Indian Journal of Chemistry Vol. 44B, September 2005, pp. 1944-1946
Note
Synthesis, characterization and anti-bacterial activity of some new 2, 3, 6-trisubstituted quinazolin-4(3H)-ones Rohit D Patel, Manish P Patel*& Ranjan G Patel Department of Chemistry, Sardar Patel University, VallabhVidyanagar 388120, India E-Mail:
[email protected] Received 11 October 2004; accepted (revised) 1 June 2005 Some new 2,3,6-trisubstituted quinazolin-4(3H)-ones 5 have been synthesized by Ullmann condensation of substituted anthranilic acids 4 and substituted benzothiazolylquinazolines 3, which are synthesized by condensation of 6-bromo-2-substituted quinazolin-4(3H)-one 1 and various substituted 2-aminobenzothiazoles 2 in the presence of pyridine. All the compounds in this series have been screened for their anti-bacterial activity. Keywords: Ullmann condensation, anthranilic acids, benzothiazolylquinazolines IPC: Int.Cl.7 C 07 D 215/00 // A 61 P 31/04
Quinazolinones are versatile nitrogen containing heterocyclic compounds, possessing broad spectrum of biological and pharmalogical activities such as hypotensive1, anticancer2,3, anti-HIV3, anti4 5 inflammatory , analgesic , anti-viral6, antitubercular7, antimicrobial8, anti-bacterial9,10 etc. Furthermore, qunazoline-4(3H)-ones substituted at 3-position with heterocyclic moieties are beneficial to bacterial activity11. In the present note, some derivatives of quinazolin-4(3H)-ones which are substituted at C-3 position with various benzothiazole derivatives and at C-6 position with substituted anthranilic acid have been discussed. Various 6-bromo-2-substituted benzoxazines 1 were prepared by the known procedure12,13 from 5bromoanthranilic acid14. The 6-bromo-2-substituted benzoxazines 1 were condensed with 2-amino-6substituted benzo-thiazole15,16 in the presence of pyridine to obtain 6-bromo-2-substituted-3-(6′-substituted benzo-thiazol-2′-yl)quinozolin-4(3H)-ones 3. The compounds 3 were reacted with bromo substituted/unsubstituted anthranilic acid by Ullmann condensation to obtain 3,5-disubstituted-2-[3-(6′substituted benzothiazol-2′-yl)-4-oxo-2-substituted-
3,4-dihydroquinazolin-6-ylamino]benzoic (Scheme I, Table I).
acid
5
Anti-bacterial activity Anti-bacterial activities of synthesized compounds were examined in vitro by known agar diffusion cup method17-20. All the compounds were tested for activity against gram-positive bacteria like Bacillus cereus, Stephylococcous aureus and Bacillus subtilis and gram-negative bacteria Escherichia coli. The culture medium was nutrient agar. All compounds were dissolved in N, N′-dimethylformamide (DMF) and DMF used as control. All the compounds were screened with reference to standard drug Ciprofloxacin. The results indicated that compounds were weakly active or inactive against all four organisms with reference to standard. The results are shown in Table II. Experimental Section All melting points were taken in open capillaries and are uncorrected. IR spectra were recorded in KBr on a Nicolet 400D spectro- photometer and 1H NMR in DMSO-d6 on a Bruker AC 300F (300MHz) using TMS as an internal standard. 6-Bromo-2-methyl/phenyl-3-(6′-methoxy/methylbenzothiazol-2′-yl)-quinazolin-4(3H)-ones 3a-d. General procedure. A mixture of 6-bromo-2methyl/phenylbenzoxazine (0.01 mole) 1 and 2amino-6-methyl/methoxybenzothiazole 2 (0.01 mole) in pyridine, was refluxed in an oil-bath for 10-12 hr. The reaction mixture was then allowed to cool to room temperature and poured in ice-cold dil. HCl. The separated product was filtered and washed with hot water till neutral. Compound 3a (R = CH3, R1 = OCH3): mp 256 oC, yield 68% (Found: C, 50.76; H, 3.01; N, 10.45. C17H12BrN3O2S requires C, 50.58; H, 3.21; N, 10.25%); IR: 2960 and 1314 (aromatic C-H stretching), 1640 (>C=O stretching), 1607 (C-N stretching), 546 cm-1 (C-Br stretching), 1H NMR: δ 2.21 (3H, s, -CH3), 3.67(3H, s, -OCH3), 7.50- 8.30 (6H, m, Ar-H). Compound 3b (R = Ph, R1 = OCH3): mp 213oC, yield 73%, Found: C, 56.91; H, 3.04; N, 9.05.
NOTES
1945
O O Br
N
O
Pyridine Reflux
+ H2 N N
S
R
Br S
N
R1
N
2
1
R1
N
R
3 R3 NH2
+
3
COOH
R2
4
Ullmann-condensation
O
R3
R1
N
NH S
N
R2
N
COOH
R
5
Compd
R
R1
R2
R3
Compd
R
R1
R2
R3
5a 5b 5c 5d
Ph Ph Ph Ph
OCH3 OCH3 OCH3 CH3
Br Br H H
Br H H H
5e 5f 5g
CH3 CH3 CH3
OCH3 OCH3 OCH3
Br Br H
Br H H
Scheme I Table I ⎯ Characterization data of compounds 5a-g. Compd*
m.p. °C
Yield (%)
Mol. formula
5a**
193
82
C29H18Br2N4O4S
5b**
181
85
C29H20BrN4O3S
5c
183
89
C29H20N4O4S
5d
205
82
C29H20N4O3S
5e**
190
73
C24H16Br2N4O4S
5f**
185
75
C24H17BrN4O4S
5g
195
80
C24H18N4O4S
Found (%) (Calcd) C H N 51.35 (51.22 58.11 (58.30 66.91 (66.70 69.03 (69.23 52.59 (52.09 53.64 (53.58 62.87 (62.63
2.67 2.54 3.19 3.39 3.87 3.64 4.00 3.94 2.74 2.65 3.19 3.29 3.96 4.11
8.26 8.04) 9.35 9.43) 10.76 10.55) 11.10 11.25) 8.46 8.55) 10.43 10.28) 12.22 12.08)
1
H NMR (δ, ppm)
3.83 (3H, s, -OCH3), 6.99-8.82 (13H, m, Ar-H), 8.84 (1H, s, -NH), 12.30 (1H, s, -COOH) 3.74 (3H, s, -OCH3), 7.00-8.86 (15H, m, Ar-H), 8.46 (1H, s, -NH), 12.41 (1H, s, -COOH) 3.85 (3H, s, -OCH3), 6.93-8.68 (15H, m, Ar-H), 8.48 (1H, s, -NH), 12.39 (1H, s, -COOH) 2.43 (3H, s,-CH3), 7.29-8.77 (15H, m, Ar-H), 8.49 (1H, s, -NH), 12.41 (1H, s, -COOH) 2.41 (3H, s, -CH3), 3.81 (3H, s, -OCH3), 6.99-8.86 (8H, m, Ar-H), 8.81 (1H, s, -NH), 12.36 (1H, s, -COOH) 2.39 (3H, s, -CH3), 3.84 (3H, s, -OCH3), 7.00-8.89 (9H, m, Ar-H), 8.79 (1H, s, -NH), 12.28 (1H, s, -COOH) 2.18 (3H, s, -CH3), 3.85 (3H, s, -OCH3), 7.09-8.27 (10H, m, Ar-H), 8.41 (1H, s,-NH), 12.30 (1H, s, -COOH)
* All compounds exhibited the characteristic IR bands at 3500-3400 (N-H stretching), 3000-2900 (aromatic C-H stretching), 2900-2800 (methyl C-H stretching), 1600-1400 (C=C aromatic and C=N stretching), 1700-1665 (carbonyl ketone), 1710-1701 cm–1 (aromatic carboxylic acid) ** These compounds exhibited the characteristic IR bands at 556-546 cm–1 (C - Br stretching)
INDIAN J. CHEM., SEC B, SEPTEMBER 2005
1946
Table II ⎯ Antibacterial screening results of the compounds 5a-g
Compd
B. subtilis
5a 5b 5c 5d 5e 5f 5g Ciprofloxacin
19 18 19 11 ---29
Inhibition zone (in mm) S.aureus B. cereus 18 17 16 18 --15 35
12 12 13 14 ---30
E. coli ------2 23
C22H14BrN3O2S requires C, 56.85; H, 2.91; N, 9.28%); IR: 2910 (aromatic C-H stretching), 1686 (>C=O stretching), 1604 (C-N stretching), 548 cm–1 (C-Br stretching), 1H NMR: δ 3.84 (3H, s, OCH3), 7.30-8.50 (11H, m, Ar-H). Compound 3c (R = Ph, R1 = CH3): mp 218 oC, yield 72%, (Found: C, 58.94; H, 3.15; N, 9.37); C22H14BrN3OS requires C, 59.09; H, 3.35; N, 9.18%); IR: 2960 and 1314 (aromatic C-H stretching), 1689 (>C=O stretching), 1602 (C-N stretching), 547 cm–1 (C-Br stretching); 1H NMR: δ 2.20 (3H, s, -CH3), 7.20-8.40 (11H, m, Ar-H). Compound 3d (R = CH3, R1 = CH3): mp 250 oC, yield 70%, (Found: C, 52.86; H, 3.13; N, 10.88. C17H12BrN3OS requires C, 52.79; H, 3.35; N, 10.64%); IR: 2965 and 1347 (aromatic C-H stretching), 1656 (>C=O stretching), 1605 (C-N stretching), 534 cm–1 (C-Br stretching); 1H NMR: δ 2.30 (6H, s, 2 x -CH3), 7.20-8.20 (6H, m, Ar-H). 3.5-Disubstituted-2-[3-(6′-substituted benzothiazol-2′-yl)-4-oxo-2-substituted-3,4-dihydroquinazolin-6-ylamino]benzoic acid 5a-h: General procedure. In a 100 mL round bottom flask compound 3 (0.01 mole) and anthranilic acid 4 (0.01 mole) in DMF had been charged. To it anhydrous potassium carbonate (0.01mole) and copper powder (0.4 g) were added. The reaction mixture was refluxed in an oilbath for 6-8 hr, and then allowed to cool to room temperature and poured over crushed ice and
acidified. The separated product was filtered and washed with hot water till neutral and recrystallized from methanol-DMF. All the compounds were characterized by elemental analysis, IR and 1H NMR data (Table I). Acknowledgement The authors are thankful to Dr KC Patel and Mr Kishor H Chauhan, Department of Biosciences, Sardar Patel University for providing facilities for the antibacterial activity and SAIF, Punjab University for 1 H NMR spectra.
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