Indian Journal of Chemistry Vol. 43B, June 2004, pp. 1306-1313

Synthesis and biological evaluation of 7-N-(n-alkoxyphthalimido)-2-hydroxy-4-aryl-6-aryliminothiazolidino [2,3-b] pyrimidines and related compounds

Bhawani Singh Singh, Deepika Mehta, Lalit K Baregama & G L Talesara*

Synthetic Organic Chemi stry Laboratory, Department of C hemi stry, M L Sukhad ia Universi ty, Udaipur-3 1:; 00 I , Indi a E-mail: gta lesara @yahoo.com. bsyadav2000@red iffmail .com

Received 12 March 2003; accepted (revised) 6 February 2004

Substituted ary l thio ureas la-c react with chloroacetic ac id in the presence of anhydrous sodium acetate to furni sh 2-

ary liminothiazolidin-4-ones 2a-c. Condensati on of w-bromoalkoxyphthalimides 3a-c with 2a-c give the correspondi ng a lkoxyphthalimide derivatives of 2-arylimino thi azo lid in -4-ones 4a-i. These on condensat ion with araldehydes 5a-c yie ld 3-

N-(alkoxyphthalimido)-S-arylidene-2-arylimino thi azolidin-4-ones 7a-a'. In an a lte rn ati ve route Sa-c react with 2a-c to g ive 6a-i, which could be cycli sed wi th urea in the presence of sodi um acetate to yie ld the correspo nding thi azo li d inopyrimid ine 8a-i . 7a-3' arc a lso preparcd from 6a-i with 33-C, which g ivc final compound 9a-3' o n eycli sation. Alternati vely, 8a-i whcn

condcn sed with 33-C al so furni sh the compound s 93-a'. Evalu ation of antimalari a l and antibacterial activity is al so reported .

IPC: Int.CI.7 C 07 DIIA 61 P 31104, 31/10, A 6 1 P 33/06

Pyrimidines playa vita l role in many biological proc­esses since their ring system is present in several vita­mi ns, coenzymes, nucleic ac ids etc. Synthetic members of thi s group are also important as chemotherapeutic agents. The pyrimidine nucleusl-3 occurs in a consider­able number of natural products of vita l importance to li ving organi sms. Pyrim idine derivatives also possess

. 4 I . 5 . . fl 6-10 I I b' antitumor , ana geslc , antl-ll1 ammatory anc ler 1-

cidalll act ivities. Literature survey revealed that vari ­ous thi azolidinone deri vat i vesl ~- 1 4 are endowed wi th wide range of pharmacological acti vities including CNS d i S h . 16 . I 17 . - epressant -, anaest etlc , antl convu sant . antl -b . II ~-"O .. I" I d . "" .. . actena -. antIvlra - an antl tu mor-- actl Vttles_ These are also employed in the synthes is or cyanine dyes, which are used in photographic fi lm industr/ 5 In continuation of our effo rts26-2~ fo r synthesizing oxygen­substituted hydroxylamine deri vatives, it was planned to design alkoxyphthalimide deri vati ves of th iazolidi ­nopyrimidines wi th a view to ach ieve enhanced bio­logical acti viti es. Studies have also been done on the reacti on of w-bromoalkoxyphthali mides with substi­tuted aryliminothiazolidinopyrimidines under different reaction conditions and resulting fused bi-heterocyc lic derivatives were screened for antimalaria l, antibacterial and anti fu ngal acti vit ies.

Results and Discussion 4-S ubstituted aniline on refluxing (6- 10 hr) wit h

aillmon ium thi ocyanate In IN HCI gave the

corresponding arylthiocarbamides la-c in 65-70% yield . Cyc li sati on of la-c with chloroacetic acid in the presence of anhydrous sodium acetate in absolute alcohol gave the substituted thiazo li din-4-ones 2a-c. JR, lllass and I H NM R studi es confirmed the fo rmation of 2a-c. The intense band at 1656 cm-I for 2a sbowed C=N stretch ing for the pIJenylimino group attached to the thi azolidinone nucleus while the ring C=O group appeared at 1710 cm-I. The chemi ca l shi ft s of the aromatic protons depended on the nature of substituent groups X at the para-position of the benzene ring. w-Bromoa lkoxyphthalimides 3a-c were prepared by the reported method2~. In thi s method N­hydroxyphthalimide30 and w,w/-d i romoalkanes3

