Home Physical Sciences DMFDMA catalyzed synthesis of 2-((Dimethylamino)methylene)-3,4-dihydro-9-arylacridin-1(2H)-ones and their derivatives: in-vitro antifungal, antibacterial and antioxidant evaluations
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DMFDMA catalyzed synthesis of 2-((Dimethylamino)methylene)-3,4-dihydro-9-arylacridin-1(2H)-ones and their derivatives: in-vitro antifungal, antibacterial and antioxidant evaluations

  • L. Jyothish Kumar , S. Sarveswari and V. Vijayakumar EMAIL logo
Published/Copyright: October 25, 2018
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Open Chemistry
From the journal Open Chemistry Volume 16 Issue 1

Abstract

A series of 3,4-dihydro-9-arylacridin-1(2H)-ones was synthesized and enaminone function was introduced at the C-2 position using DMFDMA catalyst which in turn successfully converted into pyrazole, isoxazol, 1-phenyl-1H-pyrazole by treating it with reagents such as hydrazine, hydroxylamine and phenylhydrazine. These newly synthesized compounds were evaluated for their antibacterial activity against a series of Gram-Positive bacteria including Staphylococcus aureus, Bacillus cereus, Staphylococcus aureus MLS16 and Gram-Negative bacteria including Klebsiella planticol, Escherichia coli and Pseudomonas aeruginosa and also against fungal strains including Candida albicans, Candida parapsilosis, Candida glabrata, Candida aaseri, Aspergillus niger and Issatchenkia hanoiensis. The compounds 3a and 6a exhibited considerable antifungal activity (MIC value 0.007 and 0.006 μM) against Candida albicans and Aspergillus niger respectively. The compound 4a showed excellent antibacterial activity towards Escherichia Coli (MIC = 0.003 μM) and the compound 5a found to show prominent DPPH radical scavenging activity with EC50 value 16.85±1.5μg mL−1.

Graphical Abstract

Keywords: DMFDMA; Enaminones; antifungal; antibacterial; antioxidant evaluations

1 Introduction

N, N-Dimethylformamide dimethyl acetal (DMFDMA) also known as 1, 1-dimethoxy-N, N-dimethylmethylamine or 1, 1-dimethoxytrimethylamine, as its name indicates, is a derivative of formamide [1] acts as methylating and formylating agent. Formylated products obtained by treating compounds with active methylene group and DMFDMA have proved to be very useful intermediates in the synthesis of heterocycles [1, 2, 3, 4]. Enaminone derivatives have been proven to be valuable synthon for the synthesis of a wide variety of biologically active heterocycles [4]. On the other hand, the functionalized acridines are often used to design and synthesize the compounds with various pharmacological activities such as antibacterial [5], antifungal [5], anti-inflammatory [6], anticancer [7], anti-cytotoxic [8] and anti-malarial activities [9]. Though the synthesis of enaminone and its derivatives from simple ketones using DMFDMA are available in the literature, only a very few reports are available on the enaminones from active methylene of the various heterocycles [1, 2, 3, 4 and 10, 11, 12, 13, 14]. This prompted us to attempt the present work in which we have used the active methylene group of 3,4-dihydro-9-arylacridin-1(2H)-ones to synthesize the corresponding enaminone which in turn used as a synthon to obtain the corresponding pyrazole, isoxazole and 1-aryl-1H-pyrazole using hydrazine, hydroxylamine, phenylhydrazine respectively.

Ethical approval: The conducted research is not related to either human or animal use.

2 Materials and Methods

Melting points (mp) reported in this work are recorded in Elchem microprocessor based DT apparatus in open capillary tubes and are uncorrected. 1H NMR and 13C NMR are recorded in Bruker 400 MHz NMR spectrometer with TMS as an internal reference. The chemical shift values are reported in parts per million (δ, ppm) from internal standard TMS. High-Resolution Mass spectra were recorded using Bruker MaXis HR-MS (ESI-Q-TOF-MS) instrument. All the reagents were purchased from Aldrich and used as received. Excess solvents were removed under vacuum. Organic extracts were dried with anhydrous Na2SO4. Silica gel 60F254aluminum sheets were used in analytical thin-layer chromatography. Visualization of spots on TLC plates was effected by UV illumination, exposure to iodine vapour and heating the plates dipped in a KMnO4 stain. In column chromatography, the silica gel with 230-400 mesh size was used for the purification.

2.1 General procedure for the synthesis of 3,4-dihydro-9-arylacridin-1(2H)-ones

The 2-amino benzophenone 1a (0.1 g, 0.0005 M) was treated with 1,3-cyclohexanedione (0.06 g, 0.0005 M) in presence of ortho-phosphoric acid (catalyst) in ethanol and refluxed for 12 hrs. After the completion of the reaction the crude was poured into ice cold water and the formed precipitate was filtered and dried to afford the product 2a. The obtained product was used without further purification. And the procedure was repeated with 1b-c to get 2b-c.

2.1.1 3,4-dihydro-9-phenylacridin-1(2H)-one (2a)

Yellow solid, (yield 86%), m.p: 156-157ºC; 1H NMR (400 MHz, CDCl3): δ ppm 8.00 (d, J = 9.00 Hz, 1H), 7.69 (dd, J = 9.00 Hz, 2.20 Hz, 1H), 7.53-7.49 (m, 4H), 7.41 (d, J = 2.20 Hz, 1H), 7.15 (dd, J = 7.00 Hz, 2.20 Hz, 2H), 3.36 (t, J = 6.40 Hz, 2H), 2.70 (t, J = 6.40 Hz, 2H), 2.28-2.20 (m, 2H); 13C NMR (100 MHz, CDCl3): δ ppm 197.7, 162.5, 150.5, 147.0, 136.8, 132.6, 132.4, 130.1, 128.3, 128.3, 128.0, 127.9, 126.7, 124.4, 40.6, 34.5, 21.2.

2.1.2 7-chloro-3,4-dihydro-9-phenylacridin-1(2H)-one (2b)

Yellow solid, (yield 80%), m.p: 185-187 ºC; 1H NMR (400 MHz, CDCl3): δ ppm 7.97 (d, J = 8.80 Hz, 1H), 7.68 (dd, J = 8.80 Hz, 2.40 Hz, 1H), 7.53-7.47 (m, 3H), 7.41 (d, J = 2.40 Hz, 1H), 7.15 (dd, J = 7.20 Hz, 2.40 Hz, 2H), 3.35 (t, J = 6.20 Hz, 2H), 2.70 (t, J = 6.20 Hz, 2H), 2.27-2.21 (m, 2H); 13C NMR (100 MHz, CDCl3): δ ppm 197.7, 162.5, 150.5, 147.0, 136.8, 132.6, 132.4, 130.2, 128.3, 128.3, 127.9, 126.7, 124.4, 40.6, 34.5, 21.2.

2.1.3 7-chloro-9-(2-chlorophenyl)-3,4-dihydroacridin-1(2H)-one (2c)

Yellow solid, (yield 78%), m.p: 180-181ºC ; 1H NMR (400 MHz, CDCl3): δ ppm 8.02 (d, J = 9.00 Hz, 1H), 7.71 (dd, J = 9.00 Hz, 1.40 Hz, 1H), 7.55 (d, J = 7.60 Hz, 1H), 7.46-7.42 (m,2H), 7.30 (s, 1H), 7.10 (d, J = 6.80 Hz, 1H), 3.37 (t, J = 6.00 Hz, 2H), 2.80-2.65 (m, 2H), 2.24 (t, J = 6.00 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ ppm 197.4, 162.5, 147.4, 147.0, 135.9, 133.1, 132.8, 132.1, 130.7, 130.7, 130.4, 125.9, 125.5, 40.1, 34.4, 21.2.

2.2 General procedure for synthesis of (E)-2-((dimethylamino)methylene)-3,4-dihydro-9-arylacridin-1(2H)-ones (3a-c)

A mixture of 3,4-dihydro-9-phenylacridin-1(2H)-one (0.1g, 0.0005 M) 2a-c with DMFDMA (0.1 mL, 0.0005 M) in toluene (5 mL) and refluxed for 8-10 hrs to afford the product 3a. The mixture was then evaporated under reduced pressure to afford the solid, which was filtered, washed with hexane and then dried. The similar procedure was repeated with 2b-c to get 3b-c. The obtained product used for further analysis without any purification process.

2.2.1 (E)-2-((dimethylamino)methylene)-3,4-dihydro-9-phenylacridin-1(2H)-one (3a)

Colourless solid (yield 86%), m.p: 162-163ºC; 1H NMR (400 MHz, CDCl3): δ ppm 7.98 (d, J = 8.80 Hz, 1H), 7.62 (dd, J = 8.80 Hz, 2.10 Hz, 2H), 7.50-7.45 (m, 4H), 7.42 (d, J = 2.10 Hz, 1H), 7.22 (d, J = 7.60 Hz, 2H), 3.22 (t, J = 6.40 Hz, 2H), 3.10 (s, 6H), 3.02 (t, J = 6.40 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ ppm 185.2, 162.0, 151.1, 148.3, 146.1, 137.9, 131.7, 131.2, 130.0, 129.0, 128.5, 128.3, 128.1, 127.9, 127.4, 126.9, 126.4, 104.7, 43.5, 34.6, 23.2. HRMS-ESI (m/z) calcd for C22H20N2O [M+H]+ = 329.1654, found = 329.1660.

2.2.2 (E)-7-chloro-2-((dimethylamino)methylene)-3,4-dihydro-9-phenylacridin-1(2H)-one (3b)

Colourless solid, (yield 85%), m.p: 172-174ºC; 1H NMR (400 MHz, CDCl3): δ ppm 7.98 (d, J = 9.20 Hz, 1H), 7.62 (dd, J = 9.20 Hz, 2.40 Hz, 2H), 7.50-7.46 (m, 3H), 7.44 (dd, J = 12.80 Hz, 2.40 Hz, 1H), 7.22 (dd, J = 7.80 Hz, 1.80 Hz, 2H), 3.22 (t, J = 6.40 Hz, 2H), 3.10 (s, 6H), 3.02 (t, J = 6.40 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ ppm 185.2, 162.0, 151.1, 148.3, 146.1, 137.9, 131.7, 131.2, 130.0, 129.0, 128.5, 128.3, 128.1, 127.9, 127.4, 126.9, 126.4, 104.7, 43.5, 34.6, 23.2. HRMS- ESI (m/z) calcd for C22H19ClN2O [M+H]+ = 362.1654, found = 362.1654.

2.2.3 (E)-7-chloro-2-((dimethylamino)methylene)-9-(2-chlorophenyl)-3,4 dihydroacridin-1(2H)-one (3c)

Light brown solid, (yield 84%), m.p.: 158-159ºC; 1H NMR (400 MHz, CDCl3): δ ppm 8.00 (d, J = 9.00 Hz, 1H), 7.64 (dd, J = 9.00 Hz, 2.40 Hz, 2H), 7.53 (dd, J = 7.10 Hz, 1.80 Hz, 1H), 7.42-7.36 (m, 2H), 7.27 (d, J = 2.40 Hz, 1H), 7.15 (dd, J = 7.10 Hz, 1.80 Hz, 1H), 3.24 (t, J = 6.40 Hz, 2H), 3.10 (s, 6H), 3.03 (t, J = 6.40 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ ppm 184.7, 161.9, 151.3, 146.4, 145.0, 137.1, 132.4, 132.1, 131.4, 130.2, 129.6, 129.2, 128.9, 127.0, 126.5, 125.6, 104.2, 43.6, 34.5, 23.1. HRMS- ESI (m/z) calcd for C22H18Cl2N2O [M+H]+ = 397.0874, found = 397.0871.

2.3 General procedure for the synthesis of 4,5-dihydro-11-aryl-2H-pyrazolo[3,4-a] acridines (4a-c)

A mixture of compound 3a (0.1 g, 0.0003 M), hydrazine hydrate (0.05 mL, 0.0101 M) and 1-2 drops of acetic acid (catalyst) in ethanol (10 mL) was refluxed at 80 °C for 6-8 h. The mixture was then extracted with ethyl acetate, dried over sodium sulphate and concentrated under reduced pressure to afford the crude product 4a. The obtained crude product was purified by silica gel column chromatography using ethylacetate/hexane (4:6) eluent. To check there reproducibility the reaction and to get 4b-c, the procedure was repeated with 3b-c.

2.3.1 4,5-dihydro-11-phenyl-2H-pyrazolo[3,4-a]acridine (4a)

Colourless solid, (yield 76%), m.p: 166-168ºC;1H NMR (400 MHz, CDCl3): δ ppm 8.40 (d, J = 8.00 Hz, 1H), 7.65 (dd, J = 5.40 Hz, 1.80 Hz, 4H), 7.41 (d, J = 3.00 Hz, 1H), 7.39 (d, J = 3.00 Hz, 1H), 7.37 (d, J = 5.40 Hz, 2H), 7.33 (d, J = 8.00 Hz, 1H), 3.40 (t, J = 6.80 Hz, 2H), 2.98 (t, J = 6.80 Hz, 2H), 1.90 (s, 1H). 13C NMR (100 MHz, CDCl3): δ ppm 158.1, 148.60, 147.1, 142.7, 135.9, 130.2, 129.3, 128.7, 128.5, 127.3, 127.0, 126.7, 117.4, 115.1, 33.7, 17.6; HRMS- ESI (m/z) calcd for C20H15N3 [M+H] + = 298.1344, found = 298.1338.

2.3.2 9-chloro-4,5-dihydro-11-phenyl-1H-pyrazolo[3,4-a] acridine(4b)

Colourless solid, (yield 79%), m.p: 155-157ºC; 1H NMR (400 MHz, CDCl3): δ ppm 8.00 (d, J = 8.40 Hz, 1H), 7.69 (dd, J = 8.40 Hz, 1.20 Hz, 1H), 7.62-7.59 (m, 2H), 7.58 (t, J = 2.20 Hz, 1H), 7.54 (dt, J = 1.20 Hz, 7.50 Hz, 1H), 7.39 (s, 1H), 7.35 (dd, J = 7.50 Hz, 1.60 Hz, 1H), 7.18 (d, J = 2.20 Hz, 1H), 3.38 (t, J = 3.00 Hz, 2H), 3.00 (t, J = 3.00 Hz, 2H), 2.16 (s, 1H). 13C NMR (100 MHz, CDCl3): δ ppm 159.0, 144.7, 138.9, 137.0, 136.7, 135.9, 132.4, 130.3, 130.1, 130.0, 129.7, 129.6, 129.1, 128.0, 127.9, 124.7, 119.3, 118.9, 34.4, 29.7. HRMS- ESI (m/z) calcd for C20H14ClN3 [M+H]+ = 332.0955, found = 332.1001.

2.3.3 9-chloro-11-(2-chlorophenyl)-4,5-dihydro-1H-pyrazolo[3,4-a]acridine (4c)

Brown solid, (yield 59%), m.p: 164-166ºC; 1H NMR (400 MHz, CDCl3): δ ppm 8.01 (d, J = 6.90 Hz, 1H), 7.71 (d, J = 6.90 Hz, 1H), 7.61-7.57 (m, 2H), 7.53 (t, J = 6.90 Hz, 1H), 7.39 (s, 1H), 7.36 (dd, J = 6.00 Hz, 1.80 Hz, 1H), 7.19 (d, J = 1.80 Hz, 1H), 3.38 (t, J = 3.40 Hz, 2H), 3.00 (t, J = 3.40 Hz, 2H), 2.00 (s, 1H). 13C NMR (100 MHz, CDCl3): δ ppm 159.3, 144.8, 136.2, 135.1, 133.8, 132.6, 131.0, 130.7, 130.5, 130.1, 128.0, 127.4, 124.2, 120.2, 34.4, 18.6. HRMS- ESI (m/z) calcd for C20H13Cl2N3 [M+H]+ = 366.0565, found = 366.0565.

2.4 General procedure for the synthesis of 4,5-dihydro-11-phenylisoxazolo[5,4-a] acridines (5a-c)

A mixture of compound 3a (0.1 g, 0.0003 M) in ethanol (10 mL), hydroxyl amine hydrochloride (0.02 g, 0.0003 M) was refluxed at 80°C for 6-8 h. After the completion of the reaction, the reaction mixture was poured into ice water; the obtained crude was filtered, dried to afford the product 5a. The obtained product was purified by silica gel column chromatography using ethylacetate/hexane (4:6) eluent. Similar procedure was adopted with 3b-c to get 5b-c.

2.4.1 4,5-dihydro-11-phenylisoxazolo[5,4-a]ccridine (5a)

Colourless solid, (yield 86%), m.p: 160-161ºC; 1H NMR (400 MHz, CDCl3): δ ppm 8.11 (s, 1H), 8.05 (d, J = 8.20 Hz, 1H), 7.64 (t, J = 8.20 Hz, 1H), 7.54 (t, J = 2.40 Hz, 3H), 7.48 (d, J = 7.90 Hz, 1H), 7.41 (t, J = 7.90 Hz, 1H), 7.34 (dd, J = 6.60 Hz, 2.40 Hz, 2H), 3.44 (t, J = 7.20 Hz, 2H), 2.95 (t, J = 7.60 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ ppm 158.1, 148.6, 147.1, 142.7, 135.9, 130.2, 129.3, 128.7, 128.5, 127.3, 127.0, 126.7, 117.4, 115.1, 33.7, 17.6. HRMS- ESI (m/z) calcd for C20H14N2O [M+H]+ = 299.1184, found = 299.1191.

2.4.2 9-chloro-4,5-dihydro-11-phenylisoxazolo[3,4-a] Acridine (5b)

Yellow solid, (yield 69%), m.p: 152-154ºC; 1H NMR (400 MHz, CDCl3): δ ppm 8.12 (s, 1H), 7.98 (d, J = 8.80 Hz, 1H), 7.66 (dd, J = 5.20 Hz, 2.20 Hz, 1H), 7.63 (d, J = 2.00 Hz, 1H), 7.62 (dd, J = 8.80 Hz, 2.00 Hz, 1H), 7.56 (dd, J = 4.90 Hz, 2.50 Hz, 2H), 7.32 (dd, J = 4.90 Hz, 2.50 Hz, 2H), 3.43 (t, J = 7.20 Hz, 2H), 2.96 (t, J = 7.20 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ ppm 163.8, 158.4, 148.6, 146.2, 145.5, 141.7, 135.2, 132.6, 132.2, 131.3, 130.9, 130.3, 129.4, 129.2, 129.2, 128.9, 128.7, 128.5, 128.2, 127.6, 125.7, 125.3, 122.5, 117.9, 115.9, 33.7, 17.5. HRMS- ESI (m/z) calcd for C20H13ClN2O [M+H]+ = 332.0950, found = 332.0950.

2.4.3 9-chloro-11-(2-chlorophenyl)-4,5-dihydroisoxazolo[5,4-a]Acridine (5c)

Yellow solid, (yield 49%), m.p: 168-170ºC; 1H NMR (400 MHz, CDCl3): δ ppm 8.12 (s, 1H), 7.98 (d, J = 8.80 Hz, 1H), 7.62 (d, J = 8.80 Hz, 2.40 Hz, 1H), 7.56 (dd, J = 9.00 Hz, 2.00 Hz, 2H), 7.43 (d, J = 2.40 Hz, 1H), 7.30 (dd, J = 9.00 Hz, 2.40 Hz, 2H), 3.41 (t, J = 7.30 Hz, 2H), 2.97 (t, J = 7.30 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ ppm 160.8, 152.2, 147.9, 147.4, 146.3, 144.6, 136.6, 129.9, 129.8, 129.6, 129.6, 129.5, 128.6, 128.5, 128.4, 128.2, 128.0, 127.7, 127.5, 126.7, 126.4, 126.2, 126.1, 125.9, 125.7, 33.9, 29.7. HRMS- ESI (m/z) calcd for C20H12Cl2N2O [M+H]+ = 367.0405, found = 367.0403.

2.5 General procedure for the synthesis of 4,5-dihydro-1,11-diaryl-1H-pyrazolo[3,4-a] acridine (6a-c)

A mixture of compound 3a (0.1 g, 0.0003 M), phenyl hydrazine (0.03 g, 0.0003 M) in glacial acetic acid (5 mL), was refluxed at 110°C for 12 h. The reaction mixture was then extracted with DCM, dried over sodium sulphate and concentrated under reduced pressure to afford the crude product 6a. The obtained crude product was purified by silica gel column chromatography using ethylacetate/hexane (4:6) eluent. To check the reproducibility similar procedure was adopted with 3b-c to get 6b-c.

2.5.1 4,5-dihydro-1,11-diphenyl-1H-pyrazolo[3,4-a] ccridine (6a)

Yellow solid, (yield 66%), m.p: 182-183ºC; 1H NMR (400 MHz, CDCl3): δ ppm 8.09 (d, J = 7.00 Hz, 1H), 7.71 (t, J = 7.00 Hz, 2H), 7.54 (d, J = 7.60 Hz, 2H), 7.46 (d, J = 7.00 Hz, 2H), 7.42 (dd, J = 6.00 Hz, 2.00 Hz, 2H), 7.36 (d, J = 2.00 Hz, 1H), 7.34 (t, J = 2.40 Hz, 2H), 7.31 (d, J = 7.60 Hz, 1H), 7.28-7.27 (m, 1H), 7.25 (d, J = 2.40 Hz, 1H), 3.28 (t, J = 6.60 Hz, 2H), 2.98 (t, J = 6.60 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ ppm 152.2, 147.9, 147.4, 146.3, 144.6, 136.6, 129.9, 129.6, 129.6, 129.5, 128.5, 128.4, 128.2, 127.7, 127.7, 126.7, 126.4, 126.1, 126.0, 125.7, 33.9, 29.7. HRMS- ESI (m/z) calcd for C26H19N3 [M+H]+ = 374.1675, found = 374.1655.

2.5.2 9-chloro-4,5-dihydro-1,11-diphenyl-1H-pyrazolo[3,4-a]acridine (6b)

Yellow solid, (yield 58%), m.p: 175-177ºC; 1H NMR (400 MHz, CDCl3): δ ppm 8.10 (d, J = 8.60 Hz, 1H), 7.71 (t, J = 8.60 Hz, 2H), 7.54 (d, J = 7.60 Hz, 2H), 7.47 (d, J = 7.10 Hz, 2H), 7.36 (dd, J = 7.60 Hz, 2.40 Hz, 2H), 7.35 (d, J = 1.80 Hz, 1H), 7.31 (d, J = 7.10 Hz, 2H), 7.28 (t, J = 1.80 Hz, 1H), 7.27 (d, J = 5.60 Hz, 1H), 3.29 (t, J = 6.20 Hz, 2H), 2.99 (t, J = 6.20 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ ppm 160.9, 152.9, 147.9, 147.4, 146.3, 144.6, 136.6, 129.9, 129.8, 129.6, 129.6, 128.6, 128..5, 128.4, 128.2, 128.0, 127.6, 126.6, 126.4, 126.2, 126.1, 126.0, 125.7, 33.9, 29.7. HRMS- ESI (m/z) calcd for C26H18ClN3 [M+H]+ = 408.1268, found = 408.1267.

2.5.3 9-chloro-11-(2-chlorophenyl)-4,5-dihydro-1-phenyl-1H-pyrazolo[3,4-a]acridine (6c)

Brown solid, (yield 59%), m.p: 187-189ºC; 1H NMR (400 MHz, CDCl3): δ ppm 8.10 (d, J = 8.60 Hz, 1H), 7.71 (t, J = 8.60 Hz, 2H), 7.54 (d, J = 7.60 Hz, 2H), 7.47 (d, J = 7.00 Hz, 2H), 7.42 (d, J = 1.40 Hz, 2H), 7.36 (dd, J = 7.60 Hz, 2.40 Hz, 2H), 7.31 (d, J = 7.00 Hz, 1H), 7.28 (t, J = 1.40 Hz, 1H), 3.29 (t, J = 6.20 Hz, 2H), 2.99 (t, J = 6.20 Hz, 2H).13C NMR (100 MHz, CDCl3): δ ppm 160.9, 152.2, 147.9, 147.4, 146.3, 144.6, 136.6, 129.9, 129.8, 129.6, 129.6, 129.5, 128.6, 129.5, 128.4, 128.2, 128.0, 127.7, 127.6, 126.7, 126.4, 126.2, 126.1, 126.0, 125.7, 33.9, 29.7. HRMS- ESI (m/z) calcd for C26H17Cl2N3 [M+H]+ = 442.0881, found = 442.0881.

2.6 Spectral Characterization

All these newly synthesized compounds 3a-c to 6a-c were characterized using 1H-NMR, 13C-NMR, DEPT-135, H, H-COSY, C, H-COSY, HR-MS (ESI) and the data included in the experimental section. Consequently, all the newly derived target molecules 3a-c to 6a-c subjected to the in-vitro anti-fungal, anti-bacterial and antioxidant evaluations and their results were discussed under biological evaluations.

2.6.1 Spectral Characterization of Compound 3c

The compound 3c has been characterized by 1H-NMR, 13C-NMR, DEPT-135, H, H-COSY, C, H-COSY, HR-MS (ESI) spectral data. The 1H-NMR spectrum of compound 3c exhibited the following chemical shifts, d 8.00 d [J = 9.00 Hz, one proton], 7.64 dd [J = 9.00 Hz, 2.40 Hz, two proton], 7.53 dd [J = 7.10 Hz, 1.80 Hz, one proton], 7.427.36 m [two protons], 7.27 d [J = 2.10 Hz, one proton], 7.15 dd [J = 7.10 Hz, 2.10 Hz, one proton], 3.24 t [J = 6.40 Hz, two protons], 3.10 s [six protons], 3.03 t [J = 6.40 Hz, two protons]. The examination of H, H-COSY spectrum of the molecule shows that the singlet at d 3.10 ppm which is integrating for six protons due to the two methyl groups of the molecule at C-18 and C-19 and it is appeared as a single peak due to symmetry. The remaining two methylene protons have appeared at d 3.24 and 3.03 ppm which are integrating for two protons of each at C-14 and C-15. The signals at d 8.00 d [J = 9.00 Hz, one proton], 7.64 dd [J = 9.00 Hz, 2.40 Hz, two protons] and 7.27 d [J = 2.40 Hz, one proton] are appearing as coupling partners, which is assigned to C-8, C-7 and C12 respectively. The signals at d 7.53 dd [J = 7.10 Hz, 1.80 Hz, one proton] and 7.16 dd [J = 7.20 Hz, 1.60 Hz, one proton] ppm are assigned to C-10 and C-13 respectively and are found to couple with the multiplet in the range of 7.42-7.36 ppm and hence the multiplet assigned to the protons at C-11 and C-12. The 13C-NMR spectrum exhibited the following chemical shift values: d 23.1, 34.5, 43.6, 104.2, 125.6, 126.5, 127.0, 128.9, 129.2, 130.2, 131.4, 132.1, 132.4, 137.1, 145.6, 146.4, 151.3, 161.9, 184.7 ppm. The up-field signal at d 23.1 ppm has been assigned as a methylene carbon at C-15 and one more signal at d 34.5 ppm represents at C-14. And the remaining two methyl groups at C-18 and C-19 appear as a singlet at d 43.6 ppm is due to symmetry. The extreme downfield signal at d 84.7 ppm is indicates the carbonyl group at C-22. The signal at d 151.3 ppm has been assigned to the carbon at C-17 due to the deshielding effect of adjacent functional groups. The C-7 and C-8 carbons were identified as d 130.2 and 132.4 ppm respectively. The aliphatic CH2 carbons at (C-14 and C-15) carbons were distinguished using the DEPT-135 spectrum of the compound. Remaining aromatic carbon attached hydrogen appears from the aromatic region from d 151.4 to 125.6 ppm. Similarly, the ortho, meta and para carbons of phenyl group at C-4 were identified as d 129.2, 126.5 and 125.6 ppm respectively. The signals at d 104.2, 127.0, 132.1, 137.2, 145.0, 146.4, 161.9 and 184.7 ppm were due to the non-proton bearing carbons at C-20, C-6, C-3, C-23, C-16, C-2, C-22 and ipso positions. The formation of compound 3c also been supported by the observation of (ESI-HRMS) m/z value at 397.0871 in the mass spectrum.

Figure 1 Summary of Proton d Values of 3c.
Figure 1

Summary of Proton d Values of 3c.

Figure 2 Summary of Carbon d Values of 3c.
Figure 2

Summary of Carbon d Values of 3c.

2.6.2 Spectral Characterization of Compound 4a

The compound 4a has been characterized by 1H-NMR, 13C-NMR, DEPT-135, H, H- COSY, C, H-COSY, HR-MS (ESI) spectral data. The 1H-NMR spectrum of compound 4a exhibited the following chemical shifts, d 8.40 d [J = 8.00 Hz, one proton], 7.64 dd [J = 5.40 Hz, 1.80 Hz, four protons], 7.41 d [J = 3.00 Hz, one proton], 7.39 d [J = 3.00 Hz, one proton], 7.37 d [J = 5.40 Hz, two protons], 7.33 d [J = 8.00 Hz, one proton], 3.40 t [J = 6.80 Hz, two protons], 2.98 t [J = 6.80 Hz, two protons], 1.90 s [one proton]. The examination of H, H-COSY spectrum of the molecule shows that the two triplets at d 3.40 and 2.98 ppm which is integrating for two protons of each are assigned to C-14 and C-15. The signal at d 8.40 ppm which integrates for one proton is assigned to C-8. The signal at d 7.64 [J = 5.40 Hz, 1.80 Hz, four protons] is assigned to C-7, C-6, C-5 and C-9 respectively. The signal at d 7.41 d [J = 3.00 Hz, one proton], 7.39 d [J = 3.00 Hz, one proton] are appearing as a coupling partner, which is assigned to C-10 and C-11 respectively. And a signal at d 7.33 d [J = 8.00 Hz, one proton] is assigned to C-13. The 13C-NMR spectrum exhibited the following chemical shift values: d 17.6, 33.7, 115.4, 117.2, 126.7, 127.0, 127.3, 128.7, 128.0, 128.8, 130.2, 135.9, 142.7, 147.1, 148.6, 158.1 ppm. The up-field signal at d 17.6 ppm has been assigned as methylene carbon at C-15 and one more signal at d 34.5 ppm represents at C-14. The extreme downfield signal at d 158.1 ppm is assigned to C-18. The proton bearing carbons are identified using HSQC spectrum. The signal at d 126.0 ppm has been assigned to the carbon at C-16 due to the shielding effect of adjacent functional groups. The C-7 and C-8 carbons were identified as d 129.8 and 128.7 ppm respectively. The aliphatic CH2 carbons at (C-14 and C-15) carbons were distinguished using the DEPT-135 spectrum of the compound. Remaining aromatic carbon attached hydrogen appears from the aromatic region from d 129.8 to 18.7 ppm. Similarly, the ortho, meta and para carbons of phenyl group at C-4 were identified as d 129.3, 129.1 and 126.5 ppm respectively. The signals at d 117.9, 127.0, 127.3, 130.2, 135.9, 142.7, 147.1, 158.1 ppm were due to the non-proton bearing carbons at C-21, C-17, C-20, C-3, C-19, C-18, C-2 and ipso positions. The formation of compound 4a also been supported by the observation of (ESI-HRMS) m/z value at 298.1338 in the mass spectrum.

2.6.3 Spectral Characterization of Compound 5a

The compound 5a has been characterized by 1H-NMR, 13C-NMR, DEPT-135, H, H- COSY, C, H-COSY, HR-MS (ESI) spectral data. The 1H-NMR spectrum of compound 5a exhibited the following chemical shifts, d 8.11 s [one proton], 8.05 d [J = 8.20 Hz, one proton], 7.64 t [J = 8.20 Hz, one proton], 7.54 t [J = 2.40 Hz, three protons], 7.48 d [J = 7.90 Hz, one proton], 7.41 d [J = 7.90 Hz, one proton], 7.34 dd [J = 6.60 Hz, 2.40 Hz, two protons], 3.44 t [J = 7.20 Hz, two

Figure 3 Summary of Proton d Values 4a.
Figure 3

Summary of Proton d Values 4a.

Figure 4 Summary of Carbon d Values 4a.
Figure 4

Summary of Carbon d Values 4a.

Figure 5 Summary of Proton d Values 5a.
Figure 5

Summary of Proton d Values 5a.

Figure 6 Summary of Carbon d Values 5a.
Figure 6

Summary of Carbon d Values 5a.

protons], 2.95 t [J = 7.60 Hz, two protons]. The examination of H, H-COSY spectrum of the molecule shows that the two triplets at d 3.44 and d 2.95 ppm which is integrating for two protons of each are indicated at C-14 and C-15. The signal at d 8.05d [J = 8.20 Hz, one proton] and 7.64 t [J = 8.20 Hz, one proton] are appearing as a coupling partner, which is assigned to C-8 and C-7 respectively. The signal at d 8.11 ppm is assigned to C-16. The signals at d 7.54 t [J = 2.40 Hz, three protons] and 7.34 dd [J = 6.60 Hz, 2.40 Hz, two protons] with a coupling constant of [J = 6.00 Hz, 2.40 Hz, two protons]. And the signals at d 7.48 d [J = 7.90 Hz, one proton] and 7.41 d [J = 7.90 Hz, one proton] are appearing as a coupling partners is assigned for C-10 and C-9 respectively. The 13C-NMR spectrum exhibited the following chemical shift values: d 17.6, 33.7, 115.1, 117.1, 126.7, 127.0, 127.3, 128.5, 128.7, 129.3, 130.2, 135.9, 142.7, 147.1, 148.6, 158.1 ppm. The up-field signal at d 33.7 ppm has been assigned as a methylene carbon at C-14 and one more signal at d 17.6 ppm represents at C-15. The extreme downfield signal at d 158.1 ppm is assigned to C-2. The signal at d 148.6 ppm has been assigned to the carbon at C-16 due to shielding effect of adjacent functional groups. The C-7 and C-8 carbons were identified as d 130.3 and 130.9 ppm respectively. The aliphatic CH2 carbons at (C-14 and C-15) carbons were distinguished using DEPT-135 spectrum of the compound. Remaining aromatic carbon attached hydrogen appears from aromatic region from d 148.6 to 125.7 ppm. Similarly, the ortho, meta and para carbons of phenyl group at C-4 were identified as d 129.7, 129.2 and 128.5 ppm respectively. The formation of compound 5a also been supported by the observation of (ESI-HRMS) m/z value at 299.1191 in the mass spectrum.

2.6.4 Spectral Characterization of Compound 6a

The compound 6a has been characterized by 1H-NMR, 13C-NMR, DEPT-135, H, H-COSY, C, H-COSY, HR-MS (ESI) spectral data. The 1H-NMR spectrum of compound 6a exhibited the following chemical shifts, d 8.09 d [J = 7.00 Hz, one proton], 7.71 t [J = 7.00 Hz, two protons], 7.54 d [J = 7.60 Hz, two protons], 7.46 d [J = 7.00 Hz, two protons], 7.42 dd [J = 6.00 Hz, 2.00 Hz, two protons], 7.36 d [J = 2.00 Hz, one proton], 7.34 t [J = 2.40 Hz, two protons], 7.31 d [J = 7.60 Hz, one proton], 7.28-7.27 m [one proton], 7.25 d [J = 2.40 Hz, one proton], 3.28 t [J = 6.60 Hz, two protons], 2.98 t [J = 6.60 Hz, two protons]. The examination of H, H-COSY spectrum of the molecule shows that the two triplets at d 3.28 and 2.98 ppm which is integrating for two protons of each are due to C-14 and C-15. The signals at d 8.09 d [J = 7.00 Hz, one proton], 7.71 t [J = 7.00 Hz, two protons] and 7.46 d [J = 7.00 Hz, two protons] are appearing as a coupling partners is assigned to C-8, C-7, C-9, C-5 and C10 respectively. The signals at d 7.54 d [J = 7.60 Hz, two protons] and 7.31 d [J = 7.60 Hz, one proton] are appearing as a coupling partners is assigned to C-12, C-13 and C-11 respectively. Similarly, the signals at d 7.34 t [J = 2.40 Hz, two protons] and 7.25 d [J = 2.40 Hz, one proton] is assigned for phenyl substituent at C-17. The 13C-NMR spectrum exhibited the following chemical shift values: d 29.7, 33.9, 125.7, 126.0, 126.1, 126.2, 126.4, 126.7, 127.6, 127.7, 128.0, 128.2, 128.4, 128.5, 128.6, 129.5, 129.6, 129.8, 129.9, 136.6, 144.6, 146.3, 147.4, 147.9, 152.2 ppm. The up-field signal at d 33.9 ppm has been assigned as a methylene carbon at C-14 and one more signal at d 29.7 ppm represents at C-15. The extreme downfield signal at d 152.2 ppm is assigned to C-2. The signal at d 129.8 ppm has been assigned to the carbon at C-16 due to shielding effect of adjacent functional groups. The C-7 and C-8 carbons were identified as d 129.6 and 128.6 ppm respectively. The aliphatic CH2 carbons at (C-14 and C-15) carbons were distinguished using the DEPT-135 spectrum of the compound. Remaining aromatic carbon attached hydrogen appears from the aromatic region from d 152.2 to 146.6 ppm. Similarly, the ortho, meta and para carbons of phenyl group at C-4 were identified as d 127.7, 126.7 and 125.9 ppm respectively. The signals at d 126.1, 129.9, 136.6, 144.6, 146.3, 147.4, 147.9, 152.2 ppm were due to the non-proton bearing carbons at C-18, C-3, C-4, C-17, C-19, C-20, C-2 and ipso positions. The formation of compound 6a also been supported by the observation of (ESI-HRMS) m/z value at 374.1655 in mass the spectrum.

Figure7 Summary of Proton d Values of 6a.
Figure7

Summary of Proton d Values of 6a.

Figure 8 Summary of Carbon d Values of 6a.
Figure 8

Summary of Carbon d Values of 6a.

2.7 In-vitro antibacterial studies by micro dilution method

The indicator strains used were Staphylococcus aureus MTCC 737, Bacillus Cereus MTCC 430, Staphylococcus aureus MLS16, Klebsiella planticola MTCC 2277, Escherichia Coli MTCC 1687 and Pseudomonas aeruginosa MTCC 424. The test bacterial strains were grown in nutrient broth medium and inoculums prepared were stored at 4°C for further use. The dilutions of the bacterial inoculums were cultured on a nutrient agar medium to check for the presence of contamination. The bacterial suspension was adjusted with sterile saline to a final concentration of approximately 107 CFU/mL in a final volume of 100 μL per well in 96 well plate. The bacterial pathogens were inoculated in Muller-Hinton broth along with different concentrations of compounds including 0.488, 0.244, 0.122, 0.061, 0.030, 0.015, 0.007, 0.003, 0.001 and 0.001 μM. Neomycin (Sigma) was used as positive control and Muller-Hinton culture media alone was used as negative control. The bacterial pathogens were incubated along with compounds for 24 h. After incubating for 24 h, 40 μL of INT dye solution was added to each well. The INT dye solution was prepared by dissolving 0.02% of 20 mg INT in 100 mL of 40% DMF. Further the samples were incubated for 2 h. Then the samples were spectrometrically read at 450 nm using TRIAD multi-mode reader which measures the reduction of INT dye by bacterial pathogens. The percentage of bacterial growth inhibition was calculated using the formula:

% of bacterial growth inhibition = (1−Ac/Ao) × 100.

Where Ac represents intensity of the wells with compound concentration C; Ao represents intensity of the negative control without compound concentrations. Further, minimum inhibitory concentration, MIC (μM) values representing the lowest concentration of the compound which exhibited significant decrease in bacterial viability (>95%) was determined. All the experiments were performed in triplicate and the results were expressed as the average of three independent experiments. The results were given as Table-3 along with the minimum inhibitory concentrations. The compounds exhibited a broad spectrum of antibacterial activity against the tested Gram-positive bacterial pathogens.

Table 1

Optimization for the synthesis of 3,4-dihydro-9-arylacridin-1(2H)-ones based enaminones.

S. NoSolventsT (°C)Time (h)Yield (%)
1DMF901418
2DMF1001238
3DMF>110851
4Xylene120666
5Toluene110685
6Acetonitrile904812
7Dioxane1003611
Table 2

Antifungal activity of compounds by broth dilution method.

CompoundsMinimum Inhibitory Concentration, MIC (μM )
Candida albicansCandida parapsilosisCandida aaseriCandida glabrataIssatchenkia hanoiensisAspergillus niger
MTCC 227MTCC 6510MTCC 1907MTCC 3984MTCC 4755MTCC 1344
3a0.0070.0280.2280.0570.0570.057
3b-0.051---0.051
3c-0.0940.3780.0940.0940.047
4a-0.0630.2520.031--
4c---0.1130.113-
5a-0.0310.2510.0620.251-
6a-0.023-0.050-0.006

  1. - : No Activity; Miconazole 0.022 † Standard.

Table 3

Antibacterial activity of compounds by micro dilution method.

CompoundsMinimum Inhibitory Concentration, MIC (μM)
Gram Positive BacteriaGram Negative Bacteria
StaphylococcusBacillus StaphylococcusKlebsiellaEscherichiaPseudomonas
aureuscereus aureusplanticolacoliaeruginosa
MTCC 737MTCC 430 MLS16MTCC 2277MTCC 1687MTCC 424
3a-- --0.0070.007
3b-- 0.006---
4a0.0310.007 0.2520.0070.0030.007
4c-- 0.0560.056--
5a0.0150.007 0.125-0.0150.031
6a0.012- 0.0120.0500.0250.100
6c0.021- 0.042---

  1. – : No Activity; Nm-Neomycin (0.030) † Standard.

2.8 In-vitro antioxidant activity by DPPH free radical scavenging method

The antioxidant activity of the compounds was assayed by measuring scavenging of 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radicals. In this experiment, different concentrations (10, 20, 40, 80, and 200 μg mL−1) of each compound were prepared in methanol. Then, working solutions were mixed with 100 μL 160 μM methanol solution of DPPH. The reaction mixture was thoroughly mixed for 2 min. The samples were then incubated for 30 min in the dark at 35°C. After incubating for 30 min, the absorbance of the samples was measured spectroscopically at 517 nm using a TRIAD multimode reader. In this experiment, ascorbic acid was used as positive control and methanol solution as a negative control. The radical scavenging potential is expressed as an EC50 value, representing the compound concentration at which 50% of the DPPH radicals was scavenged. All tests were performed in triplicate, and values are presented as means. The ability of the compound to scavenge the formation of DPPH free radicals was measured in a concentration-dependent manner and the DPPH scavenging activity calculated in terms of the effective concentration.

2.9 In-vitro antifungal studies by broth dilution method

The antifungal activity of the compounds was determined by broth dilution method using p-iodonitrotetrazolium (INT) dye reduction method in 96 well plates. Different test fungal pathogens used in the study include Candida albicans MTCC 227 (MTCC-Microbial Type Culture Collection), Candida parapsilosis MTCC 6510, Candida glabrata MTCC 3984, Candida aaseri MTCC 1907, Aspergillus niger MTCC 1344 and Issatchenkia hanoiensis MTCC 4755. The test fungal strains (107 CFU/mL) were inoculated in 100 μL of potato dextrose broth and the test cultures were stored at 4°C for further experiments. The purity of the test cultures was verified by culturing on nutrient agar medium. In a 96-well plate, fungal test cultures were inoculated with the final concentration of approximately 107 CFU/mL in the final volume of 100 μL per well. To each fungal suspension, compound was added at different concentrations of 0.720, 0.360, 0.180, 0.090, 0.045, 0.011, 0.005, 0.002 and 0.001 μM. In positive control experiments, miconazole (Sigma) was added to each fungal test culture, while potato dextrose broth medium alone was used as negative control. The fungal pathogens were incubated along with test compound for 24 h at 30°C. Aspergillus strain was incubated at 25°C for 72 h. After incubation periods, 40 mL INT test reagent containing 0.02% 20 mg INT in 100 mL 40% dimethylformamide (DMF) was added to each well. The samples were further incubated for 2 h at 37°C. Reduction of INT dye was monitored spectrometrically by measuring samples at 450 nm using a TRIAD multimode reader. The percentage of fungal pathogen growth inhibition was calculated using the formula:

% of fungal pathogen growth inhibition = (1−Ac/Ao) × 100.

Where AC is the INT absorbance of wells with compound at concentration C and A0 represents the INT absorbance of the negative control without compound. The minimum inhibitory concentration (MIC, μM) of the samples represents the lowest concentration of the compound with >95% decrease in fungal growth. All experiments were performed in triplicates, and the results are expressed as the average of three independent experiments.

Ethical approval: The conducted research is not related to either human or animal use.

3 Results and discussion

3.1 Chemistry

In the present work, a series of 3,4-dihydro-9-arylacridin-1(2H)-one based enaminones and their derivatives were synthesized. In the first step different benzophenone derivatives (1a-c) were converted into their corresponding 3,4-dihydro-9-arylacridin-1(2H)-ones (2a-c) by treating them with 1, 3-cyclohexanedione (Scheme) in ethanol in the presence of ortho-phosphoric acid as a catalyst. The obtained products 2a-c were further treated with DMFDMA catalyst to form corresponding enaminones (3a-c) under the conventional heating method, in which different solvents such as DMF, xylene, toluene, acetonitrile and dioxane were examined for the effective conversion of 2a-c to 3a-c (Scheme). The yield was observed to be better with toluene and hence, toluene was considered as a suitable solvent for this reaction (Table-1). All the newly formed enaminones 3a-c were characterized using 1H-NMR, 13C-NMR, DEPT-135, H, H-COSY, HSQC, HR-MS (ESI) and the detailed data included in the experimental part.

The above enaminone derivatives (3a-c) afford various cyclized derivatives of 3,4-dihydro-9-arylacridin-1(2H)-ones such as 4a-c, 5a-c and 6a-c (Scheme) while it is treated with reagents such as hydrazine, hydroxylamine hydrochloride and phenylhydrazine. All these newly synthesized compounds were characterized using 1H-NMR, 13C-NMR, DEPT-135, H, H-COSY, HSQC, HR-MS (ESI) and the data included in the experimental section. Consequently, all the newly derived compounds 3a-c, 4a-c, 5a-c and 6a-c were subjected to the antifungal, antibacterial and anti-oxidant evaluations and their results are discussed under biological evaluation.

3.2 Biological evaluations

3.2.1 In-vitro antifungal activity

The antifungal activity of the compounds is presented in terms of MIC in Table-2. These minimum inhibitory concentration values demonstrate that the compounds exhibited good to moderate antifungal activity against the tested fungal pathogens. Among the compounds, 3a and 6a showed the highest antifungal activity with MIC value 0.007 and 0.006 μM against Candida albicans and Aspergillus niger respectively. In the case of Candida parapsilosis, promising antifungal activity was observed for compounds 3a, 5a and 6a with MIC values such as 0.028, 0.031 and 0.023 μM respectively. In the case of Aspergillus niger, compound 6a showed good antifungal activity as compared with positive control miconazole with MIC value of 0.006 μM. In the case of Candida glabrata, compound 4a exhibited good antifungal activity with MIC value 0.031 μM. The other compounds such as 4b, 5b-c and 6b-c failed to exhibit the activity against the all the fungal pathogens tested and hence not included in Table-2. The compound which showed lower antifungal activity is due to substitution on benzene ring, whereas compound 3a, 4a and 6a has no such substitution and hence exhibiting better activity.

Scheme 1 Synthesis of enaminone of 3,4-dihydro-9-arylacridin-1(2H)-ones and their derivatives.
Scheme 1

Synthesis of enaminone of 3,4-dihydro-9-arylacridin-1(2H)-ones and their derivatives.

The results demonstrate that the compounds possess good antifungal activity against the fungal pathogens. Among all the compounds, the compounds 3a and 6a exhibited considerable fungal activity (MIC value as 0.89 μM) against Candida albicans MTCC 227 and Aspergillus niger MTCC 1344 respectively. Whereas other compounds, the anti-fungal activity is lower than 3a and 6a due to substitution on the aryl ring but in 3a and 6a there is no substitution on it.

3.2.2 In-vitro antibacterial activity

The compounds exhibited promising broad-spectrum antibacterial activity against the tested Gram-positive and Gram-negative bacteria pathogens. The antibacterial activity of the compounds is presented in terms of minimum inhibitory concentration in Table-3. In case of S. aureus strain, the compounds 5a and 6a exhibited the highest antibacterial activity with minimum MIC value (0.015 and 0.012 μM) compared with the positive control. In the case of K. planticola strain, compounds 4a exhibited the highest antibacterial activity with minimum MIC value (0.007 μM) compared with the positive control. The compounds 4a and 5a showed promising antibacterial activity in the case of test strain Bacillus cereus with MIC value 0.007 μM. Similarly, in the case of Staphylococcus aureus compounds 3b and 6a exhibited good antibacterial activity with minimum MIC values (0.006 and 0.012 μM) in comparison with neomycin standard. Furthermore, it was observed that compound 4a showed excellent antibacterial activity compared with neomycin standard against Escherichia coli bacterial pathogen with MIC value (0.003 μM). In the case of Pseudomonas aeruginosa, compared with standard neomycin (MIC 0.030 μM), compound 3a and 4a exhibited the highest antibacterial activity with MIC of 0.007 and 0.007 μM. This data clearly suggests that the compounds exhibit promising broad-spectrum antibacterial activity against test bacterial pathogens. The compound 4a showed excellent antibacterial activity towards Escherichia coli MTCC 1687 (MIC value 0.003 μM). The other compounds such as 3c, 4b, 5b-c and 6b failed to exhibit the activity against the all the bacterial pathogens tested and hence are not included in Table-3. The compound which showed lower antibacterial activity is due to substitution on the aryl ring, whereas in compounds 3a, 4a and 6a has no such substitution and hence exhibiting better activity.

The data clearly suggested that the compounds exhibit promising broad-spectrum of antibacterial activity against test bacterial pathogens. The compound 4a showed excellent antibacterial activity towards Escherichia Coli MTCC 1687 (MIC value 0.003 μM). Whereas other compounds, the anti-bacterial activity is low due to substitution on benzene ring but in compound 4a there is no substitution on it.

3.2.3 In-vitro antioxidant activity

The results of free radical-scavenging capacity of the compounds by DPPH methods are shown in Table-4. All of the compounds except 3c, 4b and 5b-c demonstrated inhibitory activity against the DPPH free radicals. The order of free radical-scavenging capacity of the compounds was 5a>4a>3a>6b>6a>4c = 3b>6c. The compounds 4a and 5a showed the highest free radical-scavenging capacity as compared to standard ascorbic acid with EC50 values 18.9 ± 1.9 and 16.85 ±1.5μgmL–1 respectively.

Table 4

In-vitro antioxidant activity by DPPH free radical scavenging method.

CompoundsEC(concentration of 50% scavenging of 50
DPPH free radicals) [μgmL–1]
3a19.58 ± 1.1
3b33.5 ± 1.7
4a18.9 ± 1.9
4c33.5 ± 1.7
5a16.85 ±1.5
6a24.8 ± 1.3
6b20.74 ± 1.6
6c41.7 ± 2.1
Ascorbic acid†18.22 ± 1.25

4 Conclusion

The 3,4-dihydro-9-arylacridin-1(2H)-one based enaminones was successfully synthesized by exploring the synthetic potential of DMFDMA which in turn converted into number of biologically potent heterocycles. In addition all the newly synthesized compounds were subjected to the in-vitro antifungal, antibacterial and antioxidant evaluations to find their efficacy and the potent lead molecules were found.

Acknowledgements

Authors are thankful to the administration, VIT University, Vellore, India for providing facilities to carry the research work and also thankful to SIF-Chemistry for providing NMR facility. Authors are thankful to the University of Hyderabad (Network resource centre (UGC-NRC) for HRMS facility and also NMR facilities. The authors thankful to the department of Life Sciences, University of Hyderabad, for extending their facilities to perform the biological activities. Author L. Jyothish Kumar is thankful to the VIT University for providing Research Associateship.

  1. Conflict of interest Authors declare no conflict of interest.

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Received: 2017-12-11
Accepted: 2018-06-06
Published Online: 2018-10-25

© 2018 L. Jyothish Kumar et al., published by De Gruyter

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License.

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  3. The preparation and antibacterial activity of cellulose/ZnO composite: a review
  4. Linde Type A and nano magnetite/NaA zeolites: cytotoxicity and doxorubicin loading efficiency
  5. Performance and thermal decomposition analysis of foaming agent NPL-10 for use in heavy oil recovery by steam injection
  6. Spectroscopic (FT-IR, FT-Raman, UV, 1H and 13C NMR) insights, electronic profiling and DFT computations on ({(E)-[3-(1H-imidazol-1-yl)-1-phenylpropylidene] amino}oxy)(4-nitrophenyl)methanone, an imidazole-bearing anti-Candida agent
  7. A Simplistic Preliminary Assessment of Ginstling-Brounstein Model for Solid Spherical Particles in the Context of a Diffusion-Controlled Synthesis
  8. M-Polynomials And Topological Indices Of Zigzag And Rhombic Benzenoid Systems
  9. Photochemical Transformation of some 3-benzyloxy-2-(benzo[b]thiophen-2-yl)-4Hchromen-4-ones: A Remote Substituent Effect
  10. Dynamic Changes of Secondary Metabolites and Antioxidant Activity of Ligustrum lucidum During Fruit Growth
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https://doi.org/10.1515/chem-2018-0110
Keywords for this article
DMFDMA; Enaminones; antifungal; antibacterial; antioxidant evaluations
Creative Commons
BY-NC-ND 4.0

Articles in the same Issue

  1. Regular Articles
  2. The effect of CuO modification for a TiO2 nanotube confined CeO2 catalyst on the catalytic combustion of butane
  3. The preparation and antibacterial activity of cellulose/ZnO composite: a review
  4. Linde Type A and nano magnetite/NaA zeolites: cytotoxicity and doxorubicin loading efficiency
  5. Performance and thermal decomposition analysis of foaming agent NPL-10 for use in heavy oil recovery by steam injection
  6. Spectroscopic (FT-IR, FT-Raman, UV, 1H and 13C NMR) insights, electronic profiling and DFT computations on ({(E)-[3-(1H-imidazol-1-yl)-1-phenylpropylidene] amino}oxy)(4-nitrophenyl)methanone, an imidazole-bearing anti-Candida agent
  7. A Simplistic Preliminary Assessment of Ginstling-Brounstein Model for Solid Spherical Particles in the Context of a Diffusion-Controlled Synthesis
  8. M-Polynomials And Topological Indices Of Zigzag And Rhombic Benzenoid Systems
  9. Photochemical Transformation of some 3-benzyloxy-2-(benzo[b]thiophen-2-yl)-4Hchromen-4-ones: A Remote Substituent Effect
  10. Dynamic Changes of Secondary Metabolites and Antioxidant Activity of Ligustrum lucidum During Fruit Growth
  11. Studies on the flammability of polypropylene/ammonium polyphosphate and montmorillonite by using the cone calorimeter test
  12. DSC, FT-IR, NIR, NIR-PCA and NIR-ANOVA for determination of chemical stability of diuretic drugs: impact of excipients
  13. Antioxidant and Hepatoprotective Effects of Methanolic Extracts of Zilla spinosa and Hammada elegans Against Carbon Tetrachlorideinduced Hepatotoxicity in Rats
  14. Prunus cerasifera Ehrh. fabricated ZnO nano falcates and its photocatalytic and dose dependent in vitro bio-activity
  15. Organic biocides hosted in layered double hydroxides: enhancing antimicrobial activity
  16. Experimental study on the regulation of the cholinergic pathway in renal macrophages by microRNA-132 to alleviate inflammatory response
  17. Synthesis, characterization, in-vitro antimicrobial properties, molecular docking and DFT studies of 3-{(E)-[(4,6-dimethylpyrimidin-2-yl)imino]methyl} naphthalen-2-ol and Heteroleptic Mn(II), Co(II), Ni(II) and Zn(II) complexes
  18. M-Polynomials and Topological Indices of Dominating David Derived Networks
  19. Human Health Risk Assessment of Trace Metals in Surface Water Due to Leachate from the Municipal Dumpsite by Pollution Index: A Case Study from Ndawuse River, Abuja, Nigeria
  20. Analysis of Bowel Diseases from Blood Serum by Autofluorescence and Atomic Force Microscopy Techniques
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  22. Relationships between diatoms and environmental variables in industrial water biotopes of Trzuskawica S.A. (Poland)
  23. Optimum Conversion of Major Ginsenoside Rb1 to Minor Ginsenoside Rg3(S) by Pulsed Electric Field-Assisted Acid Hydrolysis Treatment
  24. Antioxidant, Anti-microbial Properties and Chemical Composition of Cumin Essential Oils Extracted by Three Methods
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  26. Investigation of the sustained-release mechanism of hydroxypropyl methyl cellulose skeleton type Acipimox tablets
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  77. Topological study of the para-line graphs of certain pentacene via topological indices
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  87. Survey of content of cadmium, calcium, chromium, copper, iron, lead, magnesium, manganese, mercury, sodium and zinc in chamomile and green tea leaves by electrothermal or flame atomizer atomic absorption spectrometry
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  90. Freshwater green macroalgae as a biosorbent of Cr(III) ions
  91. The main influencing factors of soil mechanical characteristics of the gravity erosion environment in the dry-hot valley of Jinsha river
  92. Free amino acids in Viola tricolor in relation to different habitat conditions
  93. The influence of filler amount on selected properties of new experimental resin dental composite
  94. Effect of poultry wastewater irrigation on nitrogen, phosphorus and carbon contents in farmland soil
  95. Response of spring wheat to NPK and S fertilization. The content and uptake of macronutrients and the value of ionic ratios
  96. The Effect of Macroalgal Extracts and Near Infrared Radiation on Germination of Soybean Seedlings: Preliminary Research Results
  97. Content of Zn, Cd and Pb in purple moor-grass in soils heavily contaminated with heavy metals around a zinc and lead ore tailing landfill
  98. Topical Issue on Research for Natural Bioactive Products
  99. Synthesis of (±)-3,4-dimethoxybenzyl-4-methyloctanoate as a novel internal standard for capsinoid determination by HPLC-ESI-MS/MS(QTOF)
  100. Repellent activity of monoterpenoid esters with neurotransmitter amino acids against yellow fever mosquito, Aedes aegypti
  101. Effect of Flammulina velutipes (golden needle mushroom, eno-kitake) polysaccharides on constipation
  102. Bioassay-directed fractionation of a blood coagulation factor Xa inhibitor, betulinic acid from Lycopus lucidus
  103. Antifungal and repellent activities of the essential oils from three aromatic herbs from western Himalaya
  104. Chemical composition and microbiological evaluation of essential oil from Hyssopus officinalis L. with white and pink flowers
  105. Bioassay-guided isolation and identification of Aedes aegypti larvicidal and biting deterrent compounds from Veratrum lobelianum
  106. α-Terpineol, a natural monoterpene: A review of its biological properties
  107. Utility of essential oils for development of host-based lures for Xyleborus glabratus (Coleoptera: Curculionidae: Scolytinae), vector of laurel wilt
  108. Phenolic composition and antioxidant potential of different organs of Kazakh Crataegus almaatensis Pojark: A comparison with the European Crataegus oxyacantha L. flowers
  109. Isolation of eudesmane type sesquiterpene ketone from Prangos heyniae H.Duman & M.F.Watson essential oil and mosquitocidal activity of the essential oils
  110. Comparative analysis of the polyphenols profiles and the antioxidant and cytotoxicity properties of various blue honeysuckle varieties
  111. Special Issue on ICCESEN 2017
  112. Modelling world energy security data from multinomial distribution by generalized linear model under different cumulative link functions
  113. Pine Cone and Boron Compounds Effect as Reinforcement on Mechanical and Flammability Properties of Polyester Composites
  114. Artificial Neural Network Modelling for Prediction of SNR Effected by Probe Properties on Ultrasonic Inspection of Austenitic Stainless Steel Weldments
  115. Calculation and 3D analyses of ERR in the band crack front contained in a rectangular plate made of multilayered material
  116. Improvement of fuel properties of biodiesel with bioadditive ethyl levulinate
  117. Properties of AlSi9Cu3 metal matrix micro and nano composites produced via stir casting
  118. Investigation of Antibacterial Properties of Ag Doped TiO2 Nanofibers Prepared by Electrospinning Process
  119. Modeling of Total Phenolic contents in Various Tea samples by Experimental Design Methods
  120. Nickel doping effect on the structural and optical properties of indium sulfide thin films by SILAR
  121. The effect mechanism of Ginnalin A as a homeopathic agent on various cancer cell lines
  122. Excitation functions of proton induced reactions of some radioisotopes used in medicine
  123. Oxide ionic conductivity and microstructures of Pr and Sm co-doped CeO2-based systems
  124. Rapid Synthesis of Metallic Reinforced in Situ Intermetallic Composites in Ti-Al-Nb System via Resistive Sintering
  125. Oxidation Behavior of NiCr/YSZ Thermal Barrier Coatings (TBCs)
  126. Clustering Analysis of Normal Strength Concretes Produced with Different Aggregate Types
  127. Magnetic Nano-Sized Solid Acid Catalyst Bearing Sulfonic Acid Groups for Biodiesel Synthesis
  128. The biological activities of Arabis alpina L. subsp. brevifolia (DC.) Cullen against food pathogens
  129. Humidity properties of Schiff base polymers
  130. Free Vibration Analysis of Fiber Metal Laminated Straight Beam
  131. Comparative study of in vitro antioxidant, acetylcholinesterase and butyrylcholinesterase activity of alfalfa (Medicago sativa L.) collected during different growth stages
  132. Isothermal Oxidation Behavior of Gadolinium Zirconate (Gd2Zr2O7) Thermal Barrier Coatings (TBCs) produced by Electron Beam Physical Vapor Deposition (EB-PVD) technique
  133. Optimization of Adsorption Parameters for Ultra-Fine Calcite Using a Box-Behnken Experimental Design
  134. The Microstructural Investigation of Vermiculite-Infiltrated Electron Beam Physical Vapor Deposition Thermal Barrier Coatings
  135. Modelling Porosity Permeability of Ceramic Tiles using Fuzzy Taguchi Method
  136. Experimental and theoretical study of a novel naphthoquinone Schiff base
  137. Physicochemical properties of heat treated sille stone for ceramic industry
  138. Sand Dune Characterization for Preparing Metallurgical Grade Silicon
  139. Catalytic Applications of Large Pore Sulfonic Acid-Functionalized SBA-15 Mesoporous Silica for Esterification
  140. One-photon Absorption Characterizations, Dipole Polarizabilities and Second Hyperpolarizabilities of Chlorophyll a and Crocin
  141. The Optical and Crystallite Characterization of Bilayer TiO2 Films Coated on Different ITO layers
  142. Topical Issue on Bond Activation
  143. Metal-mediated reactions towards the synthesis of a novel deaminolysed bisurea, dicarbamolyamine
  144. The structure of ortho-(trifluoromethyl)phenol in comparison to its homologues – A combined experimental and theoretical study
  145. Heterogeneous catalysis with encapsulated haem and other synthetic porphyrins: Harnessing the power of porphyrins for oxidation reactions
  146. Recent Advances on Mechanistic Studies on C–H Activation Catalyzed by Base Metals
  147. Reactions of the organoplatinum complex [Pt(cod) (neoSi)Cl] (neoSi = trimethylsilylmethyl) with the non-coordinating anions SbF6– and BPh4–
  148. Erratum
  149. Investigation on Two Compounds of O, O’-dithiophosphate Derivatives as Corrosion Inhibitors for Q235 Steel in Hydrochloric Acid Solution
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