Abstract
A series of novel tetracoumarin derivatives (3a-f) were prepared using the reaction of ether functionalized dibenzaldehyde with 4-hydroxycoumarin in the presence of sodium acetate. The structure of compounds was validated by IR, NMR, and CHN analyzes. Antimicrobial (antibacterial and antifungal) activity was studied on the basis of the minimum bactericidal concentration, minimum inhibitory concentration and inhibitory zone diameter. Favorable biological activity was found in compound 3f.
Introduction
Coumarins are a vital category of common oxygen hetero-cyclic composites. The extensive scope of biological activities pertaining to coumarins and their therapeutic impact against various pathologies have received significant attention in developing several drugs [1, 2, 3, 4, 5]. Furthermore, medicinal chemists have been fascinated by the stability and solubility of these compounds which has led to their medicinal applicability [6,7].
Coumarin derivatives consist of numerous biological activities e.g. anticoagulant, anticonvulsant, antihypertensive, anti-inflammatory, anti-adipogenic, neuroprotective, antioxidant and anti-hyperglycemic traits, in addition to extensive cytotoxic impacts towards bacteria, tubercular cells, cancer cells, fungi, viruses [8], phytoalexin, hypnotic, anti-helminthic, insecticidal and HIV protease constraints [9,10]. Several naturally generated derivatives of coumarin are used suitably as flexible building components to stereo selectively construct natural products, namely alkaloids [11,12], macrolides [13], terpenoinds [14, 15, 16] and pheromones [17]. The widespread use of the coumarin groups include designing fluorescent chemosensors [18,19], tagged polymers [20], solar cells [21], cellular imaging tools [22], and extensive utilization for the purpose of synthesizing laser dyes [22,23].
The flexible medical and biological biscoumarins activities, bridged substituted dimers of 4-hydroxycoumarin and its derivatives, have attracted significant interest in the past few years leading to the simplicity of aromatic ring fine tuning via various substituents resulting in numerous chemical analogues with biological activities e.g. anticancer, anti-coagulants, antibacterial, anti-inflammatory, and antioxidant behavior [24, 25, 26, 27, 28, 29]. A number of biscoumarins have also been determined as urease inhibitors [30], as well as in the prevention and treatment of thrombosis [31].
Moreover, biscoumarins–Lanthanum III composites are reported to display efficient cytotoxic behavior [32]. Warfarin sodium, one such derivative, is utilized in treating numerous cancers and enhances rates of survival within patients suffering from different types of cancer [33]. Dicoumaral-taxol composites have proven to exhibit synergetic hindrance of embryos and sea urchin cell division [34,35]. By determining the significance of composites, scholars are interested in synthesizing derivatives of biscoumarin. It is believed that as the number of coumarins increases in a compound, the biological activity also increases. However, there are few reports with four coumarin skeletons in their molecular structures [36, 37, 38, 39, 40].
The biological importance of coumarin derivatives led to the belief that combining four coumarin skeletons into an individual composite by synthetic methodology whilst preparing and characterizing relevant derivatives can entail biological behavior. For this paper we design and document new tetra 4-hydroxycoumarin derivatives’ synthesis which contain ether groups.
Result and discussion
Upon our previous works using ethylene glycol-based dialdehyde derivatives [41,42], efficient synthesis of tetracoumarins was achieved by condensation of ethylene glycol-based aromatic dialdehydes and 4-hydroxycoumarin in the presence of sodium acetate in methanol (Scheme 1).
The results related to the reaction of different ethylene glycol-based dialdehyde with 4-hydroxycoumarin were summarized in Table 1.
As is clear from Table 1, the reaction of ethylene glycol‑based salicylaldehyde (1b-f) with 4-hydroxycoumarin (Table 1, entries 2-6) to give tetra 4-hydroxycoumarins (3b-f) were shown in favorable yield.
The reaction between ethylene glycol‑based naphthaldehyde, with 4-hydroxycoumarin (Table 1, entries 1) affords tetra 4-hydroxycoumarins (3a) in moderate to good yields. Nevertheless the replacement (electron-donating and -withdrawing) of the aromatic dialdehydes, the products were obtained in favorable yields.
Under the same conditions, when dialdehyde 1d-f were allowed to react with 4- hydroxycoumarin. Surprisingly, when the products were isolated, 1H NMR data did not show the formation of tetra coumarins in enolic form (Table 1, entries 4-6). While hydroxyl groups are expected to be apparent in the 1H NMR spectrum of these compounds, the 1H NMR spectra showed xanthene derivatives were obtained, formed from the cyclization of biscoumarins. The 1H NMR spectrum of 3b indicated the present protons of at δ: 4.06 (m), 4.27 (m), 5.64 (s) and 12.60-12.61 (m) belonging to the protons of O―CH2 (ethylene glycol), bridge CH and OH (enol form), respectively. Also, the structure of compound 3b was further confirmed by 13C NMR spectrum and the peaks were observed at δ: 32.9 and 65.8, 67.3 ppm for the O―CH2 and bridged CH accordingly. The 1H NMR of 3f showed a singlet and two triplet signals at δ: 3.00, 3.31 and 3.83 ppm respectively for the three methylene protons along with a singlet signal at δ: 6.19 ppm for the CH-aliphatic hydrogen. 13C NMR spectrum of this product showed three signals at δ: 67.8, 69.1, 69.9 for the methylene carbons and a signal at 33.6 ppm for the CH-aliphatic carbon as well as the carbonyl carbon at 164.9 ppm. In general, all the structures were analysed by FT-IR, 1H NMR and 13C NMR. The spectral data supported the structures of the compounds 3a-f.
On the basis of the reported synthesis of biscoumarin in the literature [43,44], our proposed mechanism (Scheme 2) shows sodium acetate as the base catalyst for the improved yield of the Knoevenagel condensation reaction of 4-hydroxycomarin 2 with diaromatic aldehyde 1 to produce 3 by elimination of a water molecule. Eventually, the second molecule of 4-hydroxycoumarin 2 will be added to the double bond of intermediate 5 and the desired product 3 is produced that could then cyclise to product 6.
Synthesis of tetracoumarin derivatives containing ether groups.
Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) determination
The microorganism’s inoculums were assembled from 12 hour broth cultures whilst suspensions were modified to 0.5 McFarland standard turbidity. The heterocyclic compounds’ MIC towards microbial strains was ascertained on the basis of micro well dilution technique. The minimum concentration hindrance growth was considered as MIC for the compounds [45]. The test bacteria MIC was ascertained via triple assays. For the purpose of validating MICs and establishing MBCs, 10 μL of broth was extracted from every well and subjected to inoculation using the Muller-Hinton agar i.e. MHA plates. These plates were subjected to incubation for a period of 24 hours under 37°C temperature whilst being observed to determine the existence or absence of growth. The least concentration inhibiting evident organism growth was considered as MBC [46]. The processes were replicated three times.
Bisarylidene tetracoumarin derivatives containing ether groups obtained by the condensation of diaromatic aldehydes with 4-hydroxycoumarin.
| Entry | Dialdehyde 1 | Product 3 | Yield (%) |
|---|---|---|---|
 | |||
Proposed mechanism for the synthesis of tetracoumarins.
Antibacterial possibilities of the compounds were experiments in terms of bacterial strains and Candida albicans. Table 2 presents the findings. Confirmation of the antibacterial behavior data determined that some of these compounds had good bactericidal properties against indicator strains. It is shown that 3c did not have any antimicrobial activity against A. baumannii. Streptomyces fradiae exhibited resistance to 3a compound. According to Table 2, 3f showed high antifungal activity and furthermore the MIC and MFC are the same as Terbinafine. All the synthesized compounds had antibacterial activity but some were bacteria were resistant. For example, A. baumannii and S. fradiae were resistant to 3c and 3a compounds respectively. Resistance to chemical agents can have different causes. The inability of the chemical to penetrate the bacterial cell wall either due to hydrophobicity, having pumps actively efflux out of the cell or generally excreting the substance out of the cell can be reasons for ineffectiveness. These mechanisms are important in medicine as it can contribute to bacterial antimicrobial agents resistance.
Biological activity of 4-hydroxycoumarin in Table 2 show that wherever synthesized tetracomarins do not have biological properties, 4-hydroxycoumarin is not biological but the amount of biological activity of these products relative to 4-hydroxycoumarin has no meaningful trend.
In conclusion, we have developed a precipitation response of ethylene glycol-based dialdehyde with 4-hydroxy-coumarin. This synthesis occurs efficiently in the presence of NaOAc, without an additional assisting catalyst in methanol to achieve tetracoumarine derivatives in good yield. Additionally, these products showed biological activity.
Experimental
Materials and instruments
The implemented substances were commercially available and purified. Melting points were ascertained using an
Antibacterial activity of the synthesized compounds against some microorganisms.
| Microorganism | Products | 4-hydroxy coumarin | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| 3a | 3b | 3c | 3d | 3e | 3f | a / b | ||||
| Gram- negative | P. aeruginosa | IZD | 12.07 | 9.82 | 11.48 | 9.74 | 12.11 | 13.94 | 9.37 | 24.65 |
| MIC | 256 | 1024 | 512 | 512 | 256 | 64 | 2048 | 0.5 | ||
| MBC | 512 | 2048 | 1024 | 1024 | 256 | 128 | 4096 | 0.5 | ||
| A. baumannii | IZD | 11.96 | 0 | 0 | 0 | 12.44 | 12.76 | 0 | 17.76 | |
| MIC | 512 | 0 | 0 | 0 | 128 | 65 | 0 | 32 | ||
| MBC | 512 | 0 | 0 | 0 | 256 | 64 | 0 | 32 | ||
| S. dysenteriae | IZD | 13.45 | 0 | 12.17 | 8.67 | 13.52 | 14.72 | 0 | 20.54 | |
| MIC | 512 | 0 | 256 | 1024 | 64 | 64 | 0 | 0.126 | ||
| MBC | 1024 | 0 | 512 | 2048 | 128 | 128 | 0 | 0. 254 | ||
| Gram- positive | E. faecalis | IZD | 14.64 | 10.79 | 13.42 | 11.31 | 13.67 | 14.76 | 10.62 | 22.01 |
| MIC | 128 | 512 | 128 | 512 | 64 | 64 | 512 | 1 | ||
| MBC | 256 | 1024 | 128 | 512 | 128 | 128 | 1024 | 2 | ||
| S. fradiae | IZD | 0 | 0 | 10.94 | 0 | 13.71 | 9.85 | 0 | 20.96 | |
| MIC | 0 | 0 | 512 | 0 | 128 | 128 | 0 | 16 | ||
| MBC | 0 | 0 | 512 | 0 | 256 | 256 | 0 | 32 | ||
| S. aureus | IZD | 8.52 | 12.56 | 13.47 | 13.47 | 10.68 | 9.92 | 11.98 | 21.27 | |
| MIC | 256 | 512 | 64 | 256 | 128 | 64 | 1024 | 2 | ||
| MBC | 512 | 1024 | 128 | 512 | 128 | 128 | 1024 | 2 | ||
| fungi | C. albicans | IZD | 8.41 | 8.47 | 8.43 | 8.43 | 8.12 | 8.26 | 8.14 | 14.26 |
| MIC | 1024 | 2048 | 512 | 1024 | 512 | 256 | 2048 | 256 | ||
| MFC | 2048 | 4096 | 1024 | 2048 | 512 | 512 | 4096 | 512 | ||
a: Gentamicin for bacteria; b: Terbinafine for fungi
IZD Values reported as mm; MIC, MBC and MFC Values reported as μg/mL
Electrothermal 9100 device and subjected to being uncorrected. An ABB FT-IR FTLA 2000 spectrometer was used to acquire IR spectra. 1H NMR and 13C NMR spectra were executed using a Bruker spectrometer modified at 400 MHz for 1H NMR and 100 MHz for 13C NMR. CDCl3 and DMSO-d6 were implemented as solvents. C, H, N and S elemental evaluations were conducted using a Heraeus CHN-S-O-Rapid analyzer.
General process for the preparation of ditosylates
40 mmol of 4-tolylsulfonyl chloride, 40 mL of DCM and 21 mmol of associated ethylene glycol was stirred for 15 min at a temperature of 0–5 °C. Subsequently, 46 mmol of triethyl amine was added in drop wise manner. TLC was used to monitor the progress of the reaction. The remaining tosylchloride was extracted by the addition of triethyl amine in powder form (11.5 mmol) and it was intensely ground for a period of 10 minutes. Upon completion, the resulting solid product was filtered and water was used to stir for 10 minutes. The resulting crude tosylate was adequately refined.
Common process to synthesize dialdehyde derivatives (1a-f)
4 mmol of polyethylene glycol ditosylate, 8 mmol of sali-cylaldehyde derivatives, and 20 mmol of K2CO3 were included in 40 mL of acetonitrile solvent. The concoction was refluxed for 24 h and monitored by TLC until total conversion of the starting materials. The mixture was initially filtered prior to the filtrate being distilled then diluted with acetonitrile (50 mL) and washed using NaOH 10 % (3 × 20 mL). The resulting product was concentrated via solvent evaporation with the use of a rotary evaporator, which did not require any extensive refinement.
Common process to synthesize tetracoumarins (3a-f)
Finally, in order to synthesize tetra tetracoumarin containing ethylene ether spacers; 1 mmol of diaromatic aldehyde containing ether groups (1a-f), 4 mmol of 4-hydroxycoumarin and 1 mmol of acetate sodium in methanol (10 mL) was mixed and refluxed for 16-20 h at 80 ⍛C. Upon completion of reaction (supervised by TLC) and after cooling, the solid substances were extracted from the solution. After this time, the reaction concoction was subjected to cooling, and the solid product was collected and recrystallized from EtOH and MeOH to afford the corresponding tetra tetracoumarins.
3,3 ´ ,3 ´´ ,3 ´´ ´- ( ( ( e thane -1 , 2-diylbi s (oxy) ) bis(naphthalene-2,1-diyl))bis(methanetriyl))tetrakis (4-hydroxy-2H-chromen-2-one) (3a): Yield: 72%. M.p. = 249-251 °C. IR (KBr, cm-1): 3448 (O-H), 1715 (C=O) and 1663 (C=C). 1H NMR (400 MHz, DMSO): δ = 4.79-4.82 (br s, 4H, 2CH2-O), 6.05 (br s, 2H, 2CH), 6.93-7.03 (m, 4H, 2CH, H-Ar), 7.27-7.47 (m, 10H, H-Ar), 7.65-7.83 (m, 10H, H-Ar), 8.14 (br s, 2H, H-Ar), 8.75-8.77 (m, 2H, H-Ar), 10.74-10.76 (br s, 4H, 4OH). 13C NMR (100 MHz, DMSO): δ = 54.75, 103.01, 115.63, 116.60, 117.27, 121.81, 123.00, 124.53, 125.56, 126.82, 127.66, 128.43, 129.43, 131.25, 131.96, 147.92, 152.17, 154.05, 160.89, 161.54, 161.99. Anal. Calc. for C60H36O16 (982.94): C, 73.32; H, 3.90 %. Found: C, 73.38; H, 4.14 %.
3,3´,3´´,3´´´-((((oxybis(ethane-2,1-diyl))bis(oxy))bis(3-bromo-6,1-phenylene))bis(methane triyl))tetrakis (4-hydroxy-2H-chromen-2-one) (3b): Yield: 77%. M.p. = 375 °C decomposed. IR (KBr, cm-1): 3448 (O-H), 1710 (C=O), 1656 (C=C). 1H NMR (400 MHz, DMSO-d6): δ = 4.06 (br s, 4H, 2CH2-O), 4.27 (br s, 4H, 2CH2-O), 5.64 (s, 2H, 2CH), 6.38 (s, 2H, H-Ar), 6.70 (d, J = 8.0 Hz, 2H, H-Ar), 7.20-7.25 (m, 8H, H-Ar), 7.47-7.55 (m, 8H, H-Ar), 7.82-7.85 (m, 4H, H-Ar), 12.60-12.61 (br s, 4H, 4OH). 13C NMR (100 MHz, DMSO): δ = 32.89, 65.88, 67.35, 111.51, 112.96, 116.33, 120.47, 123.16, 127.26, 128.35, 128.45, 132.67, 136.00, 153.47, 156.44, 160.56, 161.89, 163.72. Anal. Calc. for C54H36Br2O15 (1084.66): C, 59.80; H, 3.35 %. Found: C, 59.42; H, 3.73 %.
3,3´,3´´,3´´´-((((oxybis(ethane-2,1-diyl))bis(oxy)) bis(2,1-phenylene))bis(methanetriyl)) tetrakis (4-hydroxy-2H-chromen-2-one) (3c): Yield: 79%. M.p. = 233-235 °C. IR (KBr, cm-1): 3432 (O-H), 1656 (C=O), 1610 (C=C). 1H NMR (400 MHz, DMSO-d6): δ = 4.02 (br s, 4H, 2CH2-O), 4.25-4.26 (m, 4H, 2CH2-O), 5.62 (s, 2H, 2CH), 6.99-7.24 (m, 16H, H-Ar), 7.47-7.51 (m, 4H, H-Ar), 7.80-7.83 (m, 4H, H-Ar), 12.57 (br s, 2H, 4OH). 13C NMR (100 MHz, DMSO): δ = 32.90, 65.06, 67.33, 90.97, 104.12, 111.48, 115.72, 116.31, 118.47, 120.27, 123.46, 123.82, 126.96, 131.36, 132.66, 152.07, 155.76, 164.34, 165.34. Anal. Calc. for C54H38O15 (926.87): C, 69.98; H, 4.13 %. Found: C, 69.54; H, 4.58 %.
7,7’-((ethane-1,2-diylbis(oxy))bis(3-bromo-6,1-phenylene))bis(6H-pyrano[3,2-c:5,6-c’]dichromene-6,8(7H)-dione) (3d): Yield: 74%. M.p. = 370 °C decomposed. IR (KBr, cm-1): 1662 (C=O), 1611 (C=C). 1H NMR (400 MHz, DMSO-d6): δ = 3.64 (s, 4H, 2CH2-O), 6.15 (s, 2H, CH), 6.25 (d, J = 8.8 Hz, 2H, H-Ar), 7.04-7.06 (m, 4H, H-Ar), 7.20-7.27 (m, 8H, H-Ar), 7.49 (m, 4H, H-Ar), 7.79-7.81 (m, 4H, H-Ar). 13C NMR (100 MHz, DMSO-d6): δ = 33.37, 57.90, 110.71, 115.93, 117.15, 120.29, 123.45, 124.55, 126.28, 129.48, 131.34, 131.82, 152.78, 164.38, 167.83. Anal. Calc. for C52H32Br2O14 (1001.99): C, 62.17; H, 2.81 %. Found: C, 61.32; H, 3.13 %.
7,7’-((((ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl)) bis(oxy))bis(2,1-phenylene))bis(6H-pyrano[3,2-c:5,6-c’] dichromene-6,8(7H)-dione) (3e): Yield: 82%. M.p. = 236-239 °C. IR (KBr, cm-1): 1655 (C=O), 1609 (C=C). 1H NMR (400 MHz, DMSO): δ = 3.24 (t, J = 4.6 Hz, 4H, 2CH2-O), 3.84 (t, J = 4.6 Hz, 4H, 2CH2-O), 4.20 (t, J = 4.6 Hz, 4H, 2CH2- O), 6.27 (s, 2H, CH), 6.84-6.90 (m, 4H, H-Ar), 7.12 (d, J = 7.6 Hz, 2H, H-Ar), 7.18 (t, J = 7.8 Hz, 2H, H-Ar), 7.33-7.40 (m, 8H, H-Ar), 7.60 (td, J = 7.2 and 1.2 Hz, 4H, H-Ar), 7.92 (dd, J= 6.8 and 1.2 Hz, 4H, H-Ar) (s, 2H, 2OH). 13C NMR (100 MHz, DMSO): δ = 32.99, 66.94, 68.78, 69.30, 104.91, 111.48, 116.05, 116.90, 120.04, 123.51, 123.94, 127.29, 127.53, 127.92, 131.95, 151.88, 156.53, 162.90, 164.21. Anal. Calc. for C56H42O16 (934.23): C, 71.94; H, 4.10 %. Found: C, 71.55; H, 4.67 %.
7,7’-((((ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl)) bis(oxy))bis(3-bromo-6,1-phenylene))bis(6H-pyrano[3,2-c:5,6-c’]dichromene-6,8(7H)-dione) (3f): Yield: 89%. M.p. = 265-267 °C. IR (KBr, cm-1), 1651 (C=O), 1607 (C=C). 1H NMR (400 MHz, DMSO): δ = 3.0 (s, 4H, 2CH2-O), 3.30 (t, J = 4.8 Hz, 4H, 2CH2-O), 3.83 (t, J = 4.8 Hz, 4H, 2CH2-O), 6.19 (s, 2H, CH), 6.83 (d, J = 8.8 Hz, 2H, H-Ar), 7.19 (d, J = 2.0 Hz, 2H, H-Ar), 7.26-7.35 (m, 8H, h-Ar), 7.56 (td, J = 7.8, 1.2 Hz, 4H, H-Ar), 7.99 (dd, J = 7.8, 1.2 Hz, 4H, H-Ar). 13C NMR (100 MHz, DMSO): δ = 33.64, 67.86, 69.14, 69.90, 104.62, 112.03, 114.11, 116.35, 118.48, 124.00, 124.17, 129.99, 131.14, 132.00, 132.48, 152.59, 156.31, 164.27, 164.98. Anal. Calc. for C56H36Br2O14 (1090.05): C, 61.55; H, 3.32 %. Found: C, 60.89; H, 3.50 %.
Antimicrobial activity
The antibacterial activity of the heterocyclic compounds (3a-f) against Gram-negative bacterial strains (Pseudomonas aeruginosa (PTCC 1310), Acinetobacter baumannii (PTCC 1855), Shigella dysenteriae (PTCC 1188) and Grampositive bacterial strains (Enterococcus faecalis (PTCC 1778), Streptomyces fradiae (PTCC 1121), Staphylococcus aureus (PTCC 1189) and fungi (Candida albicans (PTCC 5027)) was examined by the disc diffusion technique by utilizing 100 μL of suspension possessing 106 CFU/mL of bacteria, spread on Muller-Hinton agar (MHA) medium [40, 41]. These microorganisms were prepared from the Persian Type Culture Collection (PTCC), Tehran, Iran. Then sterile filter paper discs (6 mm in diameter) were saturated with 20480 μg/mL of the compounds and were positioned on to Muller-Hinton agar. The plates were incubated for 18-24 h at 37°C. After this period, the diameter of the clear inhibition zone (IZD) around the disc was derived and denoted in millimeters as its antibacterial behavior. All the antibiogram assays were replicated a minimum of three times. The findings were documented as the average of three autonomous tests. Control tests were carried out under similar condition by means of standard reference antibiotics (Gentamicin for bacteria and Terbinafine for fungi).
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