1.32

were kept overnight ( 17-22 hr) in dimethylformamide medium usi ng tri et hylamine as base. Di sappearance of the N-OH group resonance at 8 6.1 (s inglet) of N­hydroxyphthalimicle in IH NMR along wi th new resonance fo r the alkyl side chain confirmed the reactio ll . Condensation of 2a-c with CJ)-bromoalkoxy­ph thai i mides 3a-c in abso l ute alcohol gave 3-alkox yphthal i mido-2-ary l i mi noth iazol idi !lA-ones 4a-i (Scheme I, Table I). TR, mass and I H NM R spectroscopy confirmed the condensat ion of 2a-c with 3a-c at the N-atom. Free stretching vibration band for -NH group at 3300-3 100 cm-I, whi ch was pre ent in its precursors 2a-c due to the HCO group, had disappeared and a stron g band at 1300-1160 cm-I

appeared for the CoN stretchin g of the CH2 CO

SINGH e/ al. : SYNTHESIS OF SUJ3STITUTED ARY LlMINOTHIAZOLlDINO PYRIMIDINES

-Q-H OH X ~ /; N + CI~

}-NH2 0 la-e S

1 a, 2a X=H j AcONaJEtOH o 1 b, 2b X=CI reflux 6-10 hr

~ le,2e X=N02 HN---f0

I ~ N-0-(CH2)nBr A-) 3a-e X~N S

3an=2 0 ~ z

5a-c

5a Z=H

~~ ~:~ 3a~c Pyr;d;::::to> ~~~~~;~~r 4a X=H, n=2 0 reflux 15-22 ~r ~ 0 4b X=CI , n=2 HN

5b Z=OH 5c Z=-:OCH3

6a, 8a X=I-J , Z=H 6b, 8b X=c: . Z=OH 6c, 8c X=N02 Z=OCH3

4d X=H , n=3 I N-0-(CH2)n X If ~ : s ~ 4c X=N02 '1=2 ~ -0- ~ 4e X=CI, n=3 ~ I =10 -

6d,8d X=H, Z=H

4f X=N02 , n=3 0 N

4g X=H, n=4 -Q~ A 4~ X=CI , n=4 X N S 41 X=N02 n=4 -

, 4a-i

6a-i

3a-c 5a-c j AcONaJAcOH reflux 10-12 hr

o Pyridine/EtOH

~ reflux 15-22 hr

I ~ N-0-(CH2)n HN

~ I 0 ~ o ~ x-o-: S x-o-: S

z

6e, 8e X=CI , Z=OH 6f, 8f X=NO;" Z=OCH3

6g, 8g X=H, Z=H 6h, 8h X=CI, Z=OH 6i, 8i X=NC2 , Z=OCH3

j Urea AcONa/AcOH reflux 10-12 hr

NyOH

.....:;:N

7a, 9a X=H, Z=H, n=2 7b, 9b X=CI, Z=OH , n=2 7c, 9c X=N02 , Z=OCH 3,n=2 7d, 9d X=H, Z=H,n=2

7a-a' ~ 8a-i ~

I ~ Urea .

7e, ge X=CI , Z=OH, n=2 71, 91 X=N02 , Z=OCH3 , n=2

79, 99 X=H, Z=H, n=2 7h, 9h X=CI , Z=OH, n=2 7i, 9i X=N02, Z=OCH3. n=2 7j, 9j X=H, Z=H, n=3 7k, 9k X=CI, Z=OH, n=3 71, 91 X=N02 , Z=OCH3,n=3 7m, 9m X=H, Z=H, n=3 7n , 9n X=CI , Z=OH, n=3 70, 90 X=N0 2 , Z=OCH3 , n=3 7p, 9p X=H, Z=H, n=3 7q, 9q X=CI , Z=OH, n=3 7r, 9r X=N02 , Z=OCH3 , n=3

~ACONa/ACOH Z 3

j a-c

Z reflux 10-12 hr 0 Pyridme/EtOH

~ reflu x 15-22 hr

I N-0-(CH2)n

75, 95 X=H, Z=H, n=4 ~ ~ I N~OH 71, 91 X=CI, Z=OH, n=4 0 I I 7u, 9u X=N02 , Z=OCH3,n=4 -0-" ~ .....:;: N 7v, 9v X=H, Z=H, n=4 X I \ N S 7w, 9w X=CI, Z=OH, n=4 -7x, 9x X=N02 , Z=OCH3 , n=4 7y, 9y X=H, Z=H,n=4 7z, 9z X=CI, Z=OH, n=4 7a', 9a' X=N02 , Z=OCH3, n=4

9a-a' Z

Scheme I

1307

1308 INDIAN J. CHEM. , SEC B, JUNE 2004

Table 1- Physica l dat a of compounds 4a-i and spectral data of representative co mpounds 4a, 4b and 4c.

