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Synthesis of Pyranobenzopyran Derivatives as a Potent Antibacterial Agent
Synthesis of Pyranobenzopyran Derivatives as a Potent Antibacterial Agent
Journal of the Korean Chemical Society. 2008. Dec, 52(6): 663-667
Copyright © 2008, The Korean Chemical Society
  • Received : May 19, 2008
  • Published : December 20, 2008
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V. V. Mulwad
A. C. Chaskar
B. P. Langi

Abstract
3-Formyl-4-hydroxy-2 H (1)-benzopyran-2-one 1a-d on reaction with diethyl malonate in the presence of piperidine give ethyl-2 H ,5 H -2,5-dioxopyrano[3,2- c ] benzopyran-3-oate. 2a-d . Michael addition of 2a-d with ethyl aceto acetate gives ethyl 2,4-dihydroxy-5 H , 12 H - 5,12-dioxo [2] benzo pyrano [4,3- c ] [1] benzopyran- 1-oate ( 3a-d ). 3a-d on Pechmann condensation with ethyl aceto acetate gives 2-acetyl-1,6-dihydroxy-3 H ,7 H ,14 H -3,7,14-trioxo-pyrano[2 / ,3 / ,5,6] [2] benzo pyrano [3,2- c ] benzopyran 4a-d . Michael addition followed by cyclisation of acetyl acetone with ethyl-2 H ,5 H -2,5-dioxo-pyrano[3,2- c ] benzopyran-3-oate 2 a-d in the presence of sodium methoxide in boiling methanol afforded1-acetyl-2-methyl-4 H ,5 H ,12 H ,4,5,12-trioxo-dipyrano[3,4-d;3 / ,2 / - c ] benzopyran. 5a-d .
Keywords
INTRODUCTION
Pyranobenzopyrans and its derivatives are reported to possess various biological activities 1 - 10 such as antibacterial, antifungal, CNS depressant, antiviral, ulcer inhibitor etc. Suksdorfin and DCK which contain pyranobenzopyran moiety are known to be potent anti -HIV agents. 3 Similarly suksdorfin inhibited HIV-1 replication in H 9 lymphocytes with an in vitro EC 50 value of 1.3 μm and a therapeutic index of value of ˃40, while DCK showed extremely potent inhibitory activity against HIV-1.Pyranobenzopyrans are also gaining importance in laser dyes. 11 The biological importance of pyranobenzopyran impressed us to synthesize new heterocyclic compounds which contain pyranobenzopyran moieties. All the synthesized compounds were screened for their antibacterial activity.
RESULTS AND DISCUSSION
In order to synthesize ethyl-2 H ,5 H -2,5-dioxopyrano[3,2- c ] benzopyran-3-oate. 2a-d , the Knoevengeal condensation of 3-formyl-4-hydroxy-2 H (1)-benzopyran-2-one 12 1a-d with diethyl malonate was carried out in the presence of piperidine to afford the above compound in quantitative yield. With an interest to carry out Michael addition, ethyl-2 H ,5 H -2,5-dioxopyrano[3,2- c ] benzopyran-3-oate 2a-d and ethyl aceto acetate were heated in presence of sodium methoxide to give ethyl 2,4-dihydroxy-5 H , 12 H -5,12-dioxo [2] benzo pyrano [4,3- c ] [1] benzopyran-1-oate 3a-d . Solution of 3a-d in NaOH gives coloration with FeCl 3 . 3a-d on Pechmann condensation with ethyl aceto acetate gives 2-acetyl-1,6-dihydroxy-3 H ,7 H ,14 H -3,7,14-trioxo-pyrano[2 / ,3 / ,5,6] [2] benzo pyrano [3,2- c ] benzopyran 4a-d . Michael addition followed by cyclisation of acetyl acetone with ethyl-2 H ,5 H -2,5-dioxo-pyrano[3,2- c ] benzopyran-3-oate 2a-d in the presence of sodium methoxide in boiling absolute methanol afforded 1-acetyl-2-methyl-4 H ,5 H ,12 H ,4,5,12-trioxo-dipyrano [3,4-d;3 / ,2 / - c ] benzopyran 5a-d . The structures of the compounds 2a-d to 5a-d were confirmed on the basis of spectral and analytical data. These synthetic reactions are summarized in 1 .
Characterization data of compounds2a-d,3a-d,4a-d,5a-d
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Characterization data of compounds 2a-d, 3a-d, 4a-d, 5a-d
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All the above synthesized compounds were screened in vitro for their antimicrobial activity against variety of bacterial strains. Gram negative strains of bacteria used were S. typhi and E. coli while gram positive bacterial strain used was S. aureus . The minimum inhibition concentration (MIC) was determined using Tube Dilution technique according to standard procedure 13 ( 2 ). The standard drugs used for comparison were ciprofloxacin, cloxacillin and gentamycin. By visualizing the antimicrobial data it could be observed that many of the compounds possess significant antibacterial activity.
Antibacterial activity of compounds2a-d,3a-d,4a-d,5a-d
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=Not active up to 150μg/mL. Std: Ciprofloxacin (5 μg/mL); Cloxacillin (10μg/mL); Gentamycin (5 μg/mL).
CONCLUSION
The antibacterial activity of the compounds 2-5(a-d) was compared and it was found that amongst them compound 3-5(a-d) showed significant activity against S.aureus , S. typhi and E. coli . due to fused pyranonebenzopyranone ring system. Compound 3b and 3d with methyl substitution at C-8 and C-10 showed significant antibacterial activities against S. aureus . Compounds 4a-4d showed comparable antibacterial activity against S. aureus and E. coli . Compound 4d having methyl group at C-12 position showed very significant activity against E. coli . The compound 5d having methyl group at C-10 position showed higher activity against S. aureus and S. typhi .
EXPERIMENTAL
Melting points were taken in open capillaries and are uncorrected. The IR spectra were recorded on a Perkin-Elmer 257 spectrometer using KBr discs. 1 H NMR and 13 C NMR spectras in DMSO-d 6 were recorded on VXR-300 MHz using TMS as internal standard and mass spectra were recorded on Shimadzu GC-MS. The homogeneity of the compounds was described by TLC on silica gel plates. The spots are developed in iodine chamber.
- Ethyl-2H, 5H-2, 5-dioxo-pyrano [3, 2-c] benzopyran-3-oate 2a-d:
A mixture of 3-formyl-4-hydroxy-2 H (1)-benzopyran-2-one 1a-d (0.01 mol), diethyl malonate (0.01 mole) and piperidine (0.5 mL) was heated on water bath for 2 hr. The mixture was left at room temperature for 3 hr. and then it was poured into ice-cold water and acidified to get solid. The solid was filtered, washed with sodium bicarbonate and finally with water, dried and recrystallized from ethanol to get ethyl-2 H ,5 H -2,5-dioxopyrano[3,2- c ] benzopyran-3-oate. 2a-d .
- Ethyl 2, 4-dihydroxy-5H, 12H- 5, 12-dioxo [2] benzo pyrano [4, 3-c] [1] benzopyran- 1-oate 3a-d:
A mixture of ethyl-2 H , 5 H -2, 5-dioxopyrano [3, 2- c ] benzopyran-3-oate 2a-d (0.01 mol), ethyl aceto acetate (0.01 mol) and sodium methoxide (0.01 mol) was heated at 170 ℃ for 8 hr. The reaction mixture was cooled, triturated with cold hydrochloric acid. The solid obtained was filtered, washed with water, dried and recrystallized from methanol to get ethyl 2,4-dihydroxy-5 H ,12 H -5,12-dioxo[2] benzo pyrano [4,3- c ] [1] benzopyran-1-oate 3a-d .
- 2-Acetyl-1,6-dihydroxy-3H, 7H, 14H, 3, 7,14-trioxo-pyrano [2/,3/, 5,6] [2] benzo pyrano [3,2-c] benzopyran. 4 a-d.
Ethyl 2, 4-dihydroxy-5 H , 12 H , 5, 12-dioxo [2] benzo pyrano [4,3- c ] [1] benzopyran 1-oate 3a-d (0.01 mol) and ethyl aceto acetate (0.01 mol) were taken in methanol (10 mL), to it piperidine (1.5 mL) was added and was refluxed for 8hr. The methanol was recovered in rotaevaporator. The reaction mixture was then decomposed into crushed ice and neutralized with dilute HCl to afforded solid product. The solid obtained was filtered, washed with water, dried and recrystallized from methanol to get 2-acetyl- 1,6-dihydroxy-3 H ,7 H ,14 H ,3,7,14-trioxo-pyrano[2 / ,3 / ,5,6] [2] benzo pyrano [3,2- c ] benzopyran 4a-d .
- 1-Acetyl-2-methyl-4H,5H,12H,4,5,12-trioxo-dipyrano [3,4-d;3/,2/-c]benzopyran 5a-d.
To a solution of sodium methoxide (0.01 mol) in absolute methanol (10 mL), acetyl acetone (0.01 mol) was added and the solution was refluxed for 20 min. then ethyl-2 H ,5 H -2,5-dioxopyrano[3,2- c ] benzopyran-3-oate 2a-d (0.01 mol) was added and the reaction mixture was refluxed for 5 hr. The methanol was recovered in rota evaporator. The reaction mixture was then decomposed into crushed ice and neutralized with dilute HCl to get the solid product. The solid obtained was filtered, washed with water, dried and recrystallized from ethanol to get 1-acetyl-2-methyl-4 H ,5 H ,12 H ,4,5,12-trioxo-dipyrano[3,4-d;3 / ,2 / - c ] benzopyran. 5a-d .
2b. IR (KBr): 1719, 1614, 1527, 1429, 1375, 1297, 1209, 1043, 814, etc cm -1 .
1 H NMR DMSO-d 6 (δ-ppm): 1.25 (t, 3H, CH3), 2.19 (s, 3H, CH3), 3.9 (q, 2H, -OCH2), 7.1 (s, 1H, C 4 -H), 7.3 (s, 1H, C10-H), 7.59 (d, 1H, C8-H, J = 7.0 Hz), 7.8 (d, 1H, C7-H, J = 7.0 Hz).
Mass m/z (relative intensity, %): 300(26) (M + ), 272(10), 244(13), 228(7), 200(9), 175(23), 172(17), 149(23), 144(19), 116(37), 91(100), 77(26) etc.
3b. IR (KBr): 3420, 2924, 2363, 1731, 1659, 1620, 1447, 1384, 1315, 1230, 1175, 1057, 906, 872, 815, 789, etc. cm -1 .
1 H NMR DMSO-d 6 (δ-ppm): 1.22 (t, 3H, CH3), 2.1 (s, 3H, CH 3 ), 4.25 (q, 2H, -OCH2), 5.6 (s, 1H, -OH, D 2 O exchangeable), 6.7 (s, 1H, C 3 -H), 7.05 (s, 1H, C 7 -H), 7.8 (d, 1H, C 9 -H, J = 7.5 Hz), 8.05 (d, 1H, C 10 -H, J = 7.5 Hz), 9.5 (s, 1H, -OH, D 2 O exchangeable).
Mass m/z (relative intensity, %): 382(24) (M + ) 354(10), 342(9),336(6), 326(14), 308(12), 298(7), 280(9), 252(8), 224(11), 209(23), 158(19), 150(28), 134(6), 106(34), 91(66), 84(47), 83(39), 77(100), 68(51), 57(55) etc.
4b. IR (KBr): 3433, 2944, 1723, 1621, 1577, 1494, 1426,1374, 1296, 1209, 1118, 1045, 817, etc. cm -1
1 H NMR CDCl 3 (δ-ppm): 2.0 (s, 3H, CH3), 2.1 (s, 3H, CH 3 ), 5.8 (s, 1H, -OH, D 2 O exchangeable), 6.8 (s, 1H, C 5 -H), 7.1 (s, 1H, C 9 -H), 7.4 (d, 1H, C 11 -H, J = 7.0 Hz), 8.1 (d, 1H, C 12 -H, J = 7.0 Hz), 9.8 (s, 1H, -OH, D 2 O exchangeable).
Mass m/z (relative intensity, %): 420 (31) (M + ) 404(14), 378(10), 350(17), 336(13), 322(10), 308(6), 294(18), 280(14), 252(12),237(20), 200(15), 174(35), 134(64), 106(100), 91(62), 77(79) etc.
5b. IR (KBr): 2925, 2357, 1731, 1658, 1620, 1448, 1385, 1315, 1228, 1176, 1057, 788 etc. cm -1 .
1 H NMR DMSO-d 6 (δ-ppm): 2.05 (s, 3H, CH 3 ), 2.15 (s, 6H, 2 CH 3 ), 6.9 (s, 1H, C 7 -H), 7.39 (d, 1H, C 9 -H, J = 7.5 Hz), 7.9 (d, 1H, C 10 -H, J = 7.5 Hz).
Mass m/z (relative intensity, %): 352(19) (M+), 338(8), 310(10), 299(5), 282(6), 254(6), 249(10), 226(13), 211(23), 196(27), 178(20), 149(30), 137(60), 121(23), 105(41), 91(100), 77(67), 51(53), etc.
Acknowledgements
Authors are grateful to National Facility for High Field NMR, TIFR Mumbai. Authors are also thankful to Padmaja Occupational Hygiene and Diagnostic Centre, Navi Mumbai for biological testing. Authors are thankful to Mr. V Chiplunkar, UICT Mumbai for elemental analysis.
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