amar-230813synthesis of new 2-thiouracil-5-sulphonamide derivatives with antibacterial and...

7/27/2019 Amar-230813Synthesis of New 2-Thiouracil-5-Sulphonamide Derivatives with Antibacterial and Antifungal Activity

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Arch Pharm Res Vo l 28, No 11, 1205-1212, 2005~ l r t b i l J e ~ o f

! larmatal ~e~eart! lhttp://apr.psk.or.kr

Sy nthes is o f New 2 -Th iourac i l-5 -Su lphonam ide Der iva tives wi thAnt ibacter ia l and Ant i fungal Act iv i tyO . A . F a t h a l la , S . M . A w a d 1, a n d M . S . M o h a m e d 1Dep ar tmen t o f Medicina l Chemis tn ,4 Nat iona l Research Ce nt re , Dok k i ,Departmen t, H elwan Univers i ty , Facul ty of Pharma cy, Helwan, E gyp t Cai ro , E gypt and 1O rgan ic Che mis t ry

(Received Jun e 9, 200 5)2-Th iou rac i l- 5 -su lphon ic ac id N - (4 -ace ty lpheny l ) Am ide (1 ) was reacted w i th a se r i es o f a ro -ma t ic a ldehydes g i ving ch a l cones 2 (C la i sen -Schem id t react ion ) , some o f t hese cha lconeswere reac ted w i th u rea and th iou rea g i v ing py r im id ine -2 -one and py r im id ine -2 th ione de r i va -t i ves respec t ive l y o f the t ype 3 a ,b an d 4a ,b . I n add i ti on many cha lcones were reac ted w i thhydro xy lam ine hydrochlor ide g iv ing isoxazo l ine der ivat ives 5a ,b . They cou ld a l so reac ted w i thpheny lhyd raz ine to g i ve py razo l i ne de r i va t ives 6a ,b , cha l cones a l so we re reacted w i the thy l cy -ano acetate and/o r malononi try l in pyr id ine g iv ing pyran der ivat ives 7a,c and 8a,c . In ano therpa thway cha lcones were ep ox id i sed by H 202 g i v ing epox ides 9a ,c w h ich i n t u rn were reactedw i th ph eny lhyd raz ine g iv ing 4 -hyd roxyp y razo l i ne de r iva t i ves 10a ,c . I n ano the r reac t i on cha l -cones were reac ted w i th e thy l cyanoace ta te in p resence o f am ma ce ta te g i v ing py r i done de r i v -a t ives 11a,d which could be prepared a lso in exe l lent y ie ld from co mp ound 1 by i ts react ionw i th ce r ta in a romat i c a ldehydes and e thy l cyanoace ta te i n p resence o f ammon ium ace ta te .F ina l l y , compound 1 was reac ted w i th semica rbaz ide g i v ing semica rbazone i n te rmed ia te 1 2which in turn was reacted wi th th iony l ch lor ide g iv ing th iad iazo le der ivat ive 13. The b io log ica le f fec ts o f some o f the new syn thes i zed com poun ds were a l so i nves t iga ted .K e y w o r d s : 2-Th iou rac i l - 5 -su lphonamide -p -pheny lderivat ive, Ant ibacter ial , Ant i- fu ng al act iv i ty

I N T R O D U C T I O NI n c o n t i n u a t i o n o f o u r w o r k ( F a t h a l la et al., 2 0 0 2 ) o n t h e

s y n t h e s i s o f s o m e 2 - t h io u r a c i l -5 - s u l p h o n a m i d e d e ri v a ti v e s ,w e r e p o r t e d h e r e t h e i n c o r p o r a t i o n o f 2 - t h i o - u r a c i l i n t op y r i m i d i n e s ( F a t h a l la , 1 9 9 2 ) , I s o x a z o l e i n e s ( C a r a d o n n aa n d S t e i n , 1 9 6 0 ) , p y r a z o l i n e s ( A r h o l d l c et aL, 1979) ,p y r a n e s ( E s s a w a y a n d W a s fy , 1 9 9 4 ), p y r i d o n e s (S a k u r a ia n d M i d o r i k a w a , 1 9 6 7 ) , a n d t h i a d i a z o l e s ( L a l e z a r i et al.,1 9 7 4 ) . T h i s s t u d y w a s u n d e r t a k e n i n v i e w o f th e f a c t t h a tp y r i m i d i n e s , i s o x a z o l i n e , p y r a z o l i n e s , p y r a n s , p y r i d o n e s ,a n d t h i a d i a z o l e s h a v e w i d e r a n g e o f p h a r m a c o l o g i c a lprope r t ies . In add i t ion 2- th ioura c i l itse lf has cer ta in b io log ica la c t i v i t i e s a s a n t i b a c t e r i a l ( W y r z y k i e w i c z e t a l . , 1 9 9 3 ) ,an t i f unga l , an t i p ro tozoa l and an t i v i ra l ac t i v i t y (Lang , 1975) ,a l s o s o m e 2 t h i o u r a c i l d e r i v a t i v e s h a v e c y t o t o x i c a c t i v i t y( F a t h a l la , 2 0 0 2 ) i n a d d i t i o n t o a n t i t h y r o id a c t iv i ty ( D a l e M .T h e e x t r a p h a r m a c o p e i a , 1 9 8 9 ) . W e d e v e l o p e d h e r e a

Correspond ence to: O. A. Fa thal la, Depa rtment of M edicinalChemistry, Nat ional Research C entre, Dokki, Cairo, EgyptE-mail : om arfathal la@ yahoo.com

p r o g r a m a i m e d t o th e s y n t h e s i s o f n o v e l 2 - t h i o u r a c i ld e r i v a ti v e s h o p p in g t h a t t h e s e c o m p o u n d s m i g h t p o s s e s sce r ta in b io log i ca l ac t i v i ty .M A T E R I A L S A N D M E T H O D S

A l l m e l t i n g p o i n t s a r e u n c o r r e c t e d a n d w e r e d e t e r m i n e di n c a p i l l a r y t u b e o n B o e t i u s m e l t in g p o i n t m i c r o s c o p e . I Rs p e c t r a w e r e r e c o r d e d o n a B e c k m a n i n f r a r e d s p e c t r o p h o -t o m e t e r P U 9 7 1 2 u s i n g K B r d i s c s . 1 H - N M R s p e c t r a w e r eo b t a in e d o n J o e l E X 2 7 0 M H Z s p e c t r o m e t e r u s i n g T M S a si n te r n a l s t a n d a rd . M a s s s p e c t r a w e r e r e c o rd e d o n S S Q 7 0 0 0M a s s s p e c t r o m e t e r a t 7 0 e . v . A l l r e a c t i o n s w e r e f o l l o w e da n d c h e c k e d b y T .L .C . u s i n g c h l o r o f o r m / m e t h a n o l ( 3 : 1 )a n d s p o t s w e r e e x a m i n e d b y U V l a m p .M A T E R I A L S A N D M E T H O D S2 - T h i o u r a c i l - 5 - s u l p h o n i c a c i d N - ( 4 - a c e t y l p h e n y l )a m i d e ( 1 )

I t w a s p r e p a r e d b y t h e p r o c e d u r e d e s c r i b e d i n li t e r a tu r e(Fa tha l l a , 1992) .

1205


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1206 O .A . Fathal la e t a l .

2 - T h i o u r a c i l - 5 - s u l p h o n i c a c i d N - ( 4 - ( 3 - s u b s t i t u t e d - 2 -p r o p e n - l - o x o ) p h e n y l ) a m i d e d e r i v a t iv e s ( 2 a -d )A mix tu re o f 1 (1 .13 g , 0 .005 mo le ) and the appropr ia te

a romat ic a ldehydes (0 .005 mo le ) in 50 mL e thano l i cs o d i u m h y d ro x i d e w a s s t ir r e d a t ro o m te m p e ra tu re f o r24 h, then re f luxed fo r 1 h, coo led an d poured in to ice -co ld water. The prec ip i ta te that appeared af ter nutra l izat ionwi th d i l. HC L was f i lte red o f f and recys ta l li zed f rom DM F/wa te r .2 - T h i o u r a c i l - 5 - s u l p h o n i c a c i d N - ( 4 - ( 1 , 2 , 5 , 6 - t e t r a h y d r o -2 - t h i o x o - 6 - s u b s t i t u t e d p y r i m i d i n y l ) p h e n y l ) a m i d ed e r i v a t i v e s ( 3 a ,b )

A m ix tu re o f appropr ia te cha lcone (0 .001 mo l ), th iou rea(0 .11 g , 0 .001 mo l ) and 0 .1 g NaOH in 25 mL o f 80% d i l .e thano l was re f luxed fo r 15 h , then concen te ra ted andcooled, the prec ip i te te was f i l tered of f and recrysta l l izedf ro m D M F /w a te r .2 - T h i o u ra c i l - s u l p h o n i c a c i d N - ( 4 - ( 1 , 2 , 5 , 6 - t e t ra h y d ro -2 - o x o - 6 - s u b s t i t u t e d p y r i m i d i n - y l ) p h e n y l ) a m i d ed e r i v a t i v e s ( 4 a , b )

To a so lu t ion o f (0 .01 g , 0 .0015 mo l ) o f u rea in 20 mLe thano l 5 mL o f conc . H CL wa s added , (0 .001 too l) o f thea p p ro p r i a t e c h a l c o n e s w a s a d d e d a n d t h e m i x tu re w a sre f luxed fo r 12 h , then concen t ra ted to ha l f i t s vo lume andcooled, i t wa s neutra lized wi th ammonium hydro x ide so lutionand the p rec ip i ta te wa s rec rys ta l li zed f rom DM F/wa te r .2 - T h i o u r a c i l - 5 - s u l p h o n i c a c i d N - ( 4 - ( 5 - s u b s t i t u t e d -3 - i s o x a z o l i n o ) p h e n y l ) a m i d e d e r i v a t i v e s ( 5 a , b )

A so lu t ion o f the appropr ia te cha lcon e (0 .005 mo l ) andhydroxy lamine hydrochlor ide (0.005 mol) in 20 mL ethanolcon ta in ing 0 .04 g sod ium hydrox ide was re fluxed fo r 11 h ,the product was iso la ted by concentration of the a lchohol icso lut ion, then f i l tered, dr ied, and recrysta l l ized f rom DMF/wa te r .2 - T h i o u r a c i l - 5 - s u l p h o n i c a c i d N - ( 4 - ( 1 - p h e n y l - 5 - s u b -s t i t u t e d - 3 - p y r a z o l i n o ) p h e n y l ) a m i d e d e r i v a t i v e s( 6 a ,b )A m ix tu re o f the appropr ia te cha lcone (0 .001 mo l ) andpheny lhyd raz ine (0 .001 mo l ) was hea ted under re f lux fo r8-12 h, in 25 mL absolute ethanol then le f t to cool , theres idual m ater ia l w as f il tered of f and rec rysta l l ized f romD M F /w a te r .2 - T h i o u r a c i l - 5 - s u l p h o n i c a c i d N - ( 4 - ( 6 - a m i n o - 5 - c y n oo r c a r b o e t h o x y - 4 - s u b s t i t u t e d p y r a n o ) p h e n y l ) a m i d ed e r i v a t i v e s ( 7 a , c ) a n d ( 8 a , c )

A m ix tu re o f the appropr ia te cha lcone (0 .001 mo l ),e thy lcyanoace ta te and /o r ma lonon i t r i le (0 .001 mo l ) and20 m L py r id ine wa s re f luxed fo r 8 h , coo led an d poured

in to i ce /HCL so lu t ion , the so l id p roduc t fo rmed wasco llected and rec rys ta l li zed f rom DM F/wa te r .E p o x i d a t i o n o f c h a l c o n e 9 a , c

A so lu t ion o f the appropr ia te cha lcone (0 .001 mo l ) in2 0 m L a c e to n e a n d 1 5 m L m e th y l a lc o h o l w a s m i x e d w i t h8 % a q u e o u s s o d i u m h y d ro x i d e (1 2 m L ) f o ll o w e d b y t h eadd i t ion o f hyd rogen pe rox ide (30%, 5 mL) , the so lu t ionwa s shaken a nd he a ted to the bo i l ing po in t du r ing 1 h ,then a l lowed to s tand overn igh t a t room tempera tu re ,w a te r w a s a d d e d a n d t h e s o l u t i o n w a s e x t ra c te d w i t he the r . The e the r laye r was evapora ted and the res iduewa s rec rys ta ll ized f rom pe t ro leum e the r to g ive wh i tepow der (m.p . 185~ in 65% y ie ld .2 - T h i o u r a c i l - 5 - s u l p h o n i c a c i d N - ( 4 - ( 1 - p h e n y l - 5 - s u b -s t it u t e d -4 - h y d r o x y p y r a z o l i n o ) p h e n y l ) a m i d ed e r i v a t i v e s ( 1 0 a , c )

The epo x ide (0 .001 mo l ) and pheny l hyd raz ine (0 .001mo l ) were re f luxed in 25 mL e thano l fo r 13 h . The so l idthat separated on cooling was fi l tered off and recrystall izedf rom DMF/wa te r .2 - T h i o u r a c i l - 5 - s u l p h o n i c a c i d N - ( 4 - ( 5 - c y n o - 6 - o x o - 4 -s u b s t i t u t e d p y r i d i n e - 2 - y l ) p h e n y l ) a m i d e d e r i v a -t i v e s ( 1 1 a , d )

A m ix tu re o f the approp r ia te cha lcone (0 .001 mo l ),e thycyanoacetate (0 .035, 0 .001 too l) and ex cess ammoniumace ta te (1 .89 g , 8 mo l ) in 50 mL abso lu te e thano l wasref luxed for 12-15 h. The react ion mix ture wa s concentratedt i l l i ts ha l f vo lume, f i l tered and the f i l t ra te was poured in toice /wa te r and the p roduced p rec ip i ta te was f i l te red o f f ,d r ied under suc t ion and c rys ta l l i zed f rom DMF/wa te r .A n o t h e r p r o c ed u r e

The same py r idone de r iva t i ves cou ld be p repared f romcom pound 1 as fo l low :

A mix tu re o f 1 (1 .13 g , 0 .003 mo l ) , the appropr ia tea ldehyde (0 .003 mo l ) , e thy l cyanoace ta te (0 .003 mo l ) ,and excess ammon ium ace ta te (1 .89 g , 8 .0 mo l ) in 50 mLabso lu te e thano l was re f luxed fo r 6 -10 h . The reac t ionmix tu re was concen t ra ted , f i l te red and the f i l t ra te waspoured in to i ce /wa te r and the p roduced p rec ip i ta te wasf i l tered of f , dr ied and crys ta l l ized f rom DMF/water.F o r m a t i o n o f s e m i c a r b a z o n e 1 2

To a so lut ion of 1 (0 .001 mol) in 50 mL ethanol wasadded a so lu t ion o f sem ica rbaz ide hyd roch lo r ide (0 .001mo l ) and sod ium ace ta te (0 .002 mo l ) in 20 mL wa te r . Thereac t ion m ix tu re wa s re f luxed fo r 4 h , evap ora ted to ha l f o fi ts vo lume and then po ured in to i ce-wa te r . T he s epara tedsol id w as f il tered of f , wa she d wi th water, dr ied an dc rys tal li zed f rom D M F/w a te r to g ive sem ica rbazone as


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New 2-Thiou rac i l -5-Sulphon am ide Der ivatives wi th B io log ica l Act iv i ty 1207

p a l e y e l l o w p o w d e r ( m . p . > 3 0 0 ) .2 - T h i o u r a c i l - 5 - s u l p h o n i c a c id N - ( 4 - (1 , 2 ,3 - t h ia d i a z -o l o ) p h e n y l ) a m i d e d e r i v a t i v e ( 1 3)

T e n m L t h i o n y l c h l o r id e w a s g r a d u a l ly a d d e d t o t h es e m i c a r b a z o n e 1 2 ( 0 . 0 0 5 m o l ) a n d t h e m i x t u re w a s g e n t l yw a r m e d a n d t h e n l e f t f o r 2 4 h a t r o o m t e m p e r a t u r e . AN a H C O 3 i c e - c o l d s a t u r a t e d s o l u t i o n w a s t h e n a d d e d , t h ep r o d u c t w a s e x t r a c t e d w i t h e t h e r a n d t h e e x t r a c t w a sw o r k e d u p a s u s u a l . T h e r e s i d u e w a s c r y s t a l li z e d f r o mD M F / w a t e r a s y e l l o w p o w d e r .T h e b i o lo g i c a l e f f e c t s o f s o m e o f t h e n e w s y n -t h e s i ze d c o m p o u n d s

A n t i b a c t e r i a l a c t i v i tyM o s t c o m p o u n d s w e r e t e st e d .B a c t e r ia : T h e f o l l o w i n g m i c r o o r g a n i s m s w e r e u s e d f o r

d e t e r m i n a t i o n o f b a c t e r o s t a t i c a n d / o r b a c t e r i c i d a l c o n -cen t ra t i on , Bac i l l us sub t i l i s , Escher i ch i a co i l , Cand i daa l b i c a n s , S t a p h y l o c o c c u s a u r e u s , S a r c i n a , P s e u d o m o n a sa e r o g i n o s a , a n d M y c o b a c t e r i u m p h l e i . A l l m i c r o o r g a n i s m s

u s e d w e r e o b t a i n e d f r o m t h e c u l t u r e c o l l e c t i o n o f t h ed e p a r t m e n t o f m i c r o b i o l o g y a n d i m m u n o l o g y , F a c u l t y o fP h a r m a c y, H e l w a n U n i v e rr is i ty . C o m p o u n d s w e r e t e s te da g a i n s t E s c h e r i c h i a c o i l , P s e u d o m o n a s a e r o g i n o s a , a n dS t a p h y l o c o c c u s a u r e u s i n n u t r i e n t b r o th , p H 7 . 0 a n da g a i n s t B a c i l l u s s u b t i l is S a r c i n a a n d M y c o b a c t e f iu m p h l e ii n b a c t o b r a i n h a r t i n f u s i o n b r o t h p H 7 . 0 a n d a g a i n s tC a n d i d a a l b i c a n s i n b ro t h c o n t a i n i n g 1 % n e o p e p t o n e , 2 %o f d e x t r o s e w i t h p H 5 . 7 . A s t r a in o f E s h e f i c i a c o i l o f k n o wa n t i b i o ti c s e n s i t i v it y s e r v e d f o r c o n t r o l p u r p o s e s .

M e d i a d i s k s e n s i t i v i t y t e s t s w e r e n u t r i e n t a n d M u l l e rH e n t o n A g a r ( M H A ) w e r e p u r c h a s e d f r om D i fc o . T h e d i s kd i a m e t e r w a s 5 m m . T h e c o m p o u n d s w i t h i n h i b it io n z o n ed i a m e t e r m o r e t h a n 5 m m w e r e a c t i v e . C o m p o u n d s w e r ed i s s o l v e d i n s t e r i l e D M S O t o y i e l d 2 . 0 0 0 p g / m L , p a s s e dt h r o u g h 0 . 2 p m m e m b r a n e f il t e rs ( M i l li p o r e c r o p . B e d f o r d .M a s s ) . T h e f i l t r a t e s w e r e d i s s o l v e d a s 2 m L s a m p l e s i n t os t e r i l e , s m a l l s c r e w c a p p e d v i a l s , a n d f r o z e n a n d k e p ts t a n d e d a t - 1 5 ~ T h e v i a ls w e r r e f ro z e n a ft e r t h a w i n g .

S e n s i t iv i t y t e s t s : D i s c d i f fu s i o n s e n s i t i v it y te s t w e r ed o n e i n a m a n n e r i d e n t i c a l t o t h a t o f ( B a u e r et a l . , 1966) ,

N -NR " ~ R'

OH10a,c[ Ph-NHNH2

OR / ~ " O R'

N C / ~ ' R ,

~R"

R NH 27a,c 8a,ca R" = COO Er R' = p-ni trophen ylc R" = CN R' = 3- indoyl

S ch em e 1. Proparationof compounds1~13

R

13I SO2CIH R =N - N - - ~ N H 2R L . . o12 H

I H 2 N 'N o ~ N H 2O ethyl cyanoacetate/R'CHO+ -R ammonium acetate

~HN~S-NS ~ \ N ~ I H

H

I 'CHOO,,,, H 2 0 2 R....JJ...v..~--~2a-d a m m o n i u mcetate

a R ' = p -n it ro p he n yl ~ . . N H 2 O Hb R' =p-chlorophenyl ~ Rc R' = 3- indolyl ~d R' = p-N-dimethytaminophe nyl R '

L ~ P h _ N H N H 2 5 a ' bH2N NH2 ~ R

N X"~NH3a,b X = S 6a,b4 a ,b X = O

ethyl cyanoacetate/R'CHO

ONC~NHR, ~ ' ~ ' R11a,b


4/8

1208 O .A . Fathal la et al .

some compounds wi th inh ib i t ion zone d iameter more than5 mm were subjected to determinat ion of MIC by ser ia ldilution method. Broth dilution tests, uti l izing serial log 2d i lur ions of the tested co mp ound s over the range of 50 to0.025 mg/mL were per formed by using l iqu id media and abacterial inoculum standardized to yield 1.5x108 orga nism s/mL at 0 t ime. For this purpose organisms in the exponentialgrowth ph ase (pregrown at 35~ for 6 h in l iqu id m edia)were ad justed to Mc far land BaSO4 standard no. 0 .5 . Theturbidi ty of wh ich c orresp ond s to that of 1.5x 108 orga nism s/mL. The ad jus ted suspens ion o f o rgan isms was fu the rdi luted 50 fold in the selected l iquid medium (correspondingto 3x106 o rgan isms/mL) . A ssa y tubes received 1 mL o fthe respective dou ble strength di lut ion of antibiot ic and 1m L of bacterial inoculum. Control tubes received 1 m L ofMHB and 1 mL of bacter ia l inocu lum. The assay andcontro l tubes were incubated at 35~ for 18 h. Theminimal inhibitory concentrat ion (MIC) of tested com poun dswe re defind as the lowe st concentrat ion of antibiot ic com -p lete ly inh ib i ting the grow th as judged by visua l inspec-t ion. Th e minimal bactericidal c oncentration (M BC ) of thed rug was de te rmined th rough subcu l tu re o f one 3 mmIoopfu l f rom clear tubes to quar ter sectors o f 5% sheepblood agar p la tes which w ere incubated at 35~ for 24 h.Th e MB C was def ined as the lowest concentra tion o f gen-tamicin yielding no growth after subculture to blood agar.R E S U L T S A N D D I S S C U S S I O N

In v iew of the above f ind ings i t wa s cons idered ofin terest to undertake the synthesis o f new 5-subst i tu ted-2-thiouraci l containing chalcones, pyrimidines, isoxazoles,pyranes, 4-hydroxypyrazol ines, pyridones, semicarbazones,and th iad iazo les hopp ing tha t these compounds migh tpos ses s certain anti me taboli t ic function aga inst l ivingmicro -o rgan isms. Syn thes is o f the descr ibed co mpo undswa s ach ieved by fi rst ly preparation o f com pound 1 (methylketone containing compound) by reacting 2-thiouraci l -5-su lphonyl ch lor ide wi th p-amino acetophenone in absolu teethanol containing pyridine a s ac id scavenger, this compoundwa s rea cted with aldehydes namely p-ni tro-benzaldehyde,p-ch lorobenzaldehyde, indo l -3-carboxaldehyde and N , N -d ime thy laminobenza ldehyde in p resence o f 10% NaOHsolut ion affording chalcone derivat ives 2a~c (ClaisenSchemidt reaction). Chalcone derivat ives were condensedwith thiourea and urea giving pyrimidines 3a,b and 4a,brespec tively. A solution o f chalcon e derivatives in ethanolicKO H on t rea tmen t w i th hyd roxy lamine hyd roch lo r ide ga veisoxazol ine der ivat ives 5a,b.

Co nde nsa tion reaction of pheny lhydra zine w ith c~, [3unsaturated ketones was investigated (Abady e t aL , 1986;H a ssa n e e n et a l . , 1995). When al lowed to react withpheny lhydrazine in e thanol in presence of few drops of

Table I. Physical and analytical data of the prepared compounds 1~13Comp No Yie led %) F o rm u la Analysiscalcd/fownd) %U.p (~ Uol. wt C H N

72 C19H14N406S2 49.78 3.08 12.222a 255 (458.47) 49.52 3. 27 11.9 8

70 019H14N3048201 50 .95 3.15 9.392b 299 (447.91) 50.82 3.27 9.1974 021H16N404S2 55.74 3.56 12.382c 288 (452.50) 55.66 3. 42 12. 2763 021H20N404S2 55.25 4.42 12.272d 315 (456.53) 55.32 4. 5 8 12.3 364 020H14N6OsS3 46.68 2.74 16.333a 310 (514.56) 45.25 2. 83 16.2 355 C20H14N503S3CI 47 .66 2. 79 13.893b 299 (504.01) 47.52 2. 72 13.6 967 020H14N6OeS 48.19 2.83 16.864a 320 (498.40) 48.32 2. 67 16.9 861 020H14N504S201 49.23 2.89 14.354b 336 (487.94) 49.18 2. 92 14.1 970 C19H13N5OeS2 48.40 2 .7 8 16 .785a 301 (471.46) 48.25 2. 99 16. 7258 019H13N404S201 49.51 2.84 12.165b 317 (460.91) 49.35 2. 94 12. 1959 C2~H18N6OsS2 54.93 3 .3 2 15 .376a 289 (546.57) 54.88 3. 47 15. 0959 C25H~sN~O3S2CI 56.01 3.3 8 13. 076b 277 (536.02) 56.34 2. 99 13. 3261 C24H21N5OsS2 50.43 3 .7 0 12 .257a 355 (571.64) 50.60 3. 40 12. 0570 026H23N50682 55.21 4.0 9 12.387c 347 (565.61) 55.59 4. 37 12.0 578 C22H16N606S2 50.37 3.08 16 .028a 333 (524.53) 50.46 3.05 16 .1354 024H18N60482 55.59 3.49 16.218c 323 (518.62) 55.38 3.09 16 .5454 019H14N4OsS2 48.10 2.97 11.819a 320 (474.46) 48.23 2.01 11.9557 021H16N405S2 53.83 3.44 11.969C 340 (468.50) 53.77 3.6 4 11 .7855 C25H2oN606S2 53.18 3. 57 14 .8910a 360 (564.59) 53.07 3. 28 14 .9970 C27H23N604S2 57.94 4. 14 15 .1910c 352 (559.63) 57.75 4. 16 15 .2573 C22H13N606S2 50.57 2. 27 16 .0911a 300 (522.51) 50.38 2.9 2 16.3 168 C24H19N604S2 52.36 3.6 6 15 .2611d 317 (550.64) 52.28 3.7 2 15 .1955 C13H14N604S2 40.82 3.6 9 21 .9812 361 (382.42) 40.68 3.8 2 21 .7257 C12HgNsO3S3 39.22 2.4 7 19 .0613 380 (367.43) 39.52 2. 48 19 .18


5/8

N e w 2 - T h i o u r a c i l - 5 - S u l p h o n a m i d e D e r i v a t i v e s w i t h B i o l o g i c a l A c t i v i t y 1 2 0 9

T a b l e I I . T h e 1 H - N M R , I R , a n d M a s s o f s o m e o f t h e p re p a r e d c o m p o u n d sC o m p N o ~ H - N M R ( D M S O - d 6 ) p p m I R ( K B r ) c m ~ M a s s M "

2 a 6 . 6 - 7 . 2 ( 2 H , r id , c h a l c o n e ) , 7 . 3 , 7 . 6 , 7 . 9 , 8 . 1 ( 8 H , d d , a r o m a t ic ) 8 . 2 3 2 2 0 ( N H , S t . , b ) , 3 0 6 0 ( C H , s t ., a r o m a t ic ) , 1 6 7 0 ( 2 C O ) , 1 6 3 0 4 5 8 . 5( 1 H , s , t h io u r a c i l) 1 1 . 2 - 1 1 . 4 ( 3 H , s , 3 N H e x c h a n g e a b l e w i t h D 2 0 ) . ( C = C ) , I 3 5 0 - 1 5 5 0 ( N O 2 ) , 1 2 7 0 ( C = S o f t h io - u r a c i l, 1 3 2 0 , 1 1 4 0 ( S O 2 )6 . 3 - 6 . 8 ( 2 H , d d , c h a l c o n e ) , 7 . 5 , 7 . 8 , 7 . 9 , 8 . 3 (4 H , d d , o f a r o m a t ic ) , 3 2 2 5 ( N H , s t ., b ) , 3 1 5 0 ( C H , s t , a r o m a t ic ) , 1 6 8 0 (2 C O ) , 1 2 6 5 (C = S 4 4 7 . 92 b 8 . 6 ( 1 H , s , t h io u r a c i l) , 1 1 . 3 , 1 1 . 4 ( 3 H , s , 3 N H e x c h a n g e a b l e w i th o f th i o u r a c i l ), 1 3 5 0 , 1 1 6 0 ( S O 2 ) .D 2 0 ) .

2 c 6 . 4 - 7 . 0 ( 2 H , d d , c h a l c o n e ) , 7 . 2 - 8 .5 ( 9 H , m , a r o m a t ic ) , 8 . 2 ( 1 H , s , 3 3 1 0 ( N H , s t, b ) , 3 1 6 0 ( C H , s t , a r o m a t ic ) , 1 6 6 0 ( 2 C O ) , 1 6 2 0 ( C = C ) , 4 5 2 . 5t h io u r a c i l) , 1 0 , 1 1 . 3 - 1 1 . 6 ( 4 H , s , 4 N H e x c h a n g e a b l e w i th D 2 0 ) . 1 2 7 0 (C = S o f t h io - u r a c i l ), 1 3 3 0 - 1 1 4 0 ( S O 2 ) .3 . 2 ( 6 H , s , N - ( C H ~ ) 2 ) , 6 . 7 - 7 . 1 ( 2 H , d d , c h a l c o n e ) , 7 . 2 , 8 . 1 ( 8 H , d d , 3 3 2 0 ( N H , s t , b ) , 3 1 5 0 ( C H , s t , a r o m a t ic ) , 2 8 9 0 ( C H , s t , a l ip h a t i c ),2 d a r o m a t ic ) , 8 . 2 ( 1 H , s , t h io u r a c i l) , 1 1 . 1 , 1 1 . 3 ( 3 H , s , 3 N H e x c h a n g e - 1 6 8 0 ( 2 C O ) , 1 6 4 0 ( C = C ) , 1 2 7 0 ( C = S o f t h io u r a c i l) , 1 3 2 0 , 1 1 4 0 4 5 6 . 5a b l e w i t h D 2 0 ) . ( S O 2 ) .6 . 9 - 7 . 8 ( S H , d d , a r o m a t ic ) , 7 .5 ( 1 H , s , o f t h io p y r i m i d in e ) , 8 . 4 ( 1 H , 3 3 5 0 ( N H , S t . , b ) , 3 1 5 0 ( C H , s t ., a r o m a t ic ) , 1 6 7 0 ( C O ) , 1 6 3 03 a s , t h io u r a c i l) , 1 1 . 0 , 1 1 . 2 , 1 1 . 3 , 1 1 . 8 ( 4 H , s , 4 N H e x c h a n g e a b l e w i t h ( C = C ) , 1 3 5 1 - 1 5 4 7 ( N O 2 ) , 1 2 7 1 (C = S o ft h io - p y r im i d in e , 1 3 2 5 , 1 1 4 2 5 1 4 . 5D 2 0 ) . ( S O 2 ) .6 . 8 - 7 . 9 ( 8 H , d d , a ro m a t ic ) , 7 . 3 ( 1 H , s , o f t h io p y r i m i d in e ) , 8 .4 ( 1 H , 3 3 0 0 ( N H , s t ., b ) , 3 1 8 0 ( C H , s t , a r o m a t ic ) , 1 6 7 0 (C O ) , 1 6 3 5 (C = C ) ,3 b s , t h io u r a c i l) , 1 1 . 2 , 1 1 . 3 , 1 1 . 8 , 1 1 . 9 ( 4 H , s , 4 N H e x c h a n g e a b l e w i t h 1 2 7 0 ( C = S o f t h io - p y r im i d in e ) , 1 3 3 5 , 1 1 4 8 ( S O 2 ) . 5 0 4 . 1D 2 0 ) .6 . 8 - 7 . 6 ( 8 H , d d , a r o m a t ic ) , 7 .4 ( 1 H , s , o f p y r im i d in - 2 - o n e ) , 8 . 3 ( 1 H , 3 3 0 0 ( N H , s t , b ) , 3 1 8 0 ( C H , s t , a r o m a t ic ) , 1 6 7 0 , 1 6 8 0 ( 2 C O ) , 1 6 3 04 a s , t h io u r a c i l) , 1 1 . 1 , 1 1 . 2 , 1 1 . 4 , 1 1 . 6 ( 4 H , s , 4 N H e x c h a n g e a b l e w i t h ( C = C ) , 1 3 5 0 - 1 5 5 0 ( N O 2 ) , 1 2 7 5 ( C = S o f t h io u r a c i l) , 1 3 3 5 - 1 1 4 8 4 9 8 . 5D 2 0 ) . ( S O 2 ) .6 . 7 - 7 . 6 ( S H , d d , c h a l c o n e ) , 7 .3 ( 1 H , s , o f p y ri m i d in - 2 - o n e ) , 8 . 3 ( 1 H , 3 3 2 0 ( N H , b ) , 3 1 8 0 ( C H a r o m a t ic ) , 1 6 7 5 , 1 6 8 5 ( 2 C = O ) , 1 6 4 04 b s , t h io u r a c i l) , 1 1 . 1 , 1 1 , 2 , 1 1 . 7 , 1 1 . 9 ( 4 H , s , 4 N H e x c h a n g e a b l e w i t h ( C = C ) , 1 2 7 0 ( C = S o h t h io u r a c i l) , 1 1 4 0 , 1 3 3 5 ( S O 2 ) . 4 8 7 . 9D 2 0 ) .

5 a 6 . 9 , 7 . 2 , 7 . 8 , 7 . 9 ( 8 H , d d , a r o m a t ic ) , 8 . 1 ( 1 H , s , o f i s o x a z o l in e ) , 8 . 4 3 3 7 0 (N H , b ) , 3 1 5 0 ( C H a r o m a t ic ) , 1 6 7 0 ( C = O ) , 1 6 3 0 ( C = C ) , 1 3 5 5 , 4 7 1 . 51 H , s , t h io u r a c il ) , 1 1 .2 - 1 1 .4 ( 3 H , s , 3 N H e x c h a n g e a b l e w i th D 2 0 ) . 1 5 5 0 N Q ) , 1 2 7 0 ( C = S o f t h io u r a c il ) , 1 1 4 0 , 1 3 5 0 (S O 2 ) .6 . 8 , 7 . 2 , 7 . 4 , 7 . 5 ( 8 H , d d , a r o m a t i c ), 8 . 0 ( 1 H , s , o f i s o x a z o l in e ) , 8 . 25 b ( 1 H , s , t h io - u r a c il ), 1 1 . 0 - 1 1 . 3 ( 3 H , s , 3 N H e x c h a n g e a b l e w i t h 3 3 6 0 ( N H , b ) , 3 1 4 5 ( C H a r o m a t ic ) , 1 6 6 0 ( C = O ) , 1 6 4 5 ( C = C ) , 1 2 7 0 4 6 0 . 9D 2 0 ) . ( C = S o h t h io u r a c i l) , 1 1 4 5 , 1 3 4 5 ( S O 2 ) .

6 a 6 . 8 , 6 . 9 , 8 . 0 , 8 . 1 ( 1 3 H , d d , a r o m a t ic ) , 7 . 6 ( 1 H , s , o f p y r a z o l in e ) , 8 . 7 3 3 4 0 (N H , b ) , 3 1 9 0 (C H a r o m a t ic ) , 1 6 6 0 ( C = O ) , 1 6 5 0 ( C = C ) , 1 3 6 0 , 5 4 6 . 5( 1 H , s , t h io u r a c i l) , 1 1 . 2 - 1 1 . 4 ( 3 H , s , 3 N H e x c h a n g e a b l e w i th D 2 0 ) . 1 5 4 0 N O 2 ) , 1 2 7 0 (C = S o f t h i o u r a c i l) , 1 1 4 1 , 1 3 4 0 ( S O 2 ) .6 b 6 . 9 , 7 . 0 , 6 . 1 , 8 . 2 (1 3 H , r id , a r o m a t ic ) , 7 . 6 ( 1 H , s , o f p y r a z o l in e ) , 8 . 7 3 3 5 1 ( N H , b ) , 3 1 5 0 ( C H a r o m a t ic ) , 1 6 7 5 ( C = O ) , 1 6 6 0 ( C = C ) , 1 2 7 0 5 3 6 . 0 2( 1 H , s , o f t h io u r a c i l) , 1 1 . 2 - 1 1 . 4 ( 3 H , s , 3 N H , e x c h a n g e a b l e w i th D 2 0 ) . ( C = S o h t h i o u r a c i l ), 1 1 4 0 , 1 3 5 2 ( S O 2 ) .

1 . 7 (3 H , t , C H ~ ) , 4 .1 ( 2 H , q , C H 2 ) , 7 .1 ( 2 H , s , N H 2 e x c h a n g e a b l e 3 4 4 0 ( N H , N H 2 , b ) , 3 1 8 0 ( C H a r o m a t ic ) , 1 7 2 0 (C = O ) , 1 6 7 0 ( C - -O7 a w i t h D 2 0 ) , 7 . 2 ( 1 H , s o f p y r a n ) , 7 . 3 - 8 . 5 ( 9 H , d d , a r o m a t ic ) , 1 1 . 2 - o f t h io u r a c i l) , 1 6 6 0 ( C = C ) , 1 3 5 5 , 1 5 5 0 ( N O 2 ) , 1 2 7 0 ( C = S o f 5 7 1 . 51 1 . 8 ( 3 H , s , 3 N H e x c h a n g e a b l e w i t h D 2 0 ) . t h io u r a c i l) , 1 1 3 5 , 1 3 5 1 ( S O 2 ) .1 . 8 3 H , t , C H 3 ) , 4 . 2 ( 2 H , q , C H 2 ) , 7 . 0 ( 2 H , s , N H 2 e x c h a n g e a b l e 3 4 0 0 ( N H , N H 2 , b ) , 3 1 9 0 ( C H a r o m a t ic ) , 1 7 2 5 (C = O ) , 1 6 6 5 ( C = O7 c w i t h D 2 0 ) , 7 . 2 ( 1 H , s o f p y r a n ) , 7 . 3 - 8 . 4 ( 9 H , m , a r o m a t ic ) , 1 0 , 1 1 . 2 - o f t h io u r a c i l) , 1 6 6 0 (C = C ) , 1 2 7 0 ( C = S o f t h io u r a c i l) , 1 1 4 0 , 1 3 5 0 5 6 5 . 51 1 . 4 ( 4 H , s , 4 N H e x c h a n g e a b l e w i t h D 2 0 ) . ( S O 2 ) .7 .1 ( 2 H , s , N H 2 e x c h a n g e a b l e w i th D 2 0 ) 7 .2 ( 1 H , s , o f p y ra n ) , 7 . 2 - 3 4 5 0 ( N H , N H 2 , b ) , 3 1 8 0 C H a r o m a t ic ) , 2 2 1 8 ( C N ) , 1 6 8 0 ( C = O ) ,8 a 8 . 4 ( S H , d d , a r o m a t ic ) , 1 1 - 1 1 . 2 ( 3 H , s , 3 N H e x c h a n g e a b l e w i t h 1 6 6 5 ( C = C ) , 1 3 5 0 , 1 5 5 0 ( N O 2 ) , 1 2 7 0 ( C = S o f t h io u r a c i l) , 1 1 4 2 , 5 2 4 . 5D 2 0 ) . 1 3 5 0 ( S O 2 ) .7 . 2 (2 H , s , N H 2 e x c h a n g e a b l e w it h D 2 0 ) , 7 . 2 (1 H , s , o f p y r a n ) , 3 4 8 0 ( N H , N H 2 , b ) , 3 1 9 0 ( C H a r o m a t ic ) , 2 2 2 0 ( C N ) , 1 6 7 0 ( C = O o f

8c 7 . 2 - 8 . 4 (9 H , m , a r o m a t ic ) , 1 0 (1 H , s , o f i n d o l e e x c h a n g e a b l e w i t h t h i o u r a c i l ) , 1 6 6 0 ( C = C ) , 1 2 7 0 (C = S o f th i o u r a c i l ), 1 1 4 0 , 1 3 5 0 ( S O 2 ) . 5 1 8 . 4 3D 2 0 ) , 1 0 . 9 -1 1 . 1 ( 3 H , s , 3 N H e x c h a n g e a b l e w i t h D 2 0 ) .1 0 a 6 . 4 - 7 . 8 ( 1 5 H , m , a r o m a t ic ) , 8 . 4 ( 1 H , s , t h io u r a c i l) , 1 1 . 2 , 1 1 . 3 , 1 1 . 4 , 3 4 2 0 (N H , O H b ) , 3 1 8 0 C H a r o m a t ic ) , 1 6 7 0 ( C = O ) , 1 6 5 0 ( C = C ) , 5 6 4 . 51 1 . 5 ( 4 H , s , O H , 3 N H e x c h a n g e a b l e w i th D 2 0 ) . 1 3 5 0 , 1 5 5 0 ( N O 2 ) , 1 2 7 0 ( C = S o f th i o u ra c i l ) , 1 1 3 8 , 1 3 5 0 ( S O 2 ) .1 1 ) c 6 . 8 -8 . 4 (1 6 H , m , a r o m a t ic ) , 8 . 6 ( 1 H , s , t h io u r a c il ) , 1 0 , 1 1 , 1 1 . 1 -1 1 . 4 3 4 1 0 (N H , O H b ) , 3 1 5 0 C H a r o m a t ic ) , 1 6 7 0 ( C = O ) , 1 6 5 0 ( C = C ) , 5 5 9 . 6 3( 5 H , O H , 4 N H e x c h a n g e a b l e w i th D 2 0 ) . 1 3 5 0 , 1 2 7 0 ( C = S o f t h io u r a c il ) , 1 1 3 8 , 1 3 5 0 ( S O 2 ) .

6 . 9 - 7 . 9 ( 9 H , m , a r o m a t ic ) , 8 . 2 ( 1 H , s , t h io u r a c i l) , 1 0 . 2 - 1 1 . 4 ( 4 H , s , 3 3 5 0 ( N H , b ) , 3 1 9 0 C H a r o m a t ic ) , 2 9 3 0 ( C H , a l ip h a t ic ) , 2 2 1 5 ( C N ) ,1 6 7 0 ( 2 C = O ) , 1 6 4 0 ( C = C ) , 1 3 5 5 , 1 5 5 0 ( N O 2 ) , 1 2 7 0 ( C = S o f 5 2 2 . 51 1 a 4 N H e x c h a n g e - a b l e w i t h D 2 0 ) . t h io u r a c i l) , 1 1 4 2 , 1 3 5 0 ( S O 2 ) .3 . 2 ( 6 H , s , N - ( C H 3 ) 2 ) , 6 . 8 - 8 ( 9 H , m , a r o m a t ic ) , 8 . 1 ( 1 H , s , 3 3 4 0 ( N H , b ) , 3 1 8 0 C H a r o m a t ic ) , 2 2 2 0 (C N ) , 1 6 8 0 ( 2 C = O ) , 1 6 5 01 1 d t h io u r a c i l) , 1 1 . 2 - 1 1 . 4 ( 4 H , s , 4 N H e x c h a n g e a b l e w i t h D 2 0 ) . ( C = C ) , 1 2 7 1 ( C = S o f th i o u r a c i l ), 1 1 3 5 , 1 3 6 0 ( S O 2 ) . 5 5 0 . 52 . 1 ( 3 H , s , C H 3 ) , 6 . 1 , 6 . 2 ( 3 H , s , N H , N H 2 , e x c h a n g e - a b l e w i t h 3 2 5 0 ( N H , N H 2 , b ) , 3 1 6 0 ( C H a r o m a t ic ) , 2 9 4 0 ( C H a l i p h a t ic ) , 1 6 7 0 3 8 2 . 51 2 D 2 0 ) , 7 . 1 , 7 . 3 ( 4 H , d d , a r o m a t i c ) , 8 . 1 ( 1 H , s , t h i o u r a c i l ), 1 1 . 1 - 1 1 . 2( 3 H , s , e x c h a n g e a b l e w i t h D 2 0 ) . ( 2 C = O ) , 1 6 4 0 ( C = C ) , 1 2 7 0 ( C = S o f t h io u r a c i l) , 1 1 4 0 , 1 3 4 2 ( S O 2 ) .6 . 9 - 7 . 8 ( 4 H , d d , a r o m a t ic ) , 7 . 2 ( 1 H , s , t h ia d i a z o l e ) , 8 . 2 ( 1 H , s , 3 2 5 0 ( N H , b ) , 3 1 6 0 ( C H a r o m a t ic ) , 1 6 7 0 ( C = O ) , 1 6 6 0 ( C = C ) , 1 2 7 5 3 6 7 . 41 3 t h io u r a c i l) , 1 1 . 1 - 1 1 . 4 ( 3 H , s , 3 N H e x c h a n g e a b l e w i t h D 2 0 ) . ( C = S o f t h io u r a c i l) , 1 1 4 0 , 1 3 6 1 ( S O 2 ) .


6/8

1210 O .A . Fatha l la e t a L

p i p r id i n e a s a b a s i c c a t a l y s t t h e c o r r e s p o n d i n g p y r a z o l i n ed e r i v a t iv e s 6 a , b w e r e p r o d u c e d .

A n a l o g o u s t o r e c e n t r e p o r t ( E s s a w y a n d W a s f y , 1 9 9 4 ) ,t h e b a s e c a t a l y z e d c o n d e n s a t i o n o f c h a l c o n e d e r i v a t i v e sw i t h e t h y l c y a n o a c e t a t e a n d / o r m a l o n o n i t r i l e a f f o r d e d t h ec o r r e s p o n d i n g p y r a n d e r i v a t i v e s 7 a , c a n d 8 a , c . S i m i l a r t ot h e b e h a v i o r o f ( E I - H a s h a s h , 1 9 9 4 ) t r e a t m e n t o f t h ea l c o h o l i c s o lu t i o n o f c h a l c o n e d e r i v a t i v e s w i t h h y d r o g e np e r o x i d e i n a l c o h o l i c m e d i u m y i e l d e d t h e c o r r e s p o n d i n gcq 13 epo xy ke tones 9a ,c . The fo rma t ion o f ox i ran e nuc leusc a n b e t h e o r e t ic a l ly e x p l a n e d a s t h e o x y i e n ( H - O - O ) d e r i v e df rom H202 a t tacks the 13 -ca rbon a tom by the M ichae l t yper e a c t io n l e a d i n g t o a n i n t e r m e d i a t e o f w h i c h t h e l o s s o f ah y d r o x i d e i o n p r o d u c i n g t h e d e s i r e d o x i r a n e . R e c e n t l y i th a s b e e n s h o w n t h a t th e o x i r a n e r in g o f cq ~ - e p o x y k e t o n e si s o p e n e d w i t h p h e n y l h y d r a z i n e i n b o i l i n g e t h a n o l t of u rn i s h 4 - h y d r o x y p y r a z o l i n e d e r i v a t iv e s 1 0 a ,c . A l s o a s( F a t h a l l a e t a l . , 2 0 0 2 ) c o m p o u n d 1 w a s r e a c t e d w i t h e t h y lc y a n o a c e t a t e a n d t h e a p p r o p r i a t e a l d e h y d e s n a m e l y p -n i t r o b e n z a l d e h y d e a n d N , N - d i m e t h y l a m i n o b e n z a l d e h y d ei n p re s e n c e o f e x c e s s a m m o n i u m a c e t a t e g i v in g t h ec o r r e s p o n d i n g p y r i d o n e d e r i v a t i v e s 1 1 a ,d w h i c h c o u l d b ep r e p a r e d b y t h e tr e a t m e n t o f c h a l c o n e d e r i v a t i v e s o f t h es a m e a l d e h y d e s w it h e t h y l c y a n o a c e t a t e i n p r e s e n c e o fe x c e s s a m m o n i u m a c e t a t e . I n a n o t h e r r e a c t io n s i m i l a r t o

r e s u l t s f r o (E s s a w y a n d W a s f y , 1 9 9 4 ) c o m p o u n d 1 w a se a s i l y c o n d e n s e d w i t h s e m i c a r b a z i d e i n a n a q u e o u se t h a n o l i c s o l u t i o n t o g i v e t h e s e m i c a r b a z o n e 1 2 . T h ep u r i f i e d s e m i c a r b a z o n e w a s t h e n s u b j e c t e d t o o x i d a t i v ec y c l i z a t i o n ( H u s s e i n e t a l . , 1986) by th iony l ch lo r i de toy i e l d th e t h i a d i a z o l d e r i v a t i v e 1 3 .I n t e r p r e t a t i o n o f m i c r o b i o l o g i c a l s t u d y o f t h e p r e -p a r e d c o m p o u n d s

T h i s w o r k i s a n a t t e m p t t o s c r e e n t h e a n t i b a c t e r i a l a n da n t i f u n g a l a c t i v it y o f s o m e n o v e l 2 - t h i o u r a c i l d e r i v a t i v e ss u b s t i t u te d a t 5 - p o s i t io n d u e t o t h e i r a n t i m e t a b o l i t e e ff e c t( i nh ib i t i on o f nuc le i c ac id syn thes i s ) .

A n t i b a c t e r i a l a c t i v i t yA c c o r d i n g t o a c t iv i t y o f t h e k n o w n u s e d c o m p o u n d s w e

can f i nd tha t 2 - th iou rac i l i t se l f has a po ten t an t i bac te r i a la g a i n s t B . s u b t i li s , E . co l i , S . a u r e u s , R a e a r g e n o s a , M .p h e i , a n t S t . f a c a l i s d u e t o i t s a n t i m e t a b o l i c e f f e c t ($ 1 ) a n dmay Ch lo rosu lphona t i on o f 2 - th iou rac i l abo l i shed i t s ac t i v i t y( $ 2 ) b u t F o r m a t i o n o f s u l p h o n a m i d e r e t a in e d t h e a c ti v i tyo f 2 - th iou rac i l ( $3 ) .

I n ano the r w ay i nco rpo ra t i on o f cq 13-unsa tu rated ke toneg a v e a c t i v e c o m p o u n d s o n l y a g a i n s t S. a u r e u s , S t .f a e c a l i s (2a ) o r B . s u b t i l i s ( 2 b a n d 2 c ) , w h i l e i n c o r p o r a t io n

Table III. Antibacterial e st of the syn thesized compounds with comparison to som e known prepared derivativesmeasured by disc diffusion methoda 5 mm (0.5 cm) disk and broth dilution methodsComp. B. subt i l is E. co i l C . a lb icans S. aureus Sarc ina R aeroge nosa M. ph le i St . faecal is

2a - - - - - - 1 .6cm - - - - - - 2 .2cm2b 1 cm . . . . . . .2c 0.75 cm . . . . . . .3a 2 cm 0.9 cm - - 2 cm . . . .3b 0.8 cm - - - - 0.8 cm . . . .4 b - - - - - - 1 c m - - - - - - 1.1 cm5a 0.75 cm - - 0.6 cm 0.7 cm - - 0.8 cm 1.1 cm - -5 b . . . . . . . .6a - - - - - - 1.5 cm - - - - - - 2 cm6b 0.7 cm . . . . . . .7a 1.15 cm - - - - 1 cm . . . .8a - - - - - - 0.9 cm - - - - - - 1 cm

10c 0.7 cm . . . . . . .11a 0.8 cm . . . . . . .12 1 c m - - - - 2 . 5 . . . .1 3 - - - - - - 1 c m - - - - - - 1.7 cmS~ 1.0 2.2 cm - - 3 cm - - 1.5 cm 0.5 cm 1.8 cmS 2 . . . . . . . .$3 1.1 0.8 cm - - - - 0.5 cm 0.7 cm - - 1.3 cm

$1 = 2 -thioura cil, $2 = 2thioura cil-5-sulphonylch loride,$3 = 2-thiouracil-5-sulphonicacid N -(4-acetylphenyl)amide.Compounds 4a, 5b, 7a, 8b, 9a, 9c, 10a, and 11b h ave no action on all bacteria.


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New 2-Thiou rac i l -5-Sulpho nam ide Der ivatives wi th B io log ica l Act iv i ty 1211

Table IV. Resultsof MIC of two compou nds3a and 5aMIC #g/LComp. Bsub t il is E . co l i C . a lb icans S . au reus S ar c in a Pa erg en us M. ph le i S t . f eaca l is

3a 1.25 412 - - 125 . . . .5a 412 -- 1600 412 -- 840 412 - -

Table V. Resultsof Ant-fungal activity of 5 selected compoundsInhibitionof z one diame tr (mm/mg)Microorganism 2a 4b 6a 8a 13

Microsporiumcanis 25 32 10 23 42Sporotrichum Sche nkii 22 11 18 30 25

o f t h i o p y r i m i d i n e r i n g g a v e a c t i v e c o m p o u n d s a g a i n s t B .s u b t i l is , E . c o l i , S a u r e u s ( 3 a ) o r a g a i n s t B . s u b t i l i s a n d S .a u r e u s o n l y ( 3 b ) a l s o i n c o r p o r a t i o n o f p y r i m i d o n e g a v e a ni n a c ti v e c o m p o u n d s ( 4 a ) o r a c o m p o u n d w i t h w e a k a c t i vi t y( 4 b ) a g a i n s t S . a u r e u s a n d S t . f a e c a l i s . I n add i t i on thei n c o r p o r a t i o n o f i s o x a z o l i n e r i n g g a v e a n a c t i v e c o m p o u n d(5a) against B . s u b ti li s , C . a lb i c a n s , S . a u r e u s , R a e r o g e n o s aa n d M . p h l e i . A l s o i n c o r p o r a t i o n o f p y r a z o l i n e r i n g g a v ec o m p o u n d s a c t i v e a g a i n s t S . a u r e u s , S t . f a e c a l i s (6a ) o rB . s u b t i l i s (6b ) .

I n a n o t h e r p a t h w a y t h e i n c o r p o r a t i o n o f p y r a n r i n g g a v ea c t i v e c o m p o u n d s a g a i n s t B . s u b t i l i s , S a u r e u s ( 7 a ) o ra g a i n s t S . a u r e u s a n d S t . f a e c a l i s ( 8 a ) . W e c a n o b s e r v et h a t c o m p o u n d s ( g a a n d 9 c ) a r e m i c r o b i l o g i c a ll y i n a c t i v ed u e t o t h e i r c h e m i c a l u n t a b i l i ty (e p o x i d e s ) . A l s o t h ei n c o r p o r a t i o n o f 4 - h y d r o x y p y r a z o l i n e r i n g a b o l i s h e d t h ea c t iv i ty o r g a v e a c o m p o u n d 1 0 c w h i c h i s o n l y w e a k l ya c t i v e a g a i n s t B . s u b t i l i s . I n add i t i on i nco rpo ra t i on o fp y r i d in e r i n g m a y a b o l i s h t h e a c t i v it y (1 1 b ) o r g a v e a w e a kc o m p o u n d 1 1 a a g a i n s t B . s u b t i l i s .

I n a n o t h e r r e a c t i o n c o n d e n s a t i o n o f m e t h y l k e t o n e 1w i t h s e m i c a r b a z i d e g a v e s i m i c a r b a z o n e d e r i v a t i v e 1 2w h i c h w a s a c t iv e a g a i n s t B . s u b t i l i s , a n d S . a u r e u s .

W h i l e t h e i n c o r p o ra t i o n o f t h ia d i a z o l e ri n g g a v e c o m p o u n d1 3 w h i c h w a s a c t i v e a g a i n s t S . a u r e u s a n d S t . f a e c a l i s .W e c a n o b s e r v e a l s o t h a t o n l y o n e c o m p o u n d o f th ep r e p a re d c o m p o u n d s w a s a c t i v e a g a in s t C . a l b i c a n s .

T o s u m u p g e n e r a l l y i n c o r p o r a t i o n o f s u l p h o n a m i d og r o u p i n t o 5 - p o s i t i o n o f 2 - t h i o u r a c i l m a y r e t a i n i t s a c t i v i t ya s a n t i - m i c r o b i a l a g e n t a l s o i n c o r p o r a t i o n o f m a n yh e t e r o c y c l i c m o i e t i e s m a y r e t a in s o m e o f th i s a c ti vi ty .

A n t i - f u n g a l a c t i v i t yT h e t e s t e d f u n g i w e r eI - M i c r o s p o r i u m c a n i s : T h e c a u s e o f r i n g w o r m i n fe c t io n s

i n m a n , i t i s o n e o f t h e d e r m a t o p h y t e s w h i c h i n f e c t t h ek e r a t i n iz e d s u r f a c e o f t h e b o d y e . g . h a i r s k i n a n d n a i l s .

I I - S p o r o t r i c h u m S c h e n k i i : th e c a u s e o f s p o r o t r i c h o s i si n m a n w h i c h i s a c h r o n i c i n fe c t i o n o f t h e s k i n a n dS u b c u t a n e o u s ti s s u e . W e c a n o b s e r v e :

A l l t h e f i v e t e s t e d c o m p o u n d s h a d a p o t e n t a c t i v i t y a sa n t i - fu n g a l a g e n t e s p e c i a l l y 2 a w h i c h i s a c h a l c o n eder iva t ive (cq [3-unsaturated keton e) and ca n eas i ly pene t ra tethe ce l l membrane o f t he fungus due to i t s h igh l i poph i l i c i t ya l s o c o m p o u n d 1 3 w a s h i g h l y a c ti v e ( t h ia d i a z o l d e r i v a t iv e sa r e o f k n o w n a n t - f u n g a l a c t iv i ty .

A n t i - f u n g a l a c t i v i t y i n v i t r oT e s te d c o m p o u n d s w e r e 2 a , 4 b , 6 a , 8 a , a n d 1 3 .P r e l i m i n a r y i n v i t r o a n t i - f u n g a i t e s t i n g u s i n g D i f f u s i o n

d i s k m e t h o d : A f i l te r p a p e r S t e r il iz e d d i s c s a t u r a t e d w i t hm e a s u r e d q u a n t i t y o f t h e s a m p l e i s p la c e d o n a p l a t ec o n t a i n in g fu n g a l m e d i u m ( D o x i s m e d iu m ) w h i c h h a sb e e n h e a v i l y s e e d e d w i t h t h e s p o r e s u s p e n s i o n o f t h et e s t e d o r g a n i s m . A f t e r i n o c u l a t i o n , t h e d i a m e t e r o f t h ec l e a r z o n e i n h i b i t io n s u r r o u n d i n g t h e s a m p l e i s t a k e n a s am e a s u r e o f t h e i n h i b it o r y p o w e r o f th e s a m p l e a g a i n s t t h ep a r t i c u l a r t e s t o r g a n i s m ( J a w e t z e t a l . , 1 9 7 4 ; G r a y e r a n dH a r b o n e , 1 9 9 4 ; M u a n a z a e t a L , 1994 ; I rob e t a l . , 1 9 9 6 ) .A C K N O W L E D G E M E N T S

Th e au tho rs a re g ra te fu l t o D r . H i sha m Radw an , P ro fesso ro f M i c r o b io l o g y , F a c u l t y o f P h a r m a c y , H e l w a n U n i v e r s i t ya n d D r . F a t in A h m e d N o u r E l d e e n , D i r e c t o r o f M i c r oA n a l y t i c a l C e n t e r a n d P r o f e s s o r o f M i c r o b i o l o g y , F a c u l t yo f S c i e n c e C a i r o U n i v e r s i t y f o r c a r r y i n g th e a n t i - m i c r o b i a la c t iv i ty o f t h e n e w c o m p o u n d s .

R E F E R E N C E SAbbady, M. A., Ezbawy, S. R., Radwan Sh. M., Bayoumy, B. E.,

and Khalaf , A. A. , S ynthes is and b io log ica l ac t iv i ty o f som enew 4-(2-pyrzol ine-3-yl)-4-92-1soxazl in-4-yl) and 4-(1,2,5,6-tetrahydro-2-thiopyrimidine-4-yl)-diarylsulphides an d diarylsu lphones. E g y p t . J . P h a r m . S c i . , 27, 43-56 (1986) .

Arho ld lc , G , Roe lof , V. H. , and Kabus, W. , Synthe s is o f newheterocycl ic compounds. J. A g r i c F o o d C h e m . , 27(2) , 406(1979).

Bauer, A. W., Kirby, W. M . M ., Sherr is, J. C., and Turck, M., An ti-biot ic subceptibi l i ty test ing by a standardized single diskmethod. A m e r . J . C l i n . P a t h o L , 45, 493-496 (1966).


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1 2 1 2 O . A . F a t h a l la et a l.

C a r a d o n n a , C . a n d S t e in , M . L . , S y n t h e s i s o f n e w i s o x a z o l i n ed e r i va t i ve s w i t h e xp e c t e d b i o l o g i ca l a c t i v i t y . Farmaco. Ed .ScL, 1 5 , 6 4 7 ( 1 9 60 ) .

D a le , M . , T h e e x t r a p h a r m a c o p e i a . ( 1 9 8 9 ) .E I - H a sh a s h , M . A . , E I -Ka d y , M . , Sa y e d , M . A . , a n d E I - Sa w y , A .

A . , S o m e r e a c t i o n s o f c h a l c o n e e p o x i d e s . Eg yp t J . Ch e m. ,2 7 , 7 1 5 ( 1 9 8 4 ) .

E s s a w y , S . a n d W a s fy , A . , C o n v e n i e n t s y n t h e s i s o f h e t e r o c y c l i cc o m p o u n d s B e a r i n g a s u c c i n i m i d o m o i t y . Eg yp t J . Ch e m. ,3 7 ( 3 ) , 2 8 3 - 2 9 3 ( 1 9 9 4 ) .

F a t h a ll a , O . A ., S y n t h e s i s o f s o m e 1 , 3 - d i m e t h y l u r a c i l -5 -s u l p h o n a m i d e - p - p h e n y l d e r iv a t iv e s w i t h e x p e c t e d b i o lo g i ca lact iv i ty. AL -Azh a r Bu l l. Sc i . , 3 ( 2 ) , 7 1 3 - 7 2 6 ( 1 9 9 2 ) .

F a t h a l l a , O . A . , Z a g h a r y , W . A . , R a d w a n , H . H . , Aw a d , S . A . ,a n d M o h a m e d , M . S ., S y n t h e s i s o f n e w 2 - t h i o u r a c i l -5 -s u l p h o n a m i d e d e r i v a t i v e s w i t h e x p e c t e d b i o l o g i c a l a c t i v i t y .Arch . Pharm. Res. , 2 5 ( 3 ) , 2 5 8 - 2 6 9 ( 2 0 0 2 ) .

G r a y e r , R . J . a n d H a r b o n e , J . B . , A s u r v e y o f a n t i - f u n g a lc o m p o u n d s f r o m h i g h e r p l a n t s . P h y t o c h e m i s t ~ 3 7 , 1 9 - 4 2( 1 9 9 4 ) .

H u sse i n , S . , E I - Ka sh e f , B . , E I - Ba yo u m y , a n d T a l a a t , I . A . ,

S e l e n i u m h e t e r o c y c l e s I : S y n t h e s i s a n d a n t i b a c t e r ia l a c t iv i tyo f s o m n e w 1 , 2 , 3 -t h ia a n d 1 , 2 , 3 - s e l e n s d i a z o l e s c o n t a in i n gs u l p h o n a m i d e s . Eg yp tJ . Ph a rm. Sc i . , 2 7 ( 1 -4 ) , 2 7 - 3 5 ( 1 9 8 6 ) .

I ro b , O . N ., M o o - Y o u n g M . , a n d A n d e r s o n , W . A . , A n t i - m i c r o b i a la c t i v i t y o f a n n a t t o e x r a c t . In te rna t iona l J . Pharmacog. , 3 4 ,8 7 - 9 0 ( 1 9 9 6 ) .

Ja w e t z , E . , M e l n i ck , J . L ., a n d Ad e l b e r g , E . A . , R e v i e w o fM i d i c a l M i c r o b i o l o g y . L a n g M e d i c a l p u b l i c a t i o n . L o s A l t o s ,C a l i f o r n i a ( 1 9 7 4 ) .

L a l eza r i, I ., Sh a fi e e, A . , a n d Ya s d a n y , S . , Syn t h e s i s o f t h i a d i a zo l ed e r i va t i ve s o f e x p e c t e d a n t - f u n g a l a c t iv it y . J . Pharm. Sc i . , 6 3 ,6 2 8 ( 1 9 7 4 ) .

L a n g , P ., A n t i m e t a b o l i te s o f N u c l ie c a c i d m e t a b o l i s m . N e w Y o r k( 1 9 7 5 ) .

M u n za , D . N . , K i m , B . W . , Eu l e r , K . L . a n d W i l l i a m s , L . , An t i -b a c t e r i a l a n d a n t i - f u n g a l a c t i v i t y o f n i n e m e d i ca l p l a n t s f r o mZ a i r e . In temat . J . Phamacog. , 3 2 , 3 3 7 - 3 4 5 ( 1 9 9 4 ) .

W y r z y k i e w i c z - E , B a r t k o w i a k , G . , a n d K e d z i a , B . , S y n t h e s i s o fa n t i - m i c r o b i a l p r o p e r t i e s o f S - s u b s t i t u t e d d e r i v a t i v e s o f 2 -t h i o u r a c i l . Farmaco. Poland., 4 8 , 9 7 9 - 9 8 8 ( 1 9 9 3 ) .

amar-230813synthesis of new 2-thiouracil-5-sulphonamide derivatives with antibacterial and...

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