Compd m.p. Yie ld Mol. formu la Ca lcd (Found) % °C (%) (M.Wt. ) C H N S

4a 234 56 C l9H 150 4N3S 59.84 3.93 11 .02 8.39 (38 1 ) (59.38 3.57 10.76 8.02)

4b 205 53 Cl9Hl404N3SCI 54.93 3.37 10 .1 2 7.7 1 (4 15) (54.4 1 3.0 1 9.8 1 7.38)

4c 140 64 C l9H 140 r,N. S 53.52 3.28 13. 14 7 .5 1 (426) (53. 19 2.9 1 12.82 7. 24)

4d 243 53 C20H l70.N3S 60.75 4 .30 10.63 f:. IO (395) (60.3 1 4.02 10.32 7.69)

4c 196 6 1 C20H 160 •N3SCI 55 .94 3.72 9.79 7.45 (429) (55 .6 1 3.29 9.52 7.0S

4f 158 66 C20H lr,Or, N.S 54.54 3.63 12.72 7.27 (440) (54.27 3.38 12.4 1 7.03)

4g 255 59 C21H I9O.N,lS 6 1.61 4.64 10.26 7.82 (409) (6 1.36 4.4 1 10.02 7.69)

4h 192 62 C21 H1SO.N,lSCI 56.88 4.06 9.48 7.22 (443) (56 .69 38 1 9. 11 684)

4i 166 68 C21H1SO(,N.S 55.50 3.96 12.33 7.04 (454) (55 .22 3 .6 1 12.09 6 .79)

4a (X=H, n=2): lH NMR 4b (X=CI , n=2): lH NMR 4c (X=N0 2, n=2): lH MR (C DCI) : 8 7.6 - 7.7 (m, 9H. Ar- (C DC I,l): 87.7 -7.6 (m, 4 H, Ar- (CDCI:\): 87.7 - 7.6 (m, 4 H, Ar-H), 4.4 (s, 2H, C I-12), 3.2 (t, 2H, H), 7 .3 (d , 2H, Ar-H (ncar CI) , H), 8.0 (d , 2H, Ar-H (near N0 2),

OCH2), 2.8 (t, 2H, NC H2) ; Mass: 6.9 (d , 2H, Ar-I-!), 4 .3 (s, 2H, 6.8 (d, 2H, Ar-H), 4.3 (s. 2H, mlz 381 (M+' ), 307 , 191 , 146, CH2), 3. 1 (t, 2H, OCH2), 2.7 (t, C H2), 3. 1 (t, 2H, OCH 2), 2 .8 (t, 132, 76,43. 2H, NCH2);

(M++2 ), 4 15 104 , 76.

group confirmed the formation a new C-N bone!. Furthermore, C=O stretching of the thiazoli di none ring was still present , which co nfirmed the formation of 4a-i. The reacti on conditi ons however were dependent upon the length of the carbon chain of the m-bromoalkoxyphthalimides and the aromatic substituents in 2a-c. Refl uxing time for complete reaction va ri ed between 15-22 hr. Pyridine was used as suitabl e base and abso lu te ethanol gave sati sfactory medium fo r high yield of the product.

The compounds 4a-i on condensati on with p­substituted benza ldehydes Sa-c in acet ic ac id in the presence of sodium acetate gave 7a-a' Cfable II). Formation of products was confirmed by di sappearance of the lR band at 2939 cm-I and the I H NMR signal at 8 4.4 (s inglet) for the CH2 group of the thiazolid inone nucleus in 4a and appearance of new IR band at 1642 cm'l and 'H MR signal at 8 6.4 (s inglet) of C=CHAr in 7a. The carbonyl peak for the ph thaI i midoyl group was sti 11 present in these compounds. Formation of the -a lkoxy (N-O-C) linkage was shown by a posi ti ve fluorescence test and

Mass: mlz 4 17 2 H, NC H2); Mass: mlz 426 (M+'), 162, 134, (M+), 162 , 146, 132, 76.

'H NMR signals at 87 .8-7.6 (multipl et). The O=C-N­C=O unit present in the phthalimido group gave a band at 1745 cm' l for 7a in the TR spectrum. Cyc li sation of the 7a-a' to the thi azo lidinopyrimid ine deri vatives 9a-a' have been achieved y the reacti on of urea in acet ic acid in the presence of sod ium acetate under refl ux for 10- J 2 hr (Table Ill ). Formation of the thi azol idine condensed pyri midi ne ri ng was con fi rmed by IR, mas, and I H M R spectroscopy and also by disappearance of IR bands fo r the C=O group and C-H of C=CHAr. In the thiazo lidinopyrimidines, the proton of OH group appeared at 8 8.2 and IR bands at 3590 and 1245 cm' l fo r 9a were consistent with an enolic hydroxy group. In an alternati ve route, 9a-a' were obtained by condensati on reac ti on of 8a-i wi th 3a-c on refl ux in ethano li c solution in the presence of pyridine as base. The proton of the OH group present in 8a-i also appeared in 9a-a' but the 'H NMR signal for the -H proton of 8a-i had di sappeared. Cyc l isation steps 6a-i to 8a-i were simi lar to that fo r 7a-a' to 9a-a'. Condensation of various para-subs ti tuted aromatic

SINGH et al.: SYNTHESIS OF SUBSTITUTED ARYLIMINOTHIAZOLIDINO PYRIMIDINES 1309

Table II - Physical data of compounds 7a-a ' and spectral data of representative compounds 7a, 7g and 7u

Compd m.p. Yield Mol. formula Ca1cd (Found) % °C (%) (M.wt.) C H N S

7a 190 53 C26HI 90 4N3S 66.52 4.05 8.95 6.82 (469) (66.31 3.76 8.62 6.61)

7b 173 55 C26Hl s04N)SCI 62 .02 3.57 8.34 6.36 (503) (61.79 3.31 8.11 6.09)

7c 103 56 C26HIS0 6N4S 60.70 3.50 10.89 6.22 (514) (60.32 3.21 10.7 1 6.01 )

7d 222 51 C26HI 9OSN3S 64.32 3.91 8.65 6.59 (485) (64.03 3.61 8.42 6.35)

7e 184 47 C26H1sOsN)SCI 59.88 3.45 8.06 6.14 (52 1 ) (59.68 3.19 7.81 5.84)

7f 187 56 C26H IS0 7N4S 58.86 3.39 10.56 6.03 (530) (58.59 3.16 10.29 5.78)

7g 210 49 C27 H210sN)S 64.92 4.20 8.41 6.41 (499) (64.68 4.01 8.16 6.09)

7h 197 43 C27 H210sN)SCI 60.78 3.75 7.87 6.00 (533) (60.51 3.48 7.61 5.8 1)

7i 176 57 C27H2007N4S 59.55 3.67 10.29 5.88 (544) (59.29 3.42 10.02 5.61)

7j 162 48 C27H2I04N)S 67.08 4.34 8.69 6.62 (483) (66.80 4.06 8.41 6.32)

7k 194 47 C27 H200 4N)SCl 62.42 3.85 8.09 6.16 (519) (62.16 3.66 7.79 5.84)

71 192 49 C27H200 6N4S 59.55 3.67 10.29 5.88 (544) (59 .19 3.31 10.03 5.63)

7m 182 42 C27H210sN)S 64.92 4.20 8.41 6.41 (499) (64.68 4.01 8.11 6.09)

7n 260 4 1 C27H200 sN)SCl 60.78 3.75 7.87 6.00 (533) (60.61 3.52 7.59 5.76)

70 196 52 C27H200 7N4S 59.55 3.67 10.29 5.88 (544) (59 .31 3.40 10.01 5.66)

7p 161 46 C2sH2)OsN)S 65.49 4.48 8.18 6.23 (513) (65 .22 4.19 8.00 6.04)

7q 237 45 C2sH220 sN3SCI 6 1.42 4.02 7.67 5.85 (547) (61.11 3.81 7.39 5.62)

7r 207 41 C2sH220 7N4S 60.2 1 3.94 10.03 5.73 (558) (59.92 3.69 9.8 1 5.52)

75 154 45 C2sH2)04N)S 67 .60 4.62 8.45 6.43 (497) (67.31 4.39 8.27 6.21)

7t 185 44 C2sH220 4N)SCl 63 .27 4.14 7.90 6.02 (531 ) (63.0 1 3.91 7.59 5.78)

7u 205 48 C2S H220 6N4S 6 1.99 4.05 10.33 5.90 (542) (61.68 3.78 10.02 5.61 )

7v 173 45 C2sH2)OsN)S 65.49 4.48 8.1 8 6.23 (513) (65 .12 4.16 7.92 6.02)

7w 197 49 C2sH22OsN)SCI 6 1.42 4.02 7.67 5.85 (547) (6 1.09 3.76 7.48 5.62)

7x 207 52 C2sH220 7N4S 60.21 3.94 10.03 5.73 (558) (60.01 3.68 9.75 5.5 1)

7y 168 49 C29H2S0 sN3S 66.03 4.74 7.96 6.07 (527) (65.71 4.48 7.72 5.76)

7z 188 46 C29H24OSN3SCl 62 .03 4.27 7.48 5.70 (56 1) (61.76 4.02 7.21 5.48)

7a' 2 17 49 C 291-iz4 0 7 N 4S 60.83 4. 19 9.79 5.59 (572) (60.62 4.01 9.48 5.31)

7a (X=H, Z=H, n=2): IH NMR 7g (X=H, Z=OCH3, n=2): IH NMR 7u (X=N020 Z=H, n=4): IH NMR (CDCI) : 0 8.2 (d, 2H, (CDCI) : 0 7.6 - 7.7 (m, 14H, Ar- (CDCl) : 0 7.7 - 7.6 (m, 9H, Ar-H), 7.1 (d, Ar-H (near N02), 6.9 (d, 2H, Ar-H), 7.7 (m, 9H, Ar-H), H), 6.4 (s, 1 H, C=CH-Ar), 3.2 (t, 2H, Ar-H (near OCH3), 6.8 (d, 2H, Ar-H), 6.4 (5 , 1 H, C=CH-Ar), 3.2 (t, 2H, OCH2) , 2.8 (t, 2H, 2H, OCH2), 2.8 (t, 2H, NCH2) ; 6.4 (5 , 1 H, C=CH-Ar), 3.6 ( 5, 3H, CH3), 3.3 NCH2) , 2.5 (quintet, 2H, OCH2 CH2CH2CH2N), 2.2 Mass: miz 469 (M+·), 162, 146, (t, 2H, OCH2), 2.8 (t, 2H, NCH2) ; Mass: (quintet, 2H, OCH2CH2CH2CH2N); Mass : mJz 542 132, 9 1, 43. miz 499 (M+), 146, 132, 104, 9 1, 77. (M+), 162 , 136, 9 1, 77

1310 INDIAN 1. CHEM. , SEC B, JUNE 2004

Table III - Physical data of compounds 9a-a' and spectral data of representative compounds 9h, 9i and 9a'

Compd m.p. Yield DC (%)

911 140 36

9b 162 42

9c 158 44

9d 144 39

ge 156 41

9f 147 44

9g 168 38

9h 185 37

9i 188 40

9j 146 39

9k 177 4 1

91 172 43

901 159 42

9n 192 44

90 182 46

15 8 4 1

9q 196 39

9r 189 46

9s 162 4 1

9t 199 38

9u 196 42

9v 172 36

9w 2 10 38

9x 209 37

Mol. formula (M.Wt.)

Calcd (Found) %

C H N S

C27HI904NsS 63.65 3.73 3.51

13.75 6.28 13.49 6.04) (509) (63 .32

C27Hl s04NsSCI 59.66 3.31 3.09

12.89 5.89 12.61 5.58) (543) (59.37

C27HI S06N6S (554)

C27HI90SNSS (525)

58.48 3.24 15.16 5.77 (58.11 3.01 15.02 5.42)

61.71 3.61 13.33 6.09 (6 1.39 3.36 13.12 5.81)

C27H lsOsNsSCI 57 .96 3.22 3.01

12.52 5.72 12.29 5.43) (559) (57.68

CZ7HI S0 7N6S 56.84 3. 15 2.91

14.73 5.61 14 .51 5.29) (570) (56.6 1

C28H210sNsS 62.33 3.89 3.62

12.98 5.93 12.63 5.69) (539) (62.08

C2sH200 sNsSCI 58.63 3.49 12 .2 1 5.58 (573) (58.41 3.27 12.04 5.37)

C2sH2007N6S 57.53 3.42 14.38 5.47 (584) (57.31 3. 18 14. 12 5. 18)

CzgH210sNsS 64.24 4.0 I 13.38 6.11 (523) (64.03 3.79 13. 11 5.89)

C2sH200 4N,SCI 60.32 3.59 12.56 5.74 (557) (60.05 3.31 12.32 5.39)

C28Hzo0 6N6S (568)

CzsHzlOsNsS (539)

59.15 3.52 14.78 5.63 (58.90 3.29 14.43 5.31)

62.33 3.89 12.98 5.93 (62.09 3.62 12.69 5.61 )

C2sH200 sNsSCI 58.63 3.49 12.2 1 5.58 (5 73) (58 .39 3.27 12.01 5.21 )

C2sH200 7N6S (584)

Cz9H2)O, N,S (553)

57.53 3.42 14.38 5.47 (57.3 1 3. 19 14. 16 5.16)

62.92 4. 15 12.65 5.78 (62 .59 4.02 12.41 5.52)

CZ9H220 , NsSCI 59.28 3.74 11 .92 5.45 (587) (59 .03 3.52 11 .63 5.23)

CZ9H220 7N6S (598)

58. 193.6714.045.35 (58.00 3.4 1 13 .78 5.09)

Cz9H230 4N,S 64 .80 4.28 4.05

13.03 12.8 1

5.95 5.62) (537) (64 .53

CZ9Hn 0 4NsSCI 60.94 3.85 3.58

12.25 12.0 1

5.60 5.33) (57 1) (60.63

C29H220 6N6S (582)

C29H230 , N,S (553)

59.79 3.78 14.43 5.49 (59.43 3.33 14. 12 5. 14)

62.92 4. 15 12.65 5.78 (62.68 4.00 12.39 5.4 1)

Cz9HzzO,N,SCI 59.28 3.74 11.92 5.45 (587) (59.06 3.42 11.68 5.11 )

Cz9H220 7Nr,S (598)

58. 19 3.67 14.04 5.35 (57.92 3.39 13.82 5.06)

-Conld

Table III - Physical data of compounds 9a-a' and spectral data of representative compounds 9h, 9i and 911'-Col1/d

Compd m.p. Yield Mol. formul a (M.wt.)

Calcd (Fou nd) % DC (%) C H N S

9y 175

9z 189

9a' 192

9b (X=CI, Z=H, n=2): IHNMR

COCl)): I) 8. 1 (s , IH, OH), 7.7 (m, 9H, Ar­H), 7.3 (d , 2H, Ar-H (near CI), 6.9 (d, 2H, Ar­H), 3.2 (t, 2H, OCHz), 2.8 (t, 2H, NCH2); Mass : mJz 545 (M++2), 543 (M+"), 190, 165, 76.

4 1

40

43

C30H2S0 sNsS (567)

63.49 4.40 12.34 5.64 (63. 124.09 12.04 5.31)

C)oH240 sNsSC I 59.90 3.99 11 .64 5.32 (601) (59.62 3.68 11 .37 5.00)

C30H240 7N6S (612)

9i (X=NOz, Z=OCH), n=2): I H NMR (COCI3): I) 8.2 (d, 2H, Ar-H (near N02), 7.6 (d, 2H, Ar-H), 8.0 (s , IH, OH), 7.6 (m, 4H, Ar-H), 7.2 (d , 2H, Ar-H (near OCH3), 6.9 (d, 2H, Ar- H), 3.7 (s, 3H, CH3), 3 .2 (t , 2H, OCH2), 2.7 (I, 2H, NCH2); Mass: mJz 584 (M+), 190, 175, 134, 76.

58.82 3.92 13.72 5.22 (58.6 1 3.62 13.51 5.04)

9a' (X=CI, Z=OCH3, n=4 ): IH NMR (COCI3): I) 8.0 (s , I H, OH), 7.6 (m, 4H, Ar­H), 7 .3 (d, 2H, Ar-H (near CI), 6 .9 (d, 2H, Ar-H) , 7 .1 (d, 2H, Ar-H (near OCH3), 6.7 (d, 2H, Ar-H), 3.7 (s, 3H, CH3), 3.2 (t, 2H, OCHz), 2.9 (t, 2H, NCH2), 2.6 (q uintet, 2H. OCH2 CHzCH2

CHzN), 2.4 (quintet, 2H. OCH2CHzCHz CHzN): Mass: mJz 603 (M++2), 60 1(M+), 190. 162, 146

Table IV-Percent inhibition of schi zont maluration of P. falciparulII

Name of ---, __ --,-::----'.A..:..:m.:.:o::.:u:.:.n:.:..t .::.of:...cd::.:.r.:.:ug~w.:e~I:.:..I-,-__ -c-:-__

Drug I ng 10 ng 100 ng I Jl.g 10 Jl.g 100 Jl.g

7a 3.32 9.52 2 1.10 25.06 38.00

7b 5.52 Il.l 0 29.42 33.8 2 49 .63

7c 4.62 9.9 1 15 .72

49 .68

24. 10

63.78

3 1.1 4

75 .63 9b 28.33 35.67

9h 16.56 33.49 48 .63 55.37 86.53

9q 15 .34 29.71 45 .38 5 1.32 63.29

9z 33.76 54.89 71.00 8 1.53 92.67

44.46

55.79

40.36

84 .95

100.00

95.12

96 .97

Each well of microlilre plale con lai ns 10 mL of blood in 90 mL of RPM! 1640 medium.

aldehydes 5a-c with ary liminothi azo lid inones 2a-c by the route already mentioned gave 6a-i. Yi elds were a lmost equal in both of the routes.

The synthes ized compounds 7a, '7b, 7c, 9b, 9h , 9q and 9z were screened for in vitro anti malari a l activity (Table IV). Compounds 9b, 9h, 9q and 9z showed increasing activity with increasing amount of drug. Compound 9h showed 100% inhibi ti on of schizont maturation at 100JLg. Compo unds 7a, 7b, 7c, 7d, 7g, 7j, 7t, 7y, 7z, 9a, 9b, 9c, ge, 9k and 9m were tested

SINGH e/ aL.: SYNTHESIS OF SUBSTITUTED ARYLIMINOTHIAZOLIDINO PYRIMIDINES 1311

Table V - Antibacterial activity of synthesized compounds

Compd Gram-~ositi ve Gram-negative Org.1 Org.2 Org.3 OrgA Org.5 Org.6 Org.7 Org.s

C1 C2 C1 C2 C1 C2 C1

22 21 25 22 12 28 20

7a 16 12 10 7b 34 25 14 7c 36 25 19 7d 20 19 7g 42 36 20 7j 17 12 7t 12 16 7y 18 16 II

7z 19 24 12 9a 12 II

9b 33 24 18 9c 32 27 21 ge 21 20 16 9k 42 34 19 9m 13 15

for antibacterial activity (Table V) against three Gram-positive and five Gram-negative organisms. Compounds 7g, 9k, 7c, 7b, 9b and 9c showed high activity against Staphylococcus aureus (Org. 1) and Staphylococcus albus (Org. 2), moderate activity against Streptococcus faecalis (Org. 3) and lower ac­tivity against organism Klebsiella pneumoniae (Org. 4), Escherichia coli (Org. 5), Pseudomonas aeurogi­nosa (Org. 6), Proteus mirabilis (Org. 7) and Salmo­nella typhi (Org. 8).

Experimental Section

Melting points were taken in open capillaries and are uncorrected. IR spectra were recorded on a Perkin-Elmer 1800 and Schimadzu 8210 PC (4000-350 cm-I) FTIR spectrometers. Only principal sharply defined IR peaks are recorded . IH NMR spectra (CDCI 3) were recorded on a Perkin-Elmer R-32 (90 MHz) IH NMR spectrometer using TMS as internal standard (chemical shifts in 8, ppm), and mass spectra were recorded on a Jeol-D-300 ET (CI) spectrometer. All compounds gave satisfactory analytical results . Purity of the synthesized compounds was checked by TLC using silica gel-G plates, benzene-methanol or toluene-methanol as developing solvent and the spots were exposed in UV/lodine chamber. 2-Arylimjno­thiazolidin-4-ones33 2a-c, 5-benzylidene-2-arylimino­thiazolidin-4-ones33 6a-i and thiazolidinopyrimidine34

8a-i were prepared by reported methods.

12 13

13 12

13 II

12

10

II

II

C2 C1 C2 C1 C2 C1 C2 C1 C2

28 13 19 16 16 12 20 20 16

14 II 16 12 II 12

10 12 II

II

18 12 II 13 12

10 10

12 12 II 12 10 10 10 10

3-N-(n-Alkoxyphthalimido)-2-aryliminothiazoli­din-4-ones 4a-i. A mixture of 2-phenyliminothiazo­Iidin-4-one 2a (1.92 g, 0 .01 mole), w-bromoethoxy­phthalimide 3a (2.7 g, 0.01 mole) , absolute alcohol (20 mL) and pyridine (2 mL) was heated to reflux for 15 hr. Excess of the solvent was removed under reduced pressure. After cooling, the product separated was col­lected by filtration and recrystallized from absolute alcohol to give 4a. Compounds 4b-i were synthesized by the similar method with different reflux times (15-22 hr). Their physical data and spectral data of repre­sentative compounds 4a-c are given in Table I.

3-N -(n-Alkoxyphthalimido )-5-arylidene-2-arylimino­thiazolidin-4-ones 7a-a'. Method I. 3-Ethoxyphthali­mido-2-phenyliminothiazolidin-4-one 4a (3.8 g, 0.01 mole), benzaldehyde Sa (1.06 g, 0.01 mole) and anhydrous CH3COONa (0.82 g, 0.01 mole) were di s­solved in acetic acid (15 mL) and the mixture was heated to refl ux for 16 hr. The mjxture was then fi 1-tered and the filtrate was poured on crushed ice. The sticky solid obtained was neutralized with dil. Na2C03 and the light yellow solid that precipitated was recrys­tallized from absolute alcohol.

Compounds 7b-a' were also synthesized in si milar way with different reflux times (15-20 hr). Their physical data and spectral data of compounds 7a, 7g and 7u are given in Table II.

Method II. Condensation of 6a-i with 3a-i. A mixture of 5-benzylidene-2-phenylimjnothiazolidin-4-one 6a (2.8 g, 0.01 mole) and 2-bromoethoxy-

1312 INDIAN J. CHEM. , SEC B, JUNE 2004

phthalimide 3a (2.7 g, 0.0 1 mole) were taken in abso­lute alcohol (20 mL). Pyridine (2 mL) was then added as base and the mixture was heated to reflux for 17 hr. Excess of the solvent was removed under reduced pressure. After cooling, the product separated out and was recrystallized from absolute alcohol.

Compounds 7b-a' were synthesized in the similar way but with different reflux times.

7 -N -(n-Alkoxyphthalimido)-2-hydroxy-4-ary 1-6-aryliminothiazolidino[2,3-b] pyrimidines 9a-a'. Method I: Compound 7a (4.69 g, 0.01 mole) and urea (LOg) were dissolved in gl ac ial acetic acid (l5ml) and anhydrous CH3COONa (0.82g, 0.01 mole) was added. The reaction mixture was heated to reflux for 11 hr. On cooling, crystals started to form gradually. After complete crystalli zation, the reaction mixture was filtered and recrystallized from glacial acetic acid.

Compounds 9b-a' were cyclised in simi lar way with different reflux times (10-12 hr). Their physical and spectral data of compounds 9h, 9i, and 9a ' are g iven in Table III.

Method II: Condensation of thiazolidino­pyrimidine 8a-i with bromoethoxyphthalimide 3a-i to give 9a-a'. A mixture of 4-benzylidene-2-hydroxy-6-phenyliminothiazolidin [2 ,3-b] pyrimidine 8a (3.2 g, 0.01 mole) , bromoethoxyphthal imide 3a (2 .7 g, 0.01 mol e) and pyridine (2 mL) was refluxed fo r 18 hr in absolute alcohol (20 mL). Excess of the solvent was removed under reduced pressure. After cooling, the product separated out as crystals and was recrystallized from absolute alcohol.

Compounds 9b-a' were synthesized in s imilar way with a small change in reflux time (15-20 hr) .

Antimalarial activity Plasmodium Jalciparum isolates were grown and

maintained in vitro routinely by the method described by Trager el aP5. P.Jalciparum, susceptible to chloro­quine, was used for this study. For conducting the experiment, the P. Jalciparum culture was syn­chronized to ring stage and diluted with fresh human erythrocytes to adjust the level of parasitaemia be­tween 1000 to 80000/IAL of blood . Schizont matura­tion inhibition assay in vitro was followed in thi s study for screening the antimalarial properties of these compounds.

The experiment was done in 96 well microtitre plates for 24-36 hr in duplicate in the presence or the absence of various concentrations of drugs by stan­dard methods36

,37 The control wells were without drug. The growth was monitored after 24-36 hr of

culture when these parasites would have developed to schizont stage. Thick smear was prepared from each well. The schizont maturation in the experimental well was compared with the control well. These tests are considered valid only if 10% schizont maturation was observed in control wells. Percentage inhibition was calculated according to the following formula.

% Inhibiti on=

100 No. of schi zontsl 200 asexual parasites in test well

x lOO No. of schizontsl 200 asexual paras ites in control well

The results of the compounds tes ted are summa­ri zed in Table IV.

Antibacterial activity Fifteen compounds were screened for antibacterial

activity. Three Gram-positive organi sms i.e. Staphy­lococcus aureus (Org. 1), Staphylococcus albus (Org. 2) , Streptococcus Jaecalis (Org. 3) and five Gram­negative organi sms i.e. Klebsiella pneumoniae (Org. 4) , Escherichia coli (Org. 5) , Pseudomonas aeurogi­nosa (Org. 6), Proteus mirabilis (Org. 7) , Salmonella typhi (Org. 8) were used . Gentamycin and Amikacin were used as control C, and C2, respect ively. Standard inhibition of zone size for Gentamicin is 15-27 mm and for Amikacin is 16-26 mm in the literature38

. The cu lture media were prepared using peptone (l %), NaCl (0.5 %) and beef extract (l %). A ll the ingredi­ents were di ssolved in di stilled water and adjusted pH as per optimum requirements. 2% Agar-agar soluti on was added and the medium was sterilized. The paper disc diffusion method39 was followed using special microbial filter paper di scs. It consisted of impregnat­ing small discs of standard filter paper with a given quantity of compound (300 lAg/disc), placing them on plates of culture media and inoculation with the or­ganism to be tested. After inoculation , we determined the degree of sensitivity by measuring the vi sibl e area of inhibition of growth into the surrounding medi a. The results are presented in Table V.

Conclusions

Pharmacology of compounds may change by intro­duction or elimination of a speG-ific group. In 3-al kox yphthal i mido-5-ary I idene-2-aryl i mi noth iazo l id­inA-ones, antimalarial activity is increased when chloro group is introduced at position-X in arylimino moiety whereas activity decreased wheri nitro group is introduced at same position (comparison between 7a, 7b and 7c in Table IV) . The antimalarial activity is

SINGH et al.: SYNTHESIS OF SUBSTITUTED ARYLIMINOTHIAZOLIDINO PYRIMIDINES 1313

found higher in thiazolidinopyrimidines than arylimi­nothiazolidinones (7b and 9b in Table IV) and found 100 percent active at 100 Ilg concentration when chloro group is present at position-X and methoxy group at position-Z (9h in Table IV). Length of alkyl chain in alkoxyphthalimide moiety al so affects to an­timalarial activity. Activity is increased when length of alkyl chain is increased (9h, 9q and 9z in Table IV).

Antibacterial activity is increased when chloro or nitro group is introduced at para-position in arylimino moiety (7a, 7b and 7c in Table V) and methoxy group is introduced at position-Z (7a, 7d and 7g in Table V). The antibacterial activity is found slightly lower in thiazolidinopyrimidines (9a, 9b and 9c in Table V) than 3-alkoxyphthalimido-5-arylidene-2-aryliminothiazolidin-4-ones (7a, 7b and 7c in Table V) . Antibacteri al activity is also increased when length of alkyl chain is increased 111

alkoxyphthalimide moiety (7a and 7j in Table V).

Acknowledgement The authors are thankful to the Head, Department

of Chemistry, M L Sukhadia University, Udaipur (Raj. ) for providing laboratory facilities and to the Director, Regional Sophisticated Instrumentation Centre, Central Drug Research Institute, Lucknow, India for providing spectral and analytical data. Our sincere thanks go to the Mal ari a Research Centre, Na­tional Institute of Communicable Diseases, Indian Council of Medical Research , Delhi , India for antima­larial testing and to the Microbial Research Labora­tory, Department of Botany, M L Sukhadia Univer­sity, Udaipur for antimicrobial testing.

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