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Synthesis, cytotoxicity and in silico study of some novel benzocoumarin-chalcone-bearing aryl ester derivatives and benzocoumarin-derived arylamide analogs

  • Nabeel A. Abdul-Ridha , Afraah D. Salmaan , Rita Sabah , Bahjat Saeed and Najim A. Al-Masoudi EMAIL logo
Published/Copyright: April 3, 2021
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Zeitschrift für Naturforschung B
From the journal Zeitschrift für Naturforschung B Volume 76 Issue 3-4

Abstract

The development of new prostate cancer protein receptor cytochrome P450 17A1 inhibitors offers the possibility of generating structures of increased potency. To this end, the chalcone analogs 7 and 8 were prepared from treatment of methyl 3-oxo-3H-benzocoumarin-2-carboxylate (4) with aryl aldehydes. Treatment of 7 and 8 with three anti-inflammatory drugs, flurbiprofen, ketoprofen and ibuprofen, in the presence of POCl3/DMAP gave the ester analogs 9–12. Analogously, treatment of ethyl 3-oxo-3H-benzocoumarin-2-carboxylate (15), prepared previously from 2-hydroxy-1-naphthaldehyde (13) and dimethylmalonate (14), with various arylamines: 4-bromoaniline, 2-amino-6-methylpyridine, amino-antipyrine and 2-amino-5-nitrothiazole, in the presence of potassium tert-butoxide gave the benzocoumarine-3-arylamide analogs. The in vitro cytotoxic activities of 9–12 and 16–19 were evaluated against human prostate cancer cell lines (PC-3) and normal human liver epithelia (WRL-68) by MTT assay. Compounds 10 and 17 were the most active cytotoxic agents among the series against PC-3 cells with IC50 values of 71.35 and 78.25 μg mL–1 with SI values of 3.0 and 4.2, respectively (calculated from the cytotoxicity effects of 10 and 17 on the normal human liver epithelia [WRL-68]). Furthermore, compounds 11 and 12 were tested against breast cancer (HER2 cell lines), prostate cancer (DU-135 cell lines) and MCF-7 but were inactive. Molecular docking studies between the protein receptor CYPP450 17A1 and compounds 10 and 17 revealed that these compounds primarily form hydrophobic interactions with the receptor.

Keywords: amide analogs; benzocoumarin; breast cancer; cytotoxicity; ester derivatives; molecular docking study

1 Introduction

Benzocoumarin compounds target a variety of biological processes and therefore are potential candidates for the treatment of a large group of diseases. Benzocoumarins have been reported to exhibit several biological activities including antidyslipidemia and lipid [1], [2], [3], antioxidant ([3], [4], [5], anti-inflammatory [6], antibacterial [7], [8], [9], antithrombotic [10], antituberculosis [11], antitumor [5], [12], [13] agents as well as selective inhibitors of alkaline phosphatase [14]. Some benzocoumarin analogs exhibited potential antiviral activity such bis-benzocoumarin-thiadiazine analog (1; Figure 1) and was found to block the function of viral neuraminidases of the influenza virus, by preventing its reproduction by budding from the host cell [15]. Meanwhile methylimidazole-methylimidazole-benzocoumarin (2; Figure 1) [16] exhibited promising anti-HCV activity with EC50 values of 5.5 μm. Further, several benzocoumarin derivatives exhibited significant antitumor activity e.g. E-4-(3,4-dimethoxystyryl)-2H-benzo[h]chromene-2-one (3; Figure 1) [17], which showed maximum antiproliferative activity in breast cancer cell lines (MDA-MB-231 and 4T1) and decreased the tumor size in the in-vivo 4T1 cell-induced orthotopic syngeneic mouse breast cancer model. Alternariol (3,7,9-1-methyl-6H-benzo[c]chromen-6-one) is reported to inhibit cholinesterase enzymes [18], meanwhile, it is reported to be a full androgen agonist in an in vitro assay [19]. In addition, it exhibited antifungal and phytotoxic activity [20]. 3,4-Benzocoumarin, a AOH (alternariol)‐like compound, has the sensibility of the antibody with an IC50 of 919.2 ng mL−1 [21].

Figure 1: Some potentially active benzocoumarin analogs.
Figure 1:

Some potentially active benzocoumarin analogs.

Fluorescence Imaging (FI) is one of the most popular imaging modes in biomedical sciences for the visualization of cells and tissues both in vitro and in vivo [22]. Benzocoumarin analogs are considered as highly fluorescent imaging agents with high emission yield, excellent photostability and extended spectral range [23]. As well, they constitute the largest class of laser dyes in the blue-green region. These types of dyes have been employed as labels for fluorescent energy transfer experiments. Murata et al. [24] reported the syntheses and fluorescence properties of benzocoumarin derivatives as novel fluorophores emitting in the longer wavelength region and their application to analytical reagents, while Rajisha et al. [25] have synthesized new benzocoumarinoxadiazolyls as strong blue-green fluorescent brighteners with good bathochromic shifts.

Chalcones derivatives possess various biological, pharmacological and biocidal properties [26]. Various substitutions on both aryl rings (A and B) of the chalcones, depending upon their positions in the aryl rings, appear to influence anticancer activity by interfering with various biological targets [27], [28], meanwhile chalcone molecules with a trimethoxyphenyl unit has been reported to be the most cytotoxic (IC50 = 0.21 nm) derivatives synthesized so far [29].

Considering the biological significance of benzocoumarin and chalcone derivatives, herein we report the synthesis of new substituted chalcone-derived benzocoumarin scaffold, as well as their cytotoxicity on prostate cancer (PC-3 and DU-135 cells), breast cancer (MCF and HER2 cells) and an in silico molecular docking study.

2 Results and discussion

2.1 Chemistry

In the present investigation we report the syntheses of some new benzocoumarin derivatives having antitumor activity. 2-Acetyl-benzocoumarin precursor (4) was prepared via Knoevenagel reaction in basic conditions following Murthi and Basak [30] method by treatment of 2-hydroxy naphthaldeyde with ethyl acetoacetate. Treatment of 4 with 4-hydroxy- (5) and 4-hydroxy-3-methoxybenzaldehyde (6) in the presence of piperidine afforded after chromatographic purification the desired chalcone analogs 7 and 8 in 86 and 79% yield, respectively.

Next, a mild and efficient method is developed for the synthesis of esters following Chen et al. [31] method by conversion of carboxylic acids into esters through carboxyl activation by the reagent combination of POCl3 and DMAP. Thus, reaction of 8 with the anti-inflammatory drugs, flurbiprofen, ketoprofen and ibuprofen, in the presence of POCl3 and catalytic amount of DMAP as a base to furnish after chromatographic purification the desired esters 9–11 in 80, 75 and 78% yield, respectively. Similarly, treatment of 7 with ibuprofen under the same condition afforded the ester 12 in 80% yield, respectively (Scheme 1).

Scheme 2: Synthesis of new benzocoumarin-derived substituted arylamide derivatives. Reagents and conditions: (i) dimethyl malonate, EtOH-piperidine, reflux, 3 h; (ii) arylamines, THF, potassium tert-butoxide, r.t., 30–60 min.
Scheme 2:

Synthesis of new benzocoumarin-derived substituted arylamide derivatives. Reagents and conditions: (i) dimethyl malonate, EtOH-piperidine, reflux, 3 h; (ii) arylamines, THF, potassium tert-butoxide, r.t., 30–60 min.

The structures of 7–12 were confirmed by their IR, 1H and 13C NMR and mass spectra. The benzocoumarin protons showed a similar pattern. In the 1H NMR spectra of 7–12, H-4 appeared as a singlet in the range δ = 8.74–8.59 ppm, while H-5 of 7–10 resonated as doublet (J = 7.5 Hz) or broad singlet in the range δ = 8.50–8.40 ppm. H-5 of compounds 11 and 12 overlapped with H-8 at δ = 8.39 ppm, while H-6–H-10 of compounds 7–12 resonated as multiplet in the range δ = 7.80–7.13 ppm. The olefinic protons H-12 and H-13 of 7 and 8 appeared in the range δ = 6.88–6.67 ppm (multiplet) and δ = 7.85–7.71 ppm (doublet, J12, 13 = 16.0 Hz), respectively, whereas these protons were overlapped with other aromatic protons of compounds 9–12. The aliphatic protons were fully analyzed (c.f. Section 4). In the 13C NMR spectra of 7–12, the carbonyl carbon atoms of benzocoumarin backbone C2=O and C11=O resonated in the ranges δ = 162.1–159.0 and 192.1–190.0 ppm, respectively, while the resonances in the range δ = 175.8–175.3 ppm assigned to the carbonyl carbon atoms C15=O of compounds 9–12. Compound 10 showed signals at δ = 197.4 ppm was attributed to the carbonyl carbon atom C17=O. The resonances at the ranges δ = 138.7–132.8, 150.8–144.5 and 117.9–115.8 ppm were assigned to C-3, C-4 and C-4a, respectively. Carbon atoms C-5+C-9, C-5a and C-6 were resonated in the ranges δ = 123.1–122.7, 131.8–128.1 and 123.0–117.9 ppm, respectively. In addition, the resonances at δ = 117.4–124.6 ppm were assigned to C-10. The olefinic carbon atoms C-12 and C-13 appeared in the ranges δ = 126.2–124.6 and 145.3 and 140.5 ppm, respectively. Carbon atom C–F of compound 10 was appeared as a doublet at δ = 158.1 (JC, F = 270 Hz). The other aromatic and aliphatic substituents carbon atoms were fully analyzed (c.f.Section 4).

We have selected ethyl 3-oxo-3H-benzocoumarin-2-carboxylate (15), prepared previously from 2-hydroxy-1-naphthaldehyde (13) and dimethyl malonate (14) (Vahini et al. 2010) [32], as precursor for the synthesis of benzocoumarin-derived amide derivatives aiming to examine their cytotoxicity against prostate cancer. Thus, treatment of 15 with the arylamines 4-bromoaniline, 2-amino-6-methylpyridine, amino-antipyrine and 2-amino-5-nitrothiazole, in the presence of potassium tert-butoxide at room temperature for 30–60 min, following the method of Kim et al. [33], afforded after purification the desired amide analogs 16–19 in 80, 74, 60 and 65% yield, respectively (Scheme 2).

Figure 2: Effect of concentration of compound 10 and 17 on PC-3 and normal human liver epithelia WRL-68 cells (n = 3) for 72 h. Cell viability was evaluated by the MTT colorimeter assay.
Figure 2:

Effect of concentration of compound 10 and 17 on PC-3 and normal human liver epithelia WRL-68 cells (n = 3) for 72 h. Cell viability was evaluated by the MTT colorimeter assay.

The structures of 16–19 were identified by 1H and 13C and mass spectral data, which showed similar patterns of protons and carbon atoms as those of the benzocoumarin precursor. In the 1H NMR spectra, H-4 of the benzocoumarin scaffold resonated as a singlet in the range δ = 8.92–8.72, while H-5 of 16–18 appeared as a broad singlet at δ = 8.78, 7.98 and 7.89 ppm, respectively. H-5 of compound 19 appeared as a doublet at δ = 7.91 ppm (J5, 6 = 7.5 Hz), whereas H-8 of 16–18 resonated as a broad singlet at δ = 8.65, 7.83 and 7.68 ppm, respectively. However, the doublet at δ = 7.69 ppm (J7, 8 = 7.5) was attributed to H-8 of 19. In the 13C NMR spectra of 16–19, the resonances at the regions δ = 158.0–157.0 and 163.6–163.0 ppm were assigned for the carbonyl carbon atoms (C-2 and C-11), respectively, whereas the carbonyl carbon atom (C-3) of pyrazole moiety (compound 18) appeared at δ = 62.2 ppm. Atoms C-3–C4a resonated in the regions δ = 135.4–130.0, 146.0–135.1 and 118.0–116.6 ppm, respectively, while the resonances in the regions δ = 125.1–120.1, 131.8–130.8, 127.3–124.1 and 125.1–120.1 ppm were assigned to the carbon atoms (C-5–C-7), respectively. However, C-8–C-10a were appeared at the regions δ = 129.1–125.1, 131.8–130.9, 116.6–114.7 and 149.4 ppm, respectively. The resonances at δ = 61.4, 144.0 and 135.1 ppm were attributed to the carbon atoms (C-2, C-4 and C-5) of the thiazole moiety of 19. The other aromatic aliphatic carbon atoms have been identified (c.f.Section 4).

2.2 Cytotoxic activity in vitro

The anticancer activities of the new benzocoumarin-chalcone-derived anti-inflammatory drugs 9–12 and 16–19 were determined in vitro by MTT assay [34] on cancer cell lines, human prostate carcinoma (PC-3 cell lines) and normal human liver epithelia (WRL-68), where doxorubicin was used as a positive control. The results are summarized in Table 1, and the cytotoxic effect expressed as IC50 values in μg mL–1. After 72 h, all the complexes showed no or relatively low cytotoxicity (Figures S1 and S2, Supplementary information available online). Among the tested compounds, 10 and 17 showed the strongest dose- and time-dependent and significant cytotoxicity effect in/on PC-3 cells with IC50 value of 71.35 and 78.25 μg mL−1 (Figure 2). However, the IC50 values for doxorubicin were found to 17.5 μg mL−1 against PCa cell lines (PC-3) with selective indices (SI) of 12 and 18, respectively.

Table 1:

In vitro cytotoxic effectsa of some new benzocoumarin analogs given as IC50b in μg mL−1.

Compd.Cell line
PC-3WRL68SI
995.02139.91.5
1071.35215.83.0
1179.01158.42.0
12115.7180.61.6
1676.27160.72.1
1778.25326.64.2
18175.2242.81.4
19136.3168.81.24
Doxo17.5

  1. aCytotoxic effects were expressed as IC50 for each cell line, obtained by MTT assay after 72 h of treatment. bData represent the mean values of three independent determinations. Doxo, Doxorubicin.

Scheme 1: Synthesis of new benzocoumarin-chalcone-derived substituted ester derivatives.
Scheme 1:

Synthesis of new benzocoumarin-chalcone-derived substituted ester derivatives.

The selective index (SI) is defined as the ratio of the cytotoxicity of the tested compound with respect to normal cells (IC50 WRL68) versus cancer cell and used to determine the criterion of effectiveness of the compound. The SI values higher than 1.0 indicