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Chem. pharm. bull. 56(11) 1617-1620 (2008)

Chem. Pharm. Bull. 56(11) 1617—1620 (2008)
Clean Synthesis and Antibacterial Activities of Spiro[pyrimido[4,5-b]-
quinoline-5,5
؅-pyrrolo[2,3-d]pyrimidine]-pentaones
Ramin GHAHREMANZADEH,a Seyyedeh Cobra AZIMI,a Nader GHOLAMI,b and Ayoob BAZGIR*,a a Department of Chemistry, Shahid Beheshti University; Tehran 1983963113, Iran: and b Petrochemical Department,Research Institute of Petroleum Industry (R.I.P.I.); P. O. Box 14665–1998, Tehran, Iran.
Received July 12, 2008; accepted August 22, 2008; published online August 25, 2008 A simple, clean and efficient method for the synthesis of spiro[pyrimido[4,5-b]quinoline-5,5؅-pyrrolo[2,3-
d ]pyrimidine]-pentaone derivatives by condensation reaction of 6-amino-uracils and isatins in aqueous media is
reported. These products were evaluated in vitro
for their antibacterial activities.
Key words
isatin; 6-amino-uracil; spiro[pyrimidoquinoline-pyrrolopyrimidine]; aqueous media Polyfunctionalized heterocyclic compounds play important spectrometer at 300.13 and 75.47 MHz, respectively. Elemental analyses roles in the drug discovery process, and market analysis of were performed using a Heracus CHN-O-Rapid analyzer.
drugs in late development shows that 68% of them are hete- Typical Procedure for Preparation of 1H-Spiro[pyrimido[4,5-b]quino-
line-5,5؅-pyrrolo[2,3-d ]pyrimidine]-2,2؅,4,4؅,6؅(1؅H,3H,3؅H,7؅H,10H )-
rocycles.1) Therefore, it is not surprising that research in the pentaone (3a)
A mixture of 6-amino-uracil (2 mmol), isatin (1 mmol) and field of synthesis of polyfunctionalized heterocyclic com- p-TSA (0.1 g) in refluxing H O (5 ml) was stirred for 6 h (TLC). After com- pounds has received special attention.
pletion of reaction, the reaction mixture was filtered and the precipitate Spirocyclic systems containing one carbon atom common washed with water and then EtOH to afford the pure product 3a as a white
powder (85%). mp Ͼ350 °C. IR (KBr) (n
to two rings are structurally interesting.2) The asymmetric 1628. 1H-NMR (300 MHz, DMSO-d ) d (ppm): 6.79—7.17 (4H, m, H-Ar), characteristic of the molecules due to the chiral spiro carbon 9.04 (1H, s, NH), 10.41 (1H, s, NH), 10.47 (1H, s, NH), 10.61 (1H, s, NH), is one of the important criteria of the biological activities.
11.02 (1H, s, NH), 11.88 (1H, s, NH). 13C-NMR (75 MHz, DMSO-d ) d The presence of a sterically constrained spiro structure in (ppm): 49.5, 82.6, 97.5, 116.6, 121.6, 123.7, 126.6, 128.6, 135.6, 146.4, various natural products also adds to the interest in the inves- 150.4, 151.5, 152.5, 159.0, 162.4, 181.7. MS, m/z (%): 366 (Mϩ, 25), 313(40), 236 (44), 57 (100). Anal. Calcd for C H N O : C, 52.46; H, 2.75; N, tigations of spiro compounds.3) Spiro compounds represent 22.94%. Found: C, 52.50; H, 2.80; N, 22.87%.
an important class of naturally occurring substances and their 7-Bromo-1H-spiro[pyrimido[4,5-b]quinoline-5,5؅-pyrrolo[2,3-d]-
characteristic is the highly pronounced biological proper- pyrimidine]-2,2؅,4,4؅,6؅(1؅H,3H,3؅H,7؅H,10H )pentaone (3b)
Uracil and its annelated substrates occupy a unique place ϭ8.4 Hz, H-Ar), 7.33 (1H, d, 3J ϭ8.3 Hz, H-Ar), 9.31 (1H, s, in the field of medicinal chemistry as useful anticancer and NH), 10.51 (1H, s, NH), 10.67 (2H, s, 2NH), 11.07 (1H, br s, NH), 11.91 antiviral drugs.6) The versatility of uracil derivatives for the (1H, br s, NH). 13C-NMR (75 MHz, DMSO-d ) d (ppm): 49.4, 82.6, 97.2, synthesis of nitrogen containing heterocycles of biological 114.8, 118.9, 123.9, 128.9, 131.5, 135.3, 146.3, 150.4, 151.6, 159.1, 162.3, importance has been well documented in the literature.7) A 181.4. MS, m/z (%): 445 (Mϩ, 5), 430 (14), 236 (30), 149 (36), 57 (100).
number of fused uracils of biological significance, such as, Anal. Calcd for C H BrN O : C, 43.17; H, 2.04; N, 18.88%. Found: C, pyrano-, pyrido-, pyrazolo-, pyrimido-, pyridazino-pyrim- 7-Nitro-1H-spiro[pyrimido[4,5-b]quinoline-5,5؅-pyrrolo[2,3-d]pyrimi-
idines have all been prepared by the functionalization of dine]-2,2؅,4,4؅,6؅(1؅H,3H,3؅H,7؅H,10H)-pentaone (3c) Yellow powder
these important heterocyclic building blocks.8,9) /cmϪ1): 3445, 3200, 1715, 1633, 1557.
As part of our program which aimed to develop new selec- H-NMR (300 MHz, DMSO-d ) d (ppm): 7.25 (1H, d, 3J 7.25 (1H, s, H-Ar), 8.04 (1H, d, 3J tive and environmentally friendly methodologies for the 10.55 (1H, s, NH), 10.84 (2H, s, NH), 11.28 (1H, s, NH), 12.02 (1H, s, NH), preparation of heterocyclic compounds,10—15) we performed 13C-NMR (75 MHz, DMSO-d ) d (ppm): 49.3, 83.5, 97.8, 117.4, 122.4, the synthesis of spiro[pyrimido[4,5-b]quinoline-5,5Ј-pyrrolo- 122.6, 124.7, 141.8, 142.9, 145.9, 145.9, 150.3, 151.4, 152.8, 159.1, 162.3, [2,3-d ]pyrimidine]-pentaone derivatives through a cyclo-con- 181.1. MS, m/z (%): 411 (Mϩ, 12), 336 (34), 319 (80), 230 (100). Anal. densation reaction employing water as the reaction medium.
Calcd for C H N O : C, 46.72; H, 2.21; N, 23.84%. Found: C, 46.66; H, In fact, as clearly stated by R. A. Sheldon, it is generally rec- 1,1؅,3,3؅-Tetramethyl-1H-spiro[pyrimido[4,5-b]quinoline-5,5؅-pyrrolo-
ognized that “the best solvent is no solvent and if a solvent [2,3-d ]pyrimidine]-2,2؅,4,4؅,6؅(1؅H,3H,3؅H,7؅H,10H)-pentaone (3d)
(diluent) is needed it should preferably be water.”16) The use White powder (80%); mp Ͼ380 °C; IR (KBr) (n of water as the reaction medium represent a remarkable ben- 1761, 1699, 1643. 1H-NMR (300 MHz, DMSO-d ) d efit since this green solvent is highly polar and therefore im- CH ), 3.09 (3H, s, CH ), 3.40 (3H, s, CH ), 3.49 (3H, s, CH ), 6.94—7.30 (4H, m, H-Ar), 9.36 (1H, s, NH), 11.59 (1H, s, NH), 13C-NMR (75 MHz, miscible with most organic compounds; moreover, the water DMSO-d ) d (ppm): 27.5, 27.9, 30.6, 31.7, 51.3, 83.2, 97.8, 117.2, 121.4, soluble catalyst resides and operates in the aqueous phase 124.1, 126.7, 128.6, 136.0, 146.4, 150.8, 151.5, 152.5, 157.3, 160.3, 181.8.
and separation of the organic materials is thus easy.
MS, m/z (%): 422 (Mϩ, 5), 393 (15), 268 (100), 183 (25). Anal. Calcd forC H N O : C, 56.87; H, 4.30; N, 19.90%. Found: C, 56.92; H, 4.26; N, Experimental
Apparatus
Melting points were measured on an Electrothermal 9100 Due to very low solubility of the products 3e and 3f, we can not report the
apparatus and are uncorrected. Mass spectra were recorded on a FINNI- GAN-MAT 8430 mass spectrometer operating at an ionization potential of 1,1؅,3,3؅-Tetramethyl-7-nitro-1H-spiro[pyrimido[4,5-b]quinoline-5,5؅-
70 eV. IR spectra were recorded on a Shimadzu IR-470 spectrometer. 1H- pyrrolo[2,3-d ]pyrimidine]-2,2؅,4,4؅,6؅(1؅H,3H,3؅H,7؅H,10H )-pentaone
and 13C-NMR spectra were recorded on a BRUKER DRX-300 AVANCE Yellow powder (78%); mp Ͼ300 °C. IR (KBr) (n ∗ To whom correspondence should be addressed. e-mail: a_bazgir@sbu.ac.ir 3106, 1769, 1710, 1635. 1H-NMR (300 MHz, DMSO-d ) d 12.20 (1H, br s, NH), 12.31 (H, s, NH). MS, m/z (%): 503 (Mϩ, 10), 477 (3H, s, CH ), 3.10 (3H, s, CH ), 3.40 (3H, s, CH ), 3.53 (3H, s, CH ), 7.52 (38), 257 (34), 97 (60), 43 (100). Anal. Calcd for C H BrN O S : C, 42.78; ϭ7.2 Hz, H-Ar), 7.74 (1H, s, H-Ar), 8.11 (1H, d, 3J ϭ8.1 Hz, H, 2.59; N, 16.63%. Found: C, 42.71; H, 2.53; N, 16.57%.
H-Ar), 10.00 (1H, s, NH), 11.82 (1H, s, NH). MS, m/z (%): 466 (MϩϪ1, 3,3؅-Dimethyl-2,2؅-bis(methylthio)-3H-spiro[pyrimido[4,5-b]quino-
50), 439 (40), 423 (100), 393 (30). Anal. Calcd for C H N O : C, 51.39; H, line-5,5؅-pyrrolo[2,3-d ]pyrimidine]-4,4؅,6؅(3؅H,7؅H,10H )-trione (7d)
3.67; N, 20.98%. Found: C, 51.44; H, 3.62; N, 20.90%.
White powder (73%); mp Ͼ350 °C. IR (KBr) (n 1,1؅,3,3؅-Tetramethyl-7-bromo-1H-spiro[pyrimido[4,5-b]quinoline-
1741, 1666, 1609. 1H-NMR (300 MHz, DMSO-d ) d 5,5؅-pyrrolo[2,3-d ]pyrimidine]-2,2؅,4,4؅,6؅(1؅H,3H,3؅H,7؅H,10H )-pen-
SCH ), 2.60 (3H, s, SCH ), 3.26 (3H, s, NCH ), 3.31 (3H, s, NCH ), 6.73— taone (3f )
White powder (80%); mp Ͼ300 °C. IR (KBr) (n 7.10 (4H, m, H-Ar), 9.80 (1H, s, NH), 10.99 (1H, s, NH). MS, m/z (%): 454 3487, 3283, 1758, 1696, 1649. 1H-NMR (300 MHz, DMSO-d ) d (Mϩ, 20), 425 (100), 379 (25), 351 (40), 88 (40). Anal. Calcd for 3.00 (3H, s, CH ), 3.06 (3H, s, CH ), 3.37 (3H, s, CH ), 3.48 (3H, s, CH ), C H N O S : C, 52.85; H, 3.99; N, 18.49%. Found: C, 52.91; H, 3.95; N, 7.11—7.36 (3H, m, H-Ar). 9.47 (1H, s, NH), 11.59 (1H, s, NH). MS, m/z (%): 500 (Mϩ, 20), 473 (60), 346 (100), 319 (16). Anal. Calcd forC H BrN O : C, 47.92; H, 3.42; N, 16.76%. Found: C, 47.97; H, 3.38; N, Results and Discussion
1,1؅-Dimethyl-1H-spiro[pyrimido[4,5-b]quinoline-5,5؅-pyrrolo[2,3-d ]-
After some preliminary experiments, it was found that a pyrimidine]-2,2؅,4,4؅,6؅(1؅H,3H,3؅H,7؅H,10H )-pentaone (3g)
mixture of 6-amino-uracil 1a and isatin 2a in the presence of
a catalytic amount of p-toluene sulfuonic acid (p-TSA) af- forded 1H-spiro[pyrimido[4,5-b]quinoline-5,5Ј-pyrrolo[2,3- (3H, s, CH ), 6.90—7.13 (4H, m, H-Ar), 9.11 (1H, s, NH), 10.74 (1H, s, d]pyrimidine]-2,2Ј,4,4Ј,6Ј(1ЈH,3H,3ЈH,7ЈH,10H)-pentaone NH), 10.83 (1H, s, NH), 11.50 (1H, s, NH). 13C-NMR (75 MHz, DMSO-d ) d (ppm): 26.8, 30.6, 50.7, 82.4, 98.1, 116.7, 121.3, 123.6, 126.9, 128.6, 3a in 85% yield in refluxing water for 6 h (Chart 1).
135.6, 145.1, 150.5, 151.3, 154.0, 158.1, 161.5, 181.9. MS, m/z (%): 394 The 1H-NMR spectrum of compound 3a exhibited a multi-
(Mϩ, 15), 350 (85), 227 (100). Anal. Calcd for C H N O : C, 54.82; H, plet at d ϭ6.79—7.17 for the four aromatic hydrogens and 3.58; N, 21.31%. Found: C, 54.86; H, 3.53; N, 21.38%.
six singlets at d 9.04, 10.41, 10.47, 10.61, 11.02 and 11.88 1,1؅-Dimethyl-7-nitro-1H-spiro[pyrimido[4,5-b]quinoline-5,5؅-
for the six NH groups. The 13C-NMR spectrum of compound pyrrolo[2,3-d]pyrimidine]-2,2؅,4,4؅,6؅(1؅H,3H,3؅H,7؅H,10H )-pentaone
(3h)

White powder (80%); mp Ͼ350 °C. IR (KBr) (n 3a showed 16 signals in agreement with the structure, and
3035, 1764, 1717, 1654. 1H-NMR (300 MHz, DMSO-d ) d the mass spectrum showed the expected molecular ion peak.
(3H, s, CH ), 3.42 (3H, s, CH ), 7.25—8.10 (3H, m, H-Ar), 10.00 (1H, s, Encouraged by this success, we have extended this reac- NH), 10.85 (2H, s, 2NH), 11.74 (1H, s, NH), 13C-NMR (75 MHz, DMSO- tion to various 6-amino-uracils 1ac and isatines 2ac
d ) d (ppm): 26.9, 30.8, 50.4, 83.3, 98.1, 117.4, 122.2, 123.1, 124.7, 141.8, 142.0, 143.0, 144.8, 151.2, 154.4, 158.2, 161.4, 181.4. MS, m/z (%): 439 under similar conditions (using H O/p-TSA), furnishing the (Mϩ, 5), 368 (30), 230 (40), 43 (100). Anal. Calcd for C H respective 1H-spiro[pyrimido[4,5-b]quinoline-5,5Ј-pyrrolo- 49.21; H, 2.98; N, 22.32%. Found: C, 49.17; H, 2.94; N, 22.39%.
[2,3-d ]pyrimidine]-2,2Ј,4,4Ј,6Ј(1ЈH,3H,3ЈH,7ЈH,10H )-pen- 1,1؅-Dimethyl-7-bromo-1H-spiro[pyrimido[4,5-b]quinoline-5,5؅-
taones 3ai in good yields (Chart 1).
pyrrolo[2,3-d ]pyrimidine]-2,2؅,4,4؅,6؅(1؅H,3H,3؅H,7؅H,10H )-pentaone
We were not able to establish the exact mechanism for the White powder (90%); mp Ͼ350 °C. IR (KBr) (n 1761, 1721, 1671, 1642. 1H-NMR (300 MHz, DMSO-d ) d formation of spiro[pyrimido[4,5-b]quinoline-5,5Ј-pyrrolo- (3H, s, CH ), 3.39 (3H, s, CH ), 6.99—7.38 (3H, m, H-Ar), 9.28 (1H, s, [2,3-d ]pyrimidine]-pentaones 3 at this time, however, a rea-
NH), 10.77 (1H, s, NH), 10.96 (1H, s, NH), 11.53 (1H, s, NH), 13C-NMR sonable suggestion is offered in Chart 2. Apparently, the re- (75 MHz, DMSO-d ) d (ppm): 26.8, 30.7, 50.5, 82.4, 97.6, 115.0, 118.8, action proceed through the intermediate 4, formed in situ by
123.7, 129.3, 131.6, 135.2, 144.9, 150.4, 151.3, 154.4, 158.1, 161.4, 181.5.
reaction of the isatins 2 with 6-amino-uracils 1, then, the in-
MS, m/z (%): 472 (Mϩ, 4), 430 (18), 192 (43), 149 (75), 43 (100). Anal.
Calcd for C H BrN O : C, 45.68; H, 2.77; N, 17.76%. Found: C, 45.72; H, termediate 4 was converted to intermediate 5 and followed
by cyclization afforded the corresponding spiro[pyrimido- 2,2؅-Bis(methylthio)-3H-spiro[pyrimido[4,5-b]quinoline-5,5؅-pyrrolo-
[4,5-b]quinoline-5,5Ј-pyrrolo[2,3-d]pyrimidine]-pentaones 3
[2,3-d ]pyrimidine]4,4؅,6؅(3؅H,7؅H,10H )-trione (7a)
SCH ), 6.65—7.13 (4H, m, H-Ar), 9.81 (1H, s, NH), 10.99 (1H, s, NH), 12.10 (1H, br s, NH), 12.39 (1H, br s, NH). 13C-NMR (75 MHz, DMSO-d ) d (ppm): 13.1, 13.4, 50.7, 89.9, 106.7, 116.1, 120.6, 122.8, 126.2, 128.6, 137.4, 149.2, 154.1, 158.1, 160.7, 161.6, 165.1, 181.4. MS, m/z (%): 426(Mϩ, 2), 257 (10), 229 (15), 97 (43), 43 (100). Anal. Calcd forC H N O S : C, 50.69; H, 3.31; N, 19.71%. Found: C, 50.74; H, 3.35; N, Due to very low solubility of the products 7bd, we can not report the
2,2؅-Bis(methylthio)-7-nitro-3H-spiro[pyrimido[4,5-b]quinoline-5,5؅-
pyrrolo[2,3-d ]pyrimidine]-4,4؅,6؅(3؅H,7؅H,10H )-trione (7b)
1635. 1H-NMR (300 MHz, DMSO-d ) d (ppm): 2.41 (3H, s, SCH ), 2.54 ϭ8.91 Hz, H-Ar), 7.48 (1H, s, H-Ar), 8.05 ϭ8.88 Hz, H-Ar), 10.61 (1H, s, NH), 11.26 (1H, s, NH), 12.45 (1H, br s, NH), 12.55 (H, br s, NH). MS, m/z (%): 472 (Mϩϩ1, 5), 430 (38),257 (24), 97 (62), 57 (100). Anal. Calcd for C H N O S : C, 45.86; H, 2.78; N, 20.80%. Found: C, 45.91; H, 2.73; N, 20.87%.
7-Bromo-2,2؅-bis(methylthio)-3H-spiro[pyrimido[4,5-b]quinoline-
5,5؅-pyrrolo[2,3-d]pyrimidine]-4,4؅,6؅(3؅H,7؅H,10H)-trione (7c) White
powder (71%); mp Ͼ350 °C. IR (KBr) (n
1706, 1637. 1H-NMR (300 MHz, DMSO-d ) d (ppm): 2.40 (3H, s, SCH ), 2.52 (3H, s, SCH ), 6.70 (1H, d, 3J Synthesis of Spiro[pyrimidoquinoline-5,5Ј-pyrrolopyrimidine]- ϭ8.73 Hz, H-Ar), 9.98 (1H, s, NH), 11.09 (1H, s, NH), pentaones 3
MIC (m g/ml) Values of Products 3 and 7
Escherichia Pseudomonas Bacillus Staphylococcus Escherichia coli ATCC 25922, Pseudomonas aeruginusa Mechanism for the Synthesis of Spiro[pyrimidoquinoline-5,5Ј- ATCC 85327 (Gram-negative bacteria), Bacillus subtilis ATCC 465, Staphylococcus aureus ATCC 25923 (Gram-positive bacteria). All of the compounds were dissolved inDMSO (100 m g/ml) and 25 m l of them were loaded to 6 mmpaper discs. 100 m l of 109 cell/ml suspension of the microor-ganisms were spread on sterile Muller Hilton Agar plates andthe discs were placed on the surface of culture plates. Table 1shows the inhibition zones of compounds around the discs.
The minimum inhibitory concentration (MIC) of the selectedcompounds which showed antibiotic activity in disc diffusiontests, were also determined by microdillution method18) andcompared to a commercial antibiotic (Table 2).
As can be seen from Table 2, good to improved antibacter- ial activity was observed for most of the compounds againstall species of Gram-positive and Gram-negative bacteria usedin the study.
Synthesis of Spiro[pyrimidoquinoline-5,5Ј-pyrrolopyrimidine]- pentaones 7
Conclusions
In summary, we have described an efficient and green syn- Antibacterial Activity of Products 3 and 7
thesis for the preparation of spiro[pyrimido[4,5-b]quinoline- 5,5Ј-pyrrolo[2,3-d]pyrimidine] via a condensation reaction of6-amino-uracils and isatins in aqueous media. These prod- Escherichia Pseudomonas Bacillus Staphylococcus ucts were evaluated in vitro for their antibacterial activities.
Almost most of the compounds exhibited good to excellentantibacterial activity against all the tested strains.
Acknowledgements
We gratefully acknowledge financial support from the Research Council of Shahid Beheshti University.
References and Notes
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volving 6-amino-thiouracils 6a, b and isatins 2 and ob-
Shaw G., “Comprehensive Heterocyclic Chemistry,” Vol. 3, ed. by tained 2,2Ј-bis(methylthio)-2Ј,3Ј-dihydro-3H-spiro[pyrimido- Katritzky A. R., Rees C. W., Pergamon Press, Oxford, 1984, pp. 57— [4,5-b]quinoline-5,5Ј-pyrrolo[2,3-d ]pyrimidine]-4,4Ј,6Ј- (1ЈH,7ЈH,10H)-trione derivatives 7ad in 70—78% yields
Agrawal A., Chauhan P. M. S., Tetrahedron Lett., 46, 1345—1348
Dabiri M., Delbari A. S., Bazgir A., Synlett, 2007, 821—823 (2007).
Finally, compounds 4a, b, c, d, f, g, i and 7a, b, d, f were
Dabiri M., Delbari A. S., Bazgir A., Heterocycles, 71, 543—548
screened for antimicrobial activity using disc diffusion method.17) The microorganisms used in this study were 12) Dabiri M., Arvin-Nezhad H., Khavasi H. R., Bazgir A., Tetrahedron, 63, 1770—1774 (2007).
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Sayyafi M., Seyyedhamzeh M., Khavasi H. R., Bazgir A., Tetrahedron, Prescott L. M., Harley J. P., Klein D. A., “Microbiology,” 5th ed., The 64, 2375—2378 (2008).
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Bazgir A., Seyyedhamzeh M., Yasaei Z., Mirzaei P., Tetrahedron Lett., NCCLS, “Methods for Dilution Antimicrobial Susceptibility Tests for 48, 8790—8794 (2007).
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