Indian Journal of Chemistry Vol . 40B, December 200 1 , pp. 1 270- 1274

Note

Synthesis and antibacterial activity of some new[1 ,3 ,4] oxadiazino [6,5-b] indoles

and acetophenonehydrazones containing 1 ,8-naphthyridine moiety

K Mogilaiah·, H Ramesh Babu & R Babu Rao

Department of Chemistry, Kakatiya University, Warangal S06 009, India

Received 8 October 1 999; accepted (revised) 17 October 2000

Condensation of 1 ,8-naphthyridin-2-one-3-carboxylic acid hy­drazide 1 with different isatins 2 gives the corresponding isatin-13-( 1 ,8-naphthyridin-2-one-3-carbonylhydrazones) 3, which on treatment with cone. H2S04 undergo cyclodehydration to afford the desired 2-( I ,8-naphthyridin-2-one-3-yl)-[ I ,3 ,4]oxadiazino­[6,S-b] indoles 4. On the other hand, the reaction of 1 with differ­ent acetophenones furnished the respecti ve acetophenone 1 ,8-naphthyridin-2-one-3-carbonylhydrazones 5. The structural as­signment of the products is based on elemental analyses and spectral data. The compounds 4 and 5 have been evaluated for their antibacterial activity against E. coli, P. aeruginosa, B. subti­lis and B. mycoides.

Among a wide variety of heterocycles that have been explored for developing pharmaceutically im-

, 3 1 3 4 d" 4 portant molecules, indoles - and , , -oxa Iazmes have played an important role in medicinal chemistry. Some of them have received considerable attention as potential antimicrobial agents5,6. Moreover, 1 ,8-naphthyridine derivatives acquired a special place in the heterocyclic field because of their diversified ac­tivities such as antibacterial7, diuretic8, antimalarial9, antihypertensive 10 and anti-inflammator/ ' . Further­more, hydrazones are associated with broad spectrum

. . I . . 1 2 t3 I . f th b a of blOloglca actlvltes ' . n view 0 ese 0 serv -

tions and our continued interest in the synthesis of . 8 h h 'd ' 14-20 · biologically active 1 , -nap t yn tnes , It was con-sidered worthwhile to synthesize some new [ 1 ,3 ,4] oxadiazino[6,5-b] indoles and acetophenone hydra­zones incorporating 1 ,8-naphthyridine moiety and evaluate their antibacterial activity. The reaction se­quence for different title compounds is outlined in Scheme I.

Ethy I 1 ,8-naphthyridin-2-one-3-carboxy late, ob­tained by the condensation of 2-aminonicotinaldehyde with diethyl malonoate in methanol containing a cata-

lytic amount of piperidine, on hydrazinolysis with refluxing hydrazine hydrate furnished the desired synthon, 1 ,8-naphthyridin-2-one-3-carboxylic acid hydrazide 12 1 . Condensation of 1 with different isatins 2 in gl. acetic acid afforded the corresponding isatin­�-( 1 , 8-naphthyridin-2-one-3-carbonylhydrazones) 3 in very good yields (Table I) . The later could be cy­clized to 2-( 1 , 8-naphthyridin-2-one-3-yl)- [ 1 , 3, 4]­oxadiazino[6,5-b ] indoles 4 using conc. H2S04 as de­hydrating agent at room temperature (Table I). The hydrazide 1 on reaction with different acetophenones in gl. acetic acid resulted in the formation of aceto­phenone 1 ,8-naphthyridin-2-one-3-carbonylhydrazo­nes 5 in good yields (Table II).

The structures of the newly synthesized compounds were established by their elemental analyses and spectral (lR and MS) data.

Antibacterial activity. All the title compounds were screened for their antibacterial activity against Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis and Bacillus mycoides by filter paper disc method22 at 400 and 600 ).!g/disc concentrations . Streptomycin was used as a standard drug for com­parison. The activity is reported by measuring the di­ameter of the inhibition zone in mm. The results are presented in Table III.

Amongst the compounds screened 4b, 4e, Sb, Sd and Sn showed good activity and compounds 4c, 4f, Sc, Sm, 50 and Sp showed moderate activity against both gram-negative and gram-positive bacteria. Other compounds exhibited weak activity against above organisms. The activity of the compound de­pends upon the nature and position of substituent at the indole or aryl moiety. The results indicate that the introduction of methyl and chloro groups in­creased the antibacterial activity. Introduction of nitro groups at aryl moiety decreases the activity of the compounds. Amongst the compounds tested, compounds 4e and Sd showed remarkable and com­parable activity against E. coli and B. subtilis with that of standard drug streptomycin at the same con­centrations.

Experimental Section Melting points were determined using an electro­

thermal melting point apparatus (Cintex) and are un-

Compd

3a

3b

3c

3d

3e

3f

3g

4a

4b

4c

4d

4e

0 " �C-NHNH2

I + � N 0 H

I U "

Ar-C-CH3/ CH3COOH

9. PH3

�C-NHN=C /'" I "" Ar � N 0

H S

0l:J[)-I ....-::: R

o N · H

2

•

NOTES

CH3COOH ..

0 " �C-NHN

tJ[}-I I R :c-.... /. N N 0 0 N

H 3 H

II tt�kJ) R

/'" I "" HO N

� N 0 H 1 Cone. H2SO4

. � " I" R /N

� GCC � /.

� I " 0 N

N N 0 H 4

Scheme I

Table I-Characterization data of compounds 3 and 4

R m.p. Yield Mol. formula Found (%) (Caled) °C (%) (Mol. wt) (Mol wt) C H

H >300 84 C17H • • Ns03 6 1 .42 3.4 1 (333) (6 1 .26 3.30

5-CH3 >300 96 C.sH I3Ns03 62.40 3.85 (347) (62.25 3.75

7-CH3 >300 90 C.sH I3Ns03 62.4 1 3.83 (347) (62.25 3.75

5-0CH3 >300 92 C.sH I3Ns04 59.67 3.68 (363) (59.50 3.58

5-CI >300 94 C17HIO Ns03CI 55.73 2.85 (367.5) (55.59 2.72

7-CI >300 88 C17HIONs03Ci 55.70 2.84 (367.5) (55.59 2.72

5-Br >300 91 C17HIONs03Br 49.66 2.54 (4 12) (49.5 1 2.43

H >300 60 C17H9NS02 64.92 2.95 (3 15) (64.76 2.86

6-CH3 >300 75 C.sH • • Ns02 65.82 3 .49 (329) (65.65 3.34

8-CH3 >300 70 C.sH • • Ns02 65.84 3.46 (329) (65.65 3.34

6-0CH3 >300 72 C.sH • • Ns03 62.84 3.30 (345) (62.6 1 3 . 19

6-CI >300 74 C17HsNs02CI 58.92 2.45 (347.5) (58.79 2.3 1

1 27 1

N

2 1 . 1 6 2 1 .02) 20.28 20. 1 7) 20.29 20. 17) 1 9.37 1 9.28) 1 9.30 1 9.07) 1 9.27 19.07) 16.78 16.99) 22.40 22.22) 2 1 .46 21 .28) 21 .47 2 1 .28) 20.4 1 20.29) 20.29 20. 17)

(Contel)

1 272 INDIAN J CHEM, SEC B, DECEMBER 2001

Table I-Characterization data of compounds 3 and 4-Contd

Compd R

4f 8-CI

4g 6-Br

m.p. °C (%)

>300

>300

Yield (Mol. wt)

68

73

Mol. formula (Mol. wt)

C'7HgNs02C1 (347.5)

C17HgNs02Br (394)

C

58.94 (58.79 5 1 .90

(5 1 .78

Found (%) (Caled) H N

2.43 20.27 2.3 1 20. 1 7 ) 2 . 1 7 17.53 2.03 1 7.77)

Table II-Characlerization data of compounds 5

Compd

Sa

5b

5c

5d

5e

Sf

5g

5h

5i

5j

5k

51

5m -

50

50

5p

Ar

Phenyl

p-Methylphenyl

p-Methoxyphenyl

p-Chloropheoyl

p-Bromophenyl

o-Hydroxyphenyl

p-Hydroxyphenyl

2-Hydroxy-5-methyl phenyl

p-Aminophenyl

m-Nitrophenyl

p-Nitrophenyl

2-Naphthyl

2,4-Dihydroxy­phenyl

2-Pyridyl

3-Pyridyl

4-Pyridyl

m.p. °C

>300

>300

>300

>300

>300

>300

>300

>300

>300

>300

>300

>300

>300

>300

>300

>300

Yield (%)

82

92

88

90

87

86

84

83

85

80

84

86

85

84

87

88

corrected. IR spectra were recorded (KBr discs) on a Perkin-Elmer 337 spectrophotometer (vrnax in cm· l ) and mass spectra on a leol lMS D-300 spectrometer. ' H NMR spectra of the compounds could not be ob­tained due to their poor solubility in common IH NMR solvents.

Isatin-r3-(l, 8-naphthyridin-2-one-3-carbonyl-hydrazone) 3a. A mixture of 1 (0.0 1 mole) and 2 (R=H, 0.0 1 mole) in gl. acetic acid (25 mL) was re-

Mol. formula (Mol. wI)

C'7H'4N402 (306)

C'8H'6N402 (320)

C'8H'6N403 (336)

CI7H '3N402CI (340.5)

C17H13 N402Br (385)

C17H '4N402 (322)

C17H'4N402 (322)

C'8H'6N403 (336)

C17H ,sNs02 (32 1 )

C17H'3NS04 (35 1 )

C1 7H I3Ns04 (35 1 )

C2 ,H ' 6N402 (356)

C17H '4N403 (338)

C'6H 1 3Ns02 (3 1 7)

C'6H '3NS02 (3 1 7)

C'6H 13Ns02 (3 17)

C

66.86 (66.67 67.68

(67.50 64.43

(64.29 60.2 1

(60.00 52.74 (52.99 63.52

(63.35 63.50

(63.35 64.41

(64.29 63.67

(63.55 58.3 1

(58. 1 2 58.34

(58. 1 2 70.6 1

(70.79 60.47

(60.36 60.73

(60.57 60.75

(60.57 60.72

(60.57

Found (%) (Caled) H N

4.64 1 8 .47 4.58 1 8 .30) 5.08 1 7.63 5.00 1 7.50) 4.87 16 .80 4.76 1 6.67) 3.7 1 1 6.58 3.82 1 6.47) 3.46 14.43 3.38 1 4.55) 4.43 1 7.50 4.35 1 7.39) 4.45 17 . 5 1 4.35 17 .39) 4.85 1 6.50

4.76 16.67)

4.76 2 1 .67 4.67 2 1 .8 1 ) 3.78 1 9.72 3.70 19.94) 3.76 19.75 3.70 1 9.94) 4.60 15 .84 4.49 1 5 .73) 4.2 1 16.70 4. 14 1 6.57) 4.25 22.21 4. 1 0 22.08) 4.2 1 22.25 4. 1 0 22.08) 4.23 22.23

4. 1 0 22.08)

fluxed for 1 5 min. The solid that separated was fil­tered, washed with methanol and recrystallized from methanol to give 3a, m.p.>300°C, yield 84%; IR (KBr); 3 1 73 (NH), 1 7 1 5 (indole C=O), 1 676 (naph­thyridine C=O), 1 624 (CONH), 1 604 cm- I (C=N); MS; mlz 333(M\ 5 .2%), 305(7 .5), 1 88(7 .3), 1 73( 1 00), 1 60( 1 4.9), 1 45(6.2), 1 32(23 .5) , 9 1 (23.5) .

Other compounds of this type were prepared simi­larly and are recorded in Table I .

NOTES 1 273

Table III-Antibacterial activity data of compounds 4 and 5

Compd Inhibition zone (in mm) against E. coli at P. aeruginosa at B. subtilis at B. rny'coides at

4001lg/ 6001lg/ 4001lg/ 6001lg/ 4001lg/ 6001lg/ 4001lg/ 6001lg/ disc disc disc

4a 4.5 5.5 3.0 4b 7.5 8.5 6.0 4c 5.5 6.5 4.5 4d 4.0 5.0 3.0 4e 10.5 1 1 .5 9.0 4f 6.5 8.0 5.5 4g 5.0 6.0 4.0 Sa 4.0 5.0 3.5 5b 9.5 10.5 7.5 5c 5.5 6.5 4.5 5d 1 1 .5 1 2.5 9.0 5e 4.5 5.5 4.0 Sf 6.0 7.5 5.0 5g 5.0 6.5 4.5 5h 5.5 7.0 5.0 5i 4.0 5.5 3.0 5j 3.0 4.0 2.5 5k 3.5 4.5 3.0 51 5.0 6.0 4.0

5m 5.5 6.5 5.0 5n 7.0 8.5 6.5 50 5.5 6.5 4.5 5p 6.0 7.5 5.5

StreEtomycin 1 3.0 1 5.0 1 5.0

2-(1,8-Naphthyridin-2-one-3-yl) [1, 3, 4] oxadi­azino [6,5-b] indole 4a. Hydrazone 3a (0.0 1 mole) was added in small amount to cold cone. H2S04 (5 mL). It was left at room temperature for 4 hr and then ice cold water added to this mass. The solid thus ob­tained was filtered, washed with water and recrystal­lized from DMF to afford 4a, m.p. > 300°C, yield 60%.; IR (KBr): 3 1 50 (NH), 1 678 (C=O), 1 600 (C=N), 1 230 cm· 1 (C-O-C); MS: mJz 3 1 5(M+, 1 l .3%), 1 87 ( 1 l .5), 1 7 1 ( 1 00), 1 70(26.4), 145( 1 0.9), 1 42( 12 .9), 1 3 1 (54.4).

Other compounds of this type were prepared simi­larly and are recorded in Table I.

Acetophenone 1, 8-naphthyridin-2-one-3-carbonylhydrazone Sa. A mixture of 1 (0.0 1 mole) and acetophenone (0.0 1 mole) in gl. acetic acid (25 mL) was refluxed for 10 min. The separated solid was filtered, washed with cold methanol and recrystallized from methanol to give Sa, m.p. > 300°C, yield 82%; IR (KBr): 3 1 28 (NH), 1 680 (ring C=O), 1 634 (CONH), 1 600 em-I (C=N); MS: mlz 306 (M+, 27%), 29 1 (29.3), 290( 1 7.5), 1 88 ( 10. 1 ), 1 73 ( 100), 1 45(75.9), 1 33(5 1 .4), 1 1 8(59), 1 03( 1 7 .9), 77(33.3).

disc

4.0 7.5 5.5 4.5 10.5 6.5 5.5 4.5 8.5 5.5 1 0.5 5.0 6.5 5.5 6.0 4.0 3.0 4.5 5.5 6.0 7.5 5.5 6.5 17 .0

disc disc disc disc

2.5 3.5 2.0 3.0 4.0 5.5 3.5 4.5 3.5 4.5 2.5 3.0 2.5 3.5 3.0 4.0 8.0 9.5 5.5 6.5 5.0 6.5 4.0 5.5 3.0 4.0 2.5 3.5 3 .5 4.0 2.5 3.5 6.5 7.5 5.5 6.5 4.0 5.0 3.0 4.5 8.5 10.5 6.0 7.5 3.0 4.5 2.5 3.0 4.0 5.5 3.5 4.5 3.5 4.0 3.0 4.0 4.5 5.5 4.0 5.0 2.5 3.5 2.0 3.5 2.0 3.0 2.5 3.0 2.5 3.5 3.0 4.0 3.5 4.5 2.5 3.5 4.0 5.5 3.5 4.5 5.0 6.5 5.5 6.0 3.5 4.5 3.0 4.0 4.5 5.5 4.0 5.5 10.0 1 2.0 9.0 1 1 .0

Other compounds of this type were prepared simi­larly and are recorded in Table II.

Acknowledgement The authors are thankful to the Head, Department

of Chemistry, Kakatiya University, Warangal for pro­viding necessary facilities and to the authorities of RSIC, CDRI, Lucknow for recording mass spectra.

References I Komet M J & Thio A P, J Med Chern, 19, 1976, 892. 2 Peterson W C, US Pat 4683000, (1987); Chern Abstr, 107,

1987, 2 17644a. 3 Baasnes B, Schwambom M, Santel H & Joachim L K, Eur

Pat Appl Ep 422470; Chern Abstr, 1 15, 1991, 7 1 589c. 4 Trepanier D L, John N E & Sprancmanis Y, J Med Chern, 9,

1966, 753. 5 Hiremath S P, Ullagaddi A & Purohit M G, Indian J Chern,

27B, 1988, 1 102. 6 Ali R, Mishra B & Nizamuddin, Indian J Chern, 28B , 1989,

526. 7 Cooper C S, Klock P L, Chu D T W, Hardy D J, Swanson R

N & Plattner J J, J Med Chern, 35, 1992, 1392. 8 Gorecki D K J & Hawes E M, J Med Chern, 20, 1977, 124. 9 Balin G B & Tan W L, Aust J Chern, 37, 1984, 1065.

1 274 INDIAN J CHEM, SEC B, DECEMBER 200 1

10 Ferrarini M, Clendio M, Calderone U & Lovella G , Eur J 1 6 Rani H S , Mogilaiah K , Rao J S & Sreenivasulu B , Indian J Med Chern, 33, 1998, 383. Chern, 35B, 1996, 745.

I I Kuroda T, Suzuki F, Tamura T, Ohmori K & Hosoe H, J 17 Mogilaiah K & Rao R B, lndian J Chern, 37B, 1998, 1 39. Med Chern, 35, 1992, 1 1 30. 1 8 Mogilaiah K & Rao R B, Indian J Chern, 37B, 1998, 894.

12 Patel J M, Dave M P, Langalia N A & Thaker K A, J Indian 1 9 Mogilaiah K, Reddy P R & Rao R B, Indian J Chern, 38B, Chern Soc, 6 1 , 1984, 7 1 8.

1 3 Mohan R R , Agarwal R & Misra V S , Indian J Chern, 25B, 1999, 495.

1986, 1 234. 20 Mogilaiah K, Rao R B & Reddy K N, Indian J Chern, 38B,

1 4 Rao J S, Sreenivasulu B & Mogilaiah K , Indian J Chern, 1999, 8 1 8.

34B, 1995, 734. 2 1 Hawes E M & Wibberley D G, J Chern Soc (C), 1966, 3 1 5. 15 Rao G R, Mogilaiah K & Sreenivasulu B, Indian J Chern, 22 Vincent J C & Vincent H W, Proc Soc Expll Bioi Med, 55,

35B, 1996, 339. 1944, 1 62.