Abstract
The present work describes the synthesis of a series of substituted 3-(5-phenyl-1,3,4-oxadiazol-2-yl)-2H-chromen-2-ones 7(a–j) using substituted aldehydes with analogues of hydrazine hydrates by grinding technique in the presence of Iodine which helps in the cyclization process. The structures of the synthesized compounds were elucidated by spectroscopic techniques such as IR, 1H NMR, 13C NMR, and LCMS. The comparative antioxidant property (using DPPH and hydroxyl radical scavenging) has been studied with the synthesized compounds 7(a-j) and the standards. Compounds 7d and 7i show the prominent radical scavenging activity.
Graphic abstract
Synopsis: Series of ten new coumarin-oxadiazole hybrids synthesized in three steps starting from salicylaldehyde and diethylmalonate. All new compounds were spectroscopically characterized. The results of radical scavenging activities show that, two compounds of the series 7d and 7i displayed potent DPPH and hydroxyl radical activity comparable to the standards employed, and therefore acts as antioxidant leads.
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1 Introduction
Heterocyclic chemistry is a predominant branch of the synthetic organic chemistry field with years of history and prospects. The heterocycles play a vital and primordial role in the synthesis of drugs for the future generation.1 In the last few decades, the synthesis of five-membered heterocyclic compounds due to their extensive array of biological activities have acknowledged extensive interest. Among the heterocycles, coumarin and 1,3,4-oxadiazoles attained more consideration in recent years because of their natural occurrence and immense biological activities. The 1,3,4-oxadiazoles are five-member heterocycles, generally prepared by oxidative cyclization of N-acyl hydrazones, and by the reaction of aromatic hydrazides with aromatic aldehydes through the dehydrative cyclization of 1,2-diacylhydrazines.1 The 1,3,4-oxadiazoles were efficiently prepared by the reaction of carboxylic acids with benzoic acid hydrazides using melamine-formaldehyde resin supported sulfuric acid as dehydration reagent under microwave-accelerated solvent-free conditions.2 The oxidative cyclization can be achieved with the utility of different oxidizing agents, which includes lead tetraacetate,3 lead dioxide,4 potassium permanganate,5 chloramine-T,6 HgO-I2,7 ferric chloride,8 and iodobenzenediacetate.9
Amongst the heterocycles, 1,3,4-oxadiazoles are an interesting class of compounds with π-conjugated electrons, and also due to their structural skeleton, which have been widely used in materials science, particularly organic light-emitting diodes (OLEDs), as electron conducting and hole blocking materials. Due to their electron-deficient and electron transporting abilities, they are utilized in energy-efficient, full color, flat-panel displays.10,11,12,13,14,15,16 The oxadiazoles are often occurring as motifs in drug-like molecules.17,18 The oxadiazoles have been extensively used as scaffolds in drug synthesis, particularly in the production of fasiplon, raltegravir, oxolamine, butalamine, and pleconaril. These have vital applications in medicinal chemistry due to their various biological activities including antibacterial,19,20,21 antifungal,22 analgesic and anti-inflammatory,23 anticonvulsant,24 hypoglycemic25 and anticancer, etc.26
The coumarin derivatives have been synthesized for decades with variant protocols, significantly through synthetic routes like Knoevenagel, Pechmann, Perkin, and Wittig reaction, etc. The coumarins endowed with various pharmacological properties such as antioxidant,27 antitubercular,28 antimalarial,29 antibacterial,30,31 antitumor,32 anti-inflammatory,33 antivirus,34 anti-Alzheimer,35,36 and antifungal,37,38 etc. Indeed, the coumarin-heterocycle hybrids possess enhanced biological potencies comparable with their parent moieties. In this context, the coumarin-1,3,4-oxadiazole hybrids were efficiently synthesized by the condensation reaction of coumarin-3-carboxylic acid with benzoic acid hydrazides using poly(ethylene glycol) supported dichlorophosphate as a dehydrating agent under the microwave-accelerated solvent-free procedure.39 A series of N-[5-(2-oxo-2H-chromen-3-yl)-[1,3,4]oxadiazol-2-yl]-benzamide derivatives displayed inhibition against COX-1, COX-2, LOX-5, LOX-12, and LOX-15, and thereby showed enhanced anti-inflammatory, and analgesic activities.40
In recent years many protocols have been followed for the cyclization using iodine in the synthesis of oxadiazole.41,42 In the present work, we have adopted the I2 catalyzed oxidative cyclization for the synthesis of 1,3,4-oxadiazoles from substituted coumarin hydrazides and aromatic aldehydes through a grinding technique43 to obtain the desired products in moderate to good yields. The synthesized new coumarin-oxadiazole hybrids were evaluated in vitro for the free radical scavenging susceptibilities.
2 Experimental
2.1 Materials and methods
All the reagents and chemicals were purchased from Sigma Aldrich, SD Fine, SRL and used without further purification. Thin-layer chromatography (TLC) was accomplished by pre-coated aluminum plates purchased from Merck (silica gel, 60 F-254). TLC plates were visualized under UV light and iodine chamber. 1H NMR spectra were recorded by 400 MHz and 13C NMR spectra by 100 MHz Agilent NMR spectrometer using with DMSO, and CD6 as solvents, TMS used as an internal standard. Mass spectra were recorded under Lynx SCN781 spectrometer TOF mode.
2.2 Synthesis
A series of ethyl-2-oxo-2H-chromene-3-carboxylates 3(a–e) were synthesized from various substituted salicylaldehyde 1(a-e), and diethylmalonate 2, in the presence of 2-3 drops of piperidine. A solution mixture of compounds 3(a–e) (10 mmol), hydrazine hydrochloride, 4 in (15 mL) was initially stirred at room temperature for an hour, then was refluxed for about 2-3 h to get the corresponding hydrazides 5(a-e).44 The mixture of resulting hydrazides, substituted benzaldehydes 6(a-c) in the presence of I2 was finely ground in a mortar for 10-15 min, the process leads to giving the target compounds 3-(5-phenyl-1,3,4-oxadiazol-2-yl)-2H-chromen-2-ones, 7(a–j) in moderate yields (Figure 1).
2.2.1 General procedure for the synthesis of compounds 7(a-j)
A mixture of coumarin hydrazide 5(a-e) (10 mmol) and substituted benzaldehydes, 6(a-c) (10 mmol), and iodine (20 mmol) were ground with a pestle for 15-20 min in a clean and dry mortar till a paste/semi-solid mass is obtained. The reaction progress was monitored by TLC at regular intervals of time. After confirming that the reaction has been completed, the mixture is washed successively with an ice-cold solution of sodium thiosulfate (20%) (3×10 mL) to remove residual iodine. The solid separated out was filtered, washed with cold water, and obtained mass was recrystallized using ethanol to get 3-(5-phenyl-1,3,4-oxadiazol-2-yl)-2H-chromen-2-ones 7(a-j).
2.3 Biological activity
2.3.1 DPPH radical scavenging activity
The antioxidant property of the synthesized oxadiazole compounds was evaluated through free radical scavenging assay by observing the changes in optical density of 1,1-diphenyl-2-picryl hydrazyl (DPPH) radical solution.45,46 The standard solution and solutions of different concentration of synthesized oxadiazole compound 7(a-j) were used for DPPH radical scavenging analysis. The DPPH produces violet color in ethanol solution and fades to shades of yellow/pale yellow color in the presence of antioxidant. The DPPH radical scavenging activity was performed as follows: A known volume of DPPH radical solution in ethanol solvent (0.4 mM) was mixed with test samples of different concentrations (0.15 mM, 0.30 mM, and 0.45 mM) in 25 mL standard flask, and kept at 37 °C for 30 min. The violet color of DPPH solution is decreasing depending on the efficiency of the sample. The experiment is carried out with ascorbic acid as the standard under similar conditions. The absorbance of standard and tested oxadiazoles were measured using Elico SL 159 UV-Vis spectrophotometer at 517 nm. The experiments were done in triplicate.
The percentage DPPH radical scavenging activity was calculated using the equation:
where A0 is the absorbance of the standard, and A1 is the absorbance of the test samples at different concentrations. The % inhibition was plotted against concentration, and from the graph, IC50 was calculated.
2.3.2 Hydroxyl radical scavenging activity
The hydroxyl radical scavenging assay was performed using butylated hydroxyanisole (BHA) following a known protocol.47 A mixture of 0.1 mL of phosphate buffer, 0.2 mL of 2-deoxyribose with different concentration of synthesized compounds, 7(a-j) (0.2, 0.4, 0.6 and 0.8 mM in methanol), 0.01 mL of FeCl3 (100 mM), 0.1 mL of H2O2 (10 mM), 0.1 mL of ascorbic acid (1 mM), and 0.1 mL of EDTA was incubated at 37 °C for 60 min. Thereafter, the reaction was terminated by adding 1 mL of cold 2.8% trichloroacetic acid and the reaction product was measured by adding 1 mL of 1% thiobarbituric acid (1g in 100 mL of 0.05 N NaOH) in boiling water for 15 min. The BHA was used as a standard. The absorbance was measured at 535 nm with Elico SL 159 UV-Vis spectrophotometer. The hydroxyl radical scavenging capacity was evaluated with the inhibition of the percentage of 2-deoxyribose oxidation on hydroxyl radicals. The percentage of hydroxyl radical scavenging activity was calculated using the relation:
where A0 is the absorbance of the control without any sample. A1 is the absorbance after adding a sample and 2-deoxyribose. A2 is the absorbance of the sample without 2-deoxyribose. The % inhibition was plotted against concentration, and from the graph IC50 was calculated. The experiment was repeated three times at each concentration.
3 Results and Discussions
3.1 Spectral characterization
The IR, 1H NMR, 13C NMR, Mass spectral studies provide the structural proof for compounds 7(a-j). In IR spectra, compounds 7(a-j) (Figure S1-S4, Supplementary Information) showed the absorption bands for C=N, C=C, lactone-COO and C-H groups in the region: 1561-1579 cm−1, 1642-1669 cm-1, 1750-1759 cm-1, 1804-1822 cm-1 for aromatic (C-H) and 2731-2758 cm-1 for alkane (C-H), respectively. Other than these absorption bands, compound 7a (Figure S1, Supplementary Information) show a band at 625 cm-1 due to C-Br stretching.
The 1H NMR spectra of compounds 7(a-j) were discussed by taking a representative compound 7f. The compound 3-(5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl)-8-ethoxy-2H-chromen-2-one, 7f (Figure S8, SI) shows a triplet at 1.136-1.172 (J=14.4Hz) ppm for methyl protons of -OCH2CH3 substituent, a quadrate at 4.134-4.187 (J=21.2Hz) ppm for methylene protons of -OCH2CH3 substituent, a singlet at δ 8.486 ppm for C4-H, and an array of signals as multiplet within the region δ 7.202-7.270 ppm and δ 7.492-7.582 ppm for aromatic protons. For compounds; 7d, (Figure S7, SI) a singlet at δ 3.810 ppm for a methoxy proton, 7g, (Figure S9, SI) and 7j, (Figure S10, SI) singlets at δ 2.356 ppm and δ 2.249 ppm for a methyl proton respectively, In the series of compounds 7(a-j), a singlet for C4-H varies from δ 8.034-8.456 ppm. All the designed series of compounds 7(a-j) (Figure S5-S10, SI) showed similar and consistent pattern signal for the aromatic protons in their respective spectra between the range δ 6.973-7.946 ppm and good agreement with the reported analogues39,48,49 of the coumarin tethered oxadiazole moieties.
In the 13C NMR spectrum, compound 7c, (Figure S12, SI) shows the absorption signals at δ 13.85 ppm for –CH3, and δ 60.50 ppm for –CH2 carbons of -OCH2CH3 substituent. The signals at δ 169.26 ppm, and δ 163.66 ppm appeared for carbons of the oxadiazole ring; while the signal for lactone C=O carbon appeared at δ 178.89 ppm. In the series of compounds 7(a-j), (Figure S11-S15, SI) the signal for lactone C=O carbon appeared in the region δ 177.93-179.89 ppm, and signals for oxadiazole ring carbons within the region δ 163.05-169.26 ppm; for a compound 7e, (Figure S13, SI) and 7i, (Figure S15, SI) a signal at δ 55.429 ppm and δ 55.438 ppm for a methoxy carbon atom; For a compound 7h, (Figure S14, SI) and 7i, (Figure S15, SI) signals appeared at δ 21.758 ppm and δ 21.652 ppm for methyl carbons, respectively. Further, all showed an array of signals within the aromatic carbon absorption region for aromatic carbons.
In mass spectrum, compound 7b, (Figure S17, SI) showed a base peak at m/z 324.1 (90%) corresponds to 35Cl isotope and its molecular mass (C17H9N2O3Cl; MW=324.04), and peak at m/z 326.1 (26%) comparable to 37Cl isotope (M+2) ion. Other compounds of the series 7(a-j), (Figure S16-S20, SI) showed the peaks corresponding to their M+ and (M+1) peaks. The chloro and bromo substituted compounds showed M+ and M+2 peaks according to their molecular masses in the ratio 3:1 and 1:1, respectively. All the designed series of compounds 7(a-j), (Figure S1-S20, SI) showed similar and consistent pattern signal in their respective spectra and have their comparable elemental analysis.
3.2 DPPH and hydroxyl radical scavenging activity
The results of the DPPH and hydroxyl radical scavenging abilities of synthesized compounds 7(a-j) are tabulated in Table 1.
From the results of the antioxidant activity screening of the tested compounds 7(a-j), it was observed that all newly synthesized compounds show good to moderate antioxidant activity as compared to the standard drugs employed. From the DPPH assay analyzed in triplicate, some compounds of the series displayed the promising radical scavenging activities with IC50 values of 7d (19.47 μM), 7e (18.62 μM), 7g (23.28 μM), 7h (22.78 μM) and 7i (17.19 μM), and these results were comparable with antioxidant ascorbic acid (IC50 = 23.80 μM), and therefore these compounds might act as lead molecules for DPPH radical scavenging activity. The compound 7c (29.33 μM) showed the lowest activity amongst the series, while the remaining compounds of the series show moderate activity.
From the hydroxyl radical scavenging assay results analyzed in triplicate, the compounds 7d (IC50 = 32.62 μM) and 7i (IC50 = 28.51 μM) exhibited promising radical scavenging activities, and these values were comparable with antioxidant BHA (IC50 = 36.05 μM). The rest of the synthesized compounds show moderate to poor antioxidant activity (IC50 = 36.88-47.81 μM) comparable to the reference standard. The better DPPH and hydroxyl radical scavenging activity showed by the compounds 7d and 7i are comparable with respective standards and also with the reported structurally related compounds.
3.3 Analytical data
3.3.1 6-Bromo-3-(5-phenyl-1,3,4-oxadiazol-2-yl)-2H-chromen-2-one, 7a
Obtained from reaction between 5a (10 mmol) and 6a (10 mmol) in the presence of I2 (15 mmol) in 68% yield (yellowish powder), M.p. 243-245 °C. IR νmax (cm−1): 625 (C-Br), 1570 (C=N), 1642 (C=C), 1750 (lactone-COO), 1804, 2749 (C-H); 1H NMR (DMSO, δ ppm): 7.102-7.160 (m, 4H, Ar-H), 7.249-7.279 (m, 1H, Ar-H), 7.422-7.448 (m, 3H, Ar-H), 8.118 (s, 1H, Ar-H); 13C NMR (DMSO, δ ppm): 107.06 (1C), 111.54 (1C), 113.09 (1C), 113.66 (2C), 115.72 (1C), 120.14 (1C), 130.42 (1C), 130.64 (1C), 131.64 (1C), 139.26 (1C), 143.26 (1C), 152.29 (1C), 154.51 (1C), 163.05 (1C), 167.05 (1C), 179.297 (1C, C=O); MS (m/z): 367.9 (M+, 96), 369.1 (M+2, 88). Anal. Calcd. for C17H9BrN2O3 (%): C, 55.31; H, 2.46; N, 7.59; Found: C, 55.20; H, 2.36; N, 7.51.
3.3.2 6-Chloro-3-(5-phenyl-1,3,4-oxadiazol-2-yl)-2H-chromen-2-one, 7b
Obtained from reaction between 5b (10 mmol) and 6a (10 mmol) in the presence of I2 (15 mmol) in 48% yield (yellowish gummy mass). IR νmax (cm−1): 832 (C-Cl), 1579 (C=N), 1651 (C=C), 1759 (lactone-COO), 1822, 2731 (C-H); 1H NMR (DMSO, δ ppm): 7.340-7.486 (m, 3H, Ar-H), 7.653-7.798 (m, 3H, Ar-H), 7.911-7.930 (d, 1H, Ar-H), 8.046 (d, 1H, Ar-H); MS (m/z): 324.1 (M+, 90), 326.10 (M+2, 26). Anal. Calcd. for C17H9ClN2O3 (%): C, 62.88; H, 2.79; N, 8.63; Found: C, 62.70 H, 2.70; N, 8.59.
3.3.3 8-Ethoxy-3-(5-phenyl-1,3,4-oxadiazol-2-yl)-2H-chromen-2-one, 7c
Obtained from reaction between 5e (10 mmol) and 6a (10 mmol) in the presence of I2 (15 mmol) in 61% yield (yellowish solid), M.p. 268-270°C. IR νmax (cm−1): 1570 (C=N), 1660 (C=C), 1750 (lactone-COO), 1813, 2749 (C-H); 13C NMR (DMSO, δ ppm): 13.85 (1C, CH3), 60.50 (1C, OCH2), 110.72 (1C), 113.29 (1C), 119.05 (1C), 125.74 (1C), 125.90 (1C), 127.37 (1C), 128.00 (1C), 129.27 (1C), 129.91 (1C), 132.42 (1C), 134.07 (1C), 137.33 (1C), 139.42 (1C), 145.24 (1C), 156.02 (1C), 163.66 (1C), 169.26 (1C), 178.03 (1C, C=O); MS (m/z): 335.1 (M+1, 88), 336.1 (M+2, 11). Anal. Calcd. for C19H14N2O4 (%): C, 68.26; H, 4.22; N, 8.38; Found: C, 68.10; H, 4.10; N, 8.33.
3.3.4 3-(5-(4-Chlorophenyl)-1,3,4-oxadiazol-2-yl)-8-methoxy-2H-chromen-2-one, 7d
Obtained from reaction between 5c (10 mmol) and 6b (10 mmol) in the presence of I2 (15 mmol) in 50% yield (yellowish gummy mass). IR νmax (cm−1): 850 (C-Cl), 1561 (C=N), 1669 (C=C), 1759 (lactone-COO), 1804, 2758 (C-H); 1H NMR (DMSO, δ ppm): 3.810 (s, 3H, OCH3), 7.103 (s, 1H, Ar-H), 7.337-7.376 (m, 2H, Ar-H), 7.415-7.462 (m, 1H, Ar-H), 7.592-7.620 (m, 1H, Ar-H), 7.918-7.946 (m, 2H, Ar-H), 8.055 (s, 1H, Ar-H); MS (m/z): 354.1 (M+, 100), 356.1 (M+2, 32). Anal. Calcd. for C18H11ClN2O4 (%): C, 60.94; H, 3.13; N, 7.90; Found: C, 60.81; H, 3.02; N, 7.87.
3.3.5 3-(5-(4-Chlorophenyl)-1,3,4-oxadiazol-2-yl)-7-methoxy-2H-chromen-2-one, 7e
Obtained from reaction between 5e (10 mmol) and 6b (10 mmol) in the presence of I2 (15 mmol) in 66% yield (yellowish solid), M.p. 212-214 °C. 13C NMR (DMSO, δ ppm): 55.42 (1C, OCH3), 107.06 (1C), 111.98 (1C), 114.94 (1C), 115.16 (1C), 123.35 (1C), 125.34 (1C), 125.34 (1C), 127.86 (1C), 128.78 (1C), 128.91 (1C), 131.15 (1C), 131.91 (1C), 132.06 (1C), 145.07 (1C), 151.85 (1C), 163.61 (1C), 168.03 (1C), 179.89(1C, C=O); MS (m/z): 354.0 (M+, 100), 356.0 (M+2, 32). Anal. Calcd. for C18H11ClN2O4 (%): C, 60.94; H, 3.13; N, 7.90; Found: C, 60.84; H, 3.04; N, 7.85.
3.3.6 3-(5-(4-Chlorophenyl)-1,3,4-oxadiazol-2-yl)-8-ethoxy-2H-chromen-2-one, 7f
Obtained from reaction between 5e (10 mmol) and 6b (10 mmol) in the presence of I2 (15 mmol) in 48% yield (greenish gummy mass). 1H NMR (DMSO, δ ppm): 1.136-1.172 (t, 3H, CH3), 4.134-4.187 (q, 2H, CH2), 7.202-7.270 (m, 5H, Ar-H), 7.492-7.582 (m, 2H, Ar-H), 8.486 (s, 1H, Ar-H); MS (m/z): 368.1 (M+, 100), 370.1 (M+2, 32). Anal. Calcd. for C19H13ClN2O4 (%):C, 61.88; H, 3.55; N, 7.60; Found: C, 61.77; H, 3.42; N, 7.57.
3.3.7 6-Bromo-3-(5-(p-tolyl)-1,3,4-oxadiazol-2-yl)-2H-chromen-2-one, 7g
Obtained from reaction between 5a (10 mmol) and 6c (10 mmol) in the presence of I2 (15 mmol) in 62% yield (yellow powder), M.p. 223-225°C. 1H NMR (DMSO, δ ppm): 2.356 (s, 3H, CH3), 6.869-6.876 (s, 1H, Ar-H), 7.114-7.276 (m, 3H, Ar-H), 7.418-7.463 (m, 2H, Ar-H), 7.911-7.996 (m, 1H, Ar-H), 8.034 (d, 1H, Ar-H); MS (m/z): 382.1 (M+, 94), 384.2 (M+2, 87). Anal. Calcd. for C18H11BrN2O3 (%): C, 56.42; H, 2.89; N, 7.31; Found: C, 56.30; H, 2.70; N, 7.28.
3.3.8 6-Chloro-3-(5-(p-tolyl)-1,3,4-oxadiazol-2-yl)-2H-chromen-2-one, 7h
Obtained from reaction between 5b (10 mmol) and 6c (10 mmol) in the presence of I2 (15 mmol) in 50% yield (greenish gummy mass). 13C NMR (DMSO, δ ppm): 21.75 (1C, CH3), 119.76 (1C), 120.32 (1C), 120.75 (1C), 120.87 (1C), 121.68 (1C), 127.36 (1C), 129.22 (1C), 129.53 (1C), 130.03 (1C), 131.44 (1C), 134.53 (1C), 139.68 (1C), 142.79 (1C), 159.85 (1C), 164.05 (1C), 167.83 (1C), 179.46 (1C, C=O); MS (m/z): 338.5 (M+, 100), 340.0 (M+2, 30). Anal. Calcd. for C18H11ClN2O3 (%): C, 63.82; H, 3.27; N, 8.27; Found: C, 63.70; H, 3.17; N, 8.23.
3.3.9 7-Methoxy-3-(5-(p-tolyl)-1,3,4-oxadiazol-2-yl)-2H-chromen-2-one, 7i
Obtained from reaction between 5d (10 mmol) and 6c (10 mmol) in the presence of I2 (15 mmol) in 45% yield (buff gummy mass). 13C NMR (DMSO, δ ppm): 21.65 (1C, CH3), 55.43 (1C, OCH3), 112.79 (1C), 119.42 (1C), 120.32 (1C), 120.81 (1C), 121.68 (1C), 127.36 (1C), 129.40 (1C), 130.03 (1C), 131.44 (1C), 134.53 (1C), 135.56 (1C), 139.68 (1C), 142.79 (1C), 159.85 (1C), 164.05 (1C), 177.93 (1C, C=O); MS (m/z): 334.3 (M+, 100), 335.3 (M+1, 12). Anal. Calcd. for C19H14N2O4 (%): C, 68.26; H, 4.22; N, 8.38; Found: C, 68.12; H, 4.12; N, 8.34.
3.3.9.1 8-Ethoxy-3-(5-(p-tolyl)-1,3,4-oxadiazol-2-yl)-2H-chromen-2-one, 7j
Obtained from reaction between 5e (10 mmol) and 6c (10 mmol) in the presence of I2 (15 mmol) in 43% yield (greenish gummy mass). 1H NMR (DMSO, δ ppm): 1.107-1.142 (t, 3H, CH3), 2.249 (s, 3H, OCH3), 4.124-4.178 (q, 2H, CH2), 6.973-6.992 (d, 2H, Ar-H), 7.171-7.248 (d, 2H, Ar-H), 7.592-7.620 (d, 2H, Ar-H), 7.918-7.946 (m, 2H, Ar-H), 8.105 (s, 1H, Ar-H); MS (m/z): 348.0 (M+, 96). Anal. Calcd. for C20H16N2O4 (%): C, 68.96; H, 4.63; N, 8.04; Found: C, 68.83; H, 4.58; N, 8.00.
4 Conclusions
The new series of coumarin tethered compounds have been synthesized by a green chemistry method using the molecular iodine by a simple grinding technique. The structures of the newly synthesized compounds were confirmed by their spectral data. The results of DPPH and hydroxyl radical scavenging assay, the coumarin appended oxadiazole derivatives, 7(a-j) exhibit modest to good radical scavenging susceptibilities. The compounds, 7d (IC50=19.47 μM, and 32.62 μM) and 7i (IC50=17.19 μM, and 28.51 μM) of the synthesized series, demonstrated potent DPPH and hydroxyl radical scavenging abilities, respectively, and therefore these could act as antioxidant leads in the future.
References
Pouliot M F, Angers L, Hamel J D and Paquin J F 2012 Synthesis of 1,3,4-oxadiazoles from 1,2-diacylhydrazines using [Et2NSF2]BF4 as a practical cyclodehydration agent Org. Biomol. Chem. 10 988
Lei Y, Liu S, Li H and Ding M 2013 Microwave promoted synthesis of 2,5-diaryl-1,3,4-oxadiazoles using melamine formaldehyde resin supported sulfuric acid Asian J. Chem. 25 10454
Stolle R J, Milcent R, Barbier G, Reddy P S, Reddy P P, Chiba T, Okimoto M, Yang R Y, Dai L X, Jedlovska E and Lesko J 1906 A simple one-pot procedure for the synthesis of 1, 3, 4–oxadiazoles Prakt. Chem. 73 277
Milcent R and Barbier G 1983 Oxidation of hydrazones with lead dioxide: new synthesis of 1, 3, 4‐oxadiazoles and 4‐amino‐1, 2, 4‐triazol‐5‐one derivatives J. Heterocycl. Chem. 20 77
Reddy P S and Reddy P P 1987 Fusion of aroylhydrazines with acids. A new synthesis of 2, 5‐diaryl‐1, 3, 4‐oxadiazoles Ind. J. Chem. 26B 890
Mogilaiah K and Prashanthi M A 2005 Convenient synthesis of 5-aryl-2-[p-(1, 8-naphthyridin-2-yl) phenoxymethyl]-1, 3, 4-oxadiazoles under microwave irradiation Ind. J. Heterocycl. Chem. 14 185
Vagdevi H M, Ravindra K C, Vaidya V P and Basavaraj P 2006 Synthesis, antimicrobial and anti-inflammatory activities of 1, 3, 4-oxadiazoles linked to naphthol [2, 1-b] furan Ind. J. Chem. 45B 2506
Rani R and Makrandi J K 2008 A facile synthesis of symmetrical and unsymmetrical 2, 5-disubtituted 1, 3, 4-oxadiazoles Ind. J. Heterocycl. Chem. 18 81
Mogilaiah K and Reddy P R 2001 Hypervalent iodine mediated solid state synthesis of 1, 8-naphthyridinyl-1, 3, 4-oxadiazoles Ind. J. Chem. 40B 619
Yang X, Muller D C, Nether D and Meerholz K 2006 Highly efficient polymeric electrophosphorescent diodes Adv. Mater. 18 948
Wang J, Wang R, Yang J, Zheng Z, Carducci M D, Cayou T, Peyghambarian N and Jabbour G E 2001 First oxadiazole-functionalized terbium (III) β-diketonate for organic electroluminescence J. Am. Chem. Soc. 123 6179
Rehmann N, Ulbricht C, Kohnen A, Zacharias P, Gather M C, Hertel D, Holder E, Meerholz K and Schubert U S 2008 Advanced device architecture for highly efficient organic light‐emitting diodes with an orange‐emitting crosslinkable iridium (III) complex Adv. Mater. 20 129
Chan L H, Lee R H, Hsieh C F, Yeh H C and Chen C T 2002 Optimization of high-performance blue organic light-emitting diodes containing tetraphenylsilane molecular glass materials J. Am. Chem. Soc. 124 6469
He G S, Tan L S, Zheng Q and Prasad P N 2008 Multiphoton absorbing materials: molecular designs, characterizations, and applications Chem. Rev. 108 1245
Martin P J and Bruce D W 2007 Hydrogen‐bonded oxadiazole mesogens Liq. Cryst. 34 767
Guan M, Bian Z Q, Zhou Y F, Li F Y, Li Z J and Huang C H 2003 High-performance blue electroluminescent devices based on 2-(4-biphenylyl)-5-(4-carbazole-9-yl) phenyl-1, 3, 4-oxadiazole Chem. Commun. 21 2708
Siwach A and Verma P K 2020 Therapeutic potential of oxadiazole or furadiazole containing compounds BMC Chem. 14 70
Pitasse-Santos P, Sueth-Santiago V and Lima, M E F 2018 1,2,4- and 1,3,4-Oxadiazoles as scaffolds in the development of antiparasitic agents J. Braz. Chem. Soc. 29 435
Hiremath S P, Sonar V N, Sekhar K R and Purohit M G 1989 Synthesis and antibacterial activity of 1,3,4, oxadiazole Ind. J. Chem. 28B 626
Gurunanjappa P and Kariyappa A K 2016 Design, synthesis and biological evaluation of 1,3,4-oxadiazoles/thiadiazoles bearing pyrazole scaffold as antimicrobial and antioxidant candidates Curr. Chem. Lett. 5 109
Frank P V and Kalluraya B 2005 Synthesis of 1, 3, 4-oxadiazoles carrying imidazole moiety Ind. J. Chem. 44B 1456
Chen H, Li Z and Han Y 2000 Synthesis and fungicidal activity against Rhizoctonia solani of 2-alkyl (alkylthio)-5-pyrazolyl-1,3,4-oxadiazoles (thiadiazoles) J. Agric. Food Chem. 48 5312
Misra U, Hitkari A, Saxena A K, Gurtu S and Shanker K 1996 Biologically active indolylmethyl-1, 3, 4-oxadiazoles, 1, 3, 4-thiadiazoles, 4H-1, 3, 4-triazoles and 1, 2, 4-triazines Eur. J. Med. Chem. 31 629
Patil S G, Girisha M, Badiger J, Kudari S M and Purohit M G 2007 Synthesis and anticonvulsant, antimicrobial activity of some bis-1, 3, 4-oxadiazole and bis-1, 2, 4-triazole derivatives from sebacic acid Ind. J. Heterocycl. Chem. 17 37
Sahin G, Palaska E, Kelicen P, Demirdamar R and Altinok G 2001 Synthesis of some new 1-acylthiosemicarbazides, 1, 3, 4-oxadiazoles, 1, 3, 4-thiadiazoles and l, 2, 4-triazole-3-thiones and their anti-inflammatory activities Arzneim. Forsch Drug Res. 51 478
Holla B S, Poojary K N, Bhat K S, Ashok M and Poojary B 2005 Synthesis and anticancer activity studies on some 2-chloro-1, 4-bis-(5-substituted-1, 3, 4-oxadiazol-2-ylmethyleneoxy) phenylene derivatives Ind. J. Chem. 44B 1669
Nagamallu R and Kariyappa A K 2013 Synthesis and biological evaluation of novel formyl-pyrazoles bearing coumarin moiety as potent antimicrobial and antioxidant agents Bioorg. Med. Chem. Lett. 23 6406
Hu Y Q, Xu Z, Zhang S, Wu X, Ding J W, Lv Z S and Feng L S 2017 Recent developments of coumarin-containing derivatives and their anti-tubercular activity Eur. J. Med. Chem. 136 122
Hu Y Q, Gao C, Zhang S, Xu L, Xu Z, Feng L S, Wu X and Zhao F 2017 Quinoline hybrids and their antiplasmodial and antimalarial activities Eur. J. Med. Chem. 139 22
Chougala B M, Samundeeswari S, Holiyachi M, Shastri L A, Dodamani S, Jalapure S, Dixit S R, Joshi S D and Sunagar V A 2017 Synthesis, characterization and molecular docking studies of substituted 4-coumarinylpyrano[2,3-c]pyrazole derivatives as potent antibacterial and anti-inflammatory agents Eur. J. Med. Chem. 125 101
Renuka N and Ajay Kumar K 2015 Synthesis and biological evaluation of fused pyrans bearing coumarin moiety as potent antimicrobial agents Philip. J. Sci. 144 91
Akhtar J, Khan A A, Ali Z, Haider R and Yar M S 2017 Structure-activity relationship (SAR) study and design strategies of nitrogen-containing heterocyclic moieties for their anticancer activities Eur. J. Med. Chem. 125 143
Chen L Z, Sun W W, Bo L, Wang J Q, Xiu C, Tang W J, Shi J B, Zhou H P and Liu X H 2017 New arylpyrazoline-coumarins: Synthesis and anti-inflammatory activity Eur. J. Med. Chem. 138 170
Hassan M Z, Osman H, Ali M A and Ahsan M J 2016 Therapeutic potential of coumarins as antiviral agents Eur. J. Med. Chem. 123 236
Yang H L, Cai P, Liu Q H, Yang X L, Li F, Wang J, Wu J J, Wang X B and Kong L Y 2017 Design, synthesis and evaluation of coumarin-pargyline hybrids as novel dual inhibitors of monoamine oxidases and amyloid-β aggregation for the treatment of Alzheimer's disease Eur. J. Med. Chem. 138 715
Lan J S, Ding Y, Liu Y, Kang P, Hou J W, Zhang X Y, Xie S S and Zhang T 2017 Design, synthesis and biological evaluation of novel coumarin-N-benzyl pyridinium hybrids as multi-target agents for the treatment of Alzheimer's disease Eur. J. Med. Chem. 139 48
Nagamallu R, Gurunanjappa P and Kariyappa A K 2017 Synthesis of coumarin appended 1, 3-oxazines as potent antimicrobial and antioxidant agents Pharm. Chem. J. 51 582
Nagamallu R, Srinivasan B, Ningappa M B and Kariyappa A K 2016 Synthesis of novel coumarin appended bis(formylpyrazole) derivatives: Studies on their antimicrobial and oxidant activities Bioorg. Med. Chem. Lett. 26 690
Li Z, Yu J, Ding R, Wang Z and Wang X 2004 Microwave accelerated solvent-free synthesis of 1,3,4-oxadiazoles using polymer supported dehydration reagent Synth. Commun. 34 2981
Akhter M, Akhter N, Alam M M, Zaman M S, Saha R and Kumar A 2011 Synthesis and biological evaluation of 2,5-disubstituted 1,3,4-oxadiazole derivatives with both COX and LOX inhibitory activity J. Enz. Inh. Med. Chem. 26 767
Rout S K 2012 A one pot synthesis of [1, 3, 4]-oxadiazoles mediated by molecular iodine RSC Adv. 2 3180
Niu P, Kang J, Tian X, Song L, Liu H, Wu J, Yu W and Chang J 2015 Synthesis of 2-amino-1,3,4-oxadiazoles and 2-amino-1,3,4-thiadiazoles via sequential condensation and I2-mediated oxidative C–O/C–S bond formation J. Org. Chem. 80 1018
Kumar A and Makrandi J K 2011 A facile solvent free synthesis of 3-arylidenechroman-4-ones using grinding technique Green Chem. Let. Rev. 4 87
Vagish C B, Vivek H K, Karthik K, Dileep Kumar A, Lokanath N K and Ajay Kumar K 2020 Design and synthesis of coumarin-triazole hybrids: Biocompatible anti-diabetic agents, in silico molecular docking and ADME screening Heliyon. 6 e05290
Salar U, Khan K M, Chigurupati S, Taha M, Wadood A, Vijayabalan S and Perveen S 2017 New hybrid hydrazinyl thiazole substituted chromones: As potential α-amylase inhibitors and radical (DPPH & ABTS) scavengers Sci. Rep. 7 16980
Rafique R, Khan K M, Arshia S, Chigurupati A, Wadood A U, Rehman U, Salar V, Venugopal S, Shamim M and Perveen Taha S J 2020 Synthesis, in vitro α-amylase inhibitory, and radicals (DPPH & ABTS) scavenging potentials of new N-sulfonohydrazide substituted indazoles Bioorg. Chem. 94 103410
Renuka N, Vivek H K, Pavithra G and Ajay Kumar K 2017 Synthesis of coumarin appended pyrazolyl-1,3,4-oxadiazoles and pyrazolyl-1,3,4-thiadiazoles: Evaluation of their in vitro antimicrobial and antioxidant activities and molecular docking studies Russ. J. Bioorg. Chem. 43 197
Kovalenko S M, Bylov I E, Sytnik K M, Chernykh V P and Bilokin Y V 2000 A new pathway to 3-hetaryl-2-oxo-2H-chromenes: on the proposed mechanisms for the reaction of 3-carbamoyl-2-iminochromenes with dinucleophiles Molecules 5 1146
Sudha B N, Sastry V G, Harika M S and Yellasubbaiah N 2018 Synthesis of 3-(5-phenyl-1, 3, 4-oxadiazol-2-yl)-2H-chromen-2-ones as anticonvulsant agents Ind. J. Chem. 57 737
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The authors are grateful to the IOE Instrumentation Facility, Vijnana Bhavana, University of Mysore, for recording spectra.
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Supplementary information contains IR, Mass, 1H and 13C NMR spectra. Figures S1-S20 are available at www.ias.ac.in/chemsci.
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BASAPPA, V.C., PENUBOLU, S., ACHUTHA, D.K. et al. Synthesis, characterization and antioxidant activity studies of new coumarin tethered 1,3,4-oxadiazole analogues. J Chem Sci 133, 55 (2021). https://doi.org/10.1007/s12039-021-01914-5
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DOI: https://doi.org/10.1007/s12039-021-01914-5