h o t o a f f i n i t y l a .

b e l s a n d a s f l u o r e s c e n t p r o b e s u s e d t o d e t e c t c a n c e .

O u r g e n e r a l s y n t h e t i c s t r a t e g y t o 9 a m i n o a c .r c e l l s .

r i d i n e s i s s u m m a r i z e d i n D e r i v a t i v e s o f s u b s t i t u t e d .

s a l i c y l i c a c i d c h e m s e t 5 w e r e c o u p l e d t o a n i l i n e c .

a s .h e m s e t 6 t o g e n e r a t e 9 c h l o r o a c r i d i n e c h e m s e t 7 .

T h e u s e o f s a l i c y l i c a c .w a s p r e v i o u s l y i n t r o d u c e d .

a c t i v a t e d a s t r i f l a t e s . i s n o v e l a n d .i d p r e c u r s o r s .

d e v i a t e s f r o m a n e a r l i e r a p p r o a c h t o 9 c h l o r o a c r i d .

i n e s b a s e d o n t h e U l m a n n c o u p l i n g o f a n i l i n e s w i t h .

o f w h i c h m u c h f e w e r a .2 b r o m o a r y l c a r b o x y l i c a c i d s .

r e c o m m e r c i a l l y a v a i l a b l e . T o a p p r o a c h t h e a m i n e s i .

d e c h a i n . 3 d i a m i n o p r o p a n e ( 8 ) w a s d u a l l y f u n c t i o . 1 .

n a l i z e d t o g e n e r a t e a l i b r a r y o f r e q u i s i t e d i a m i n e .

p a r a l l e l c o u p l i n . F i n a l l y .b u i l d i n g b l o c k c h e m s e t 9 .

g o f 9 c h l o r o a c r i d i n e s w i t h t h e d i a m i n e s w a s d o n e t .

o g e n e r a t e t h e d e s i r e d 9 a m i n o a c r i d i n e c h e m s e t 1 0 . .

A n o t a b l e f e a t u r e o f t h i s s t r a t e g y i s t h a t i t a l l o w .

s q u i c k a c c e s s t o v a r i a t i o n s o f t h e t r i c y c l i c a c r i d .

w h i .i n e h e t e r o c y c l e a s w e l l a s t h e a m i n e s i d e c h a i n .

c h w i l l a l l o w p r o b i n g o f t h e c o o p e r a t i v i t y o f t h e s e .

t w o s t r u c t u r a l f e a t u r e s . M E C H A N I S M O F A C T .

9 ' a m i n o .I O N : T h e e f f e c t s o f a l k y l e n e b i s 9 .

2 . 4 t e t r a h y d r o 9 a m i n o a c r i . 3 .a c r i d i n e s a n d 1 .

d i n e ( T H A ) w e r e s t u d i e d o n s i n g l e c h a n n e l c u .

r r e n t s a c t i v a t e d b y N m e t h y l D a s p a r t a t e ( N M .

D A ) i n o u t s i d e o u t p a t c h e s f r o m c u l t u r e d r a t .

T h e s e c o m p o u n d s r e d u c e .h i p p o c a m p a l n e u r o n s .

d t h e c h a n n e l o p e n t i m e s w i t h c o n c e n t r a t i o n .

a n d v o l t a g e d e p e n d e n c e . w h i c h w a s c o n s i s t e n t .

w i t h a n o p e n c h a n n e l b l o c k a d e m e c h a n i s m o f .

a c t i o n . . I n n o m i n a l l y M g ( 2 + ) f r e e s o l u t i o n s .

t h e f o r w a r d b l o c k i n g r a t e c o n s t a n t s f o r 1 . 2 - .

4 b u t a n e 9 . 9 ' a m i n o a c r i d i n e .p r o p a n e b i s 9 . 1 .

9 ' a m i n o a c r i d i n e . 1 x 1 0 ( 8 ) . a n d T H A w e r e 1 .. .

4 x 1 0 ( 8 ) . a n d 3 . r e s .1 . 5 x 1 0 ( 7 ) M 1 s e c 1 .

a t a h o l d i n g p o t e n t i a l o f 8 0 m V .p e c t i v e l y . .

T h e u n b l o c k i n g r a t e c o n s t a n t s f o r t h e b i s 9 .

a m i n o a c r i d i n e s w e r e s i m i l a r a n d i n t h e r a n g .

e o f 7 s e c 1 . w h e r e a s T H A h a d a n u n b l o c k i n g .

r a t e c o n s t a n t o f a p p r o x i m a t e l y 6 . 2 x 1 0 ( 3 ) s .

e c 1 . I n t h e p r e s e n c e o f M g 2 + ( a p p r o x i m a t e l y .

t h e p r e d i c t i o n s o f t h e m o d e l f o r .5 m i c r o M ) .

o p e n c h a n n e l b l o c k a d e b y t h e 9 a m i n o a c r i d i n .

e s w e r e i n v a l i d . b e c a u s e t h e r e l a t i o n s h i p s b .

e t w e e n t h e c h a n n e l l i f e t i m e s a n d 9 a m i n o a c r i .

T h e e f f .d i n e c o n c e n t r a t i o n s w e r e n o t l i n e a r .

e c t s o f M g 2 + ( a p p r o x i m a t e l y 0 5 0 m i c r o M ) o n .

t h e o p e n c h a n n e l b l o c k a d e o f t h e N M D A r e c e p t .

o r b y t h e 9 a m i n o a c r i d i n e s w e r e e v a l u a t e d f u .

r t h e r b y m e a s u r i n g t h e b u r s t t i m e s i n t h e p r .

2 p r o p a n e b i s 9 .e s e n c e o f 1 . 9 ' a m i n o a c r i d i n e .

( 5 m i c r o M ) . T h e r e s u l t s s u g g e s t e d t h a t t h e .

i n t e r a c t i o n s o f 9 a m i n o a c r i d i n e s a n d M g 2 + w i .

t h t h e i o n c h a n n e l o f t h e N M D A r e c e p t o r w e r e .

S i m u l t a n e o u s o c c u p a .n o t m u t u a l l y e x c l u s i v e .

n c y o f t h e N M D A r e c e p t o r i o n c h a n n e l b y M g 2 + .

a n d a c h a n n e l b l o c k i n g o r g a n i c a c t i o n c o u l d .

b e a c o m m o n m e c h a n i s m o f c h a n n e l b l o c k a d e f .

o r t h i s r e c e p t o r u n d e r p h y s i o l o g i c a l c o n d i t i .

o n s . S T R U C T U R E A C T I V I T Y R E L A T I O N S H .

6-Chloro-9-[[4-(diethylamino)-1-methylbutyl] amino]-2methoxy-acridine dihydrochloride dihydrate . P . 4-Pentane-diamine. Mepacrine Hydrochloride BAN. Ind. therefore. they have been successfully replaced by the 4-aminoquinoline analogues to a great extent. Mepacrine Hydrochloride BP . A few typical examples of this category are d i s c u s s e d b e l o w : A. 1. Acrinamine . dihydrochloride. Quinacrine Hydrochloride USAN. P . Quinacrine Hydrochloride USP . however.I P : Aminoacridines The earlier hypothesis put forward by Ehrlich that methylene blue exerts antimalarial activity paved the way for the discovery of a number of acridine analogues. Eur. are found to be extremely toxic in nature and. P . Synthesis : It essentially consists of the following steps : (i) Preparation of the side chain : 4-Diethylamine-1-methylbutylamine . N4-(6-chloro-2-methoxy-9acridinyl)-N1. Atabrine Hydrochloride(R) (Winthrop). dihydrate . Int. Mepacrine INN. The 9-aminoacridine analogues. . N1-diethyl-.

It is found to be more toxic and less effective than chloroquine.. it has also been used in giardiasis. 5-Dichloro-7-methoxy acridine may be prepared by the oxidation of 2.) ANTIMALARIALS 635 CHAPTER 20 (c) Condensation of (a) and (b) above . and (d) Treatment with Hydrochloric Acid 2. (iii) Condensation of (i) and (ii) (iv) Preparation of the hydrochloride salt. (a) Preparation of the side chain 2-Hydroxy triethylamine hydrochloride is obtained by the interaction of ethylene oxide and diethylamine in the presence of methanol and hydrochloric acid which on chlorination with thionylchloride yields 1-chloro-triethylamine. Besides. tapeworm and pinworm infestations.. Dose : As therapeutic.(ii) Preparation of the acridine nucleus : 2. 200 mg with 300 mg of sodium bicarbonate each 6 hours up to 5 doses. 5-Dichloro-7-methoxy-acridine . 4-dichloro toluene and treating the resulting acid with 4-amino anisole at 220°C in the presence of KOH and n-butanol . One mole each of the side chain and the acridine residue get condensed to yield the mepacrine base which on treatment with hydrochloric acid gives the official compound. It is considered neither as a causal prophylactic nor as a radical curative agent. f o l l o w e d b y . 634 MEDICINAL CHEMISTRY The resulting compound on treatment with the lactam-form of ethylacetoacetate forms an intermediate which when subjected to reduction and oximation gives 4-diethylamine-1-mthyl butylamine. the additional compound when reacted with either POCl3 or SOCl2 undergoes cyclization. Mepacrine hydrochloride inhibits the erythrocytic state of development of the malarial parasite. (b) Preparation of the acridine nucleus (Contd. amebiasis.

a s s u p p r e s .1 0 0 m g 3 t i m e s p e r d a y f o r 6 d a y s .

.s i v e . 1 0 0 m g o n c e d a i l y .

.

A N T I .

M A L A R I A L S .

nlm.gov/pmc/articles/PM C1474025 .ncbi.nih.REFERENCES: http://www.

http://molpharm.org/content/4 6/1/151 Medicinal Chemistry: By Ashutosh Kar .aspetjournals.

Sign up to vote on this title
UsefulNot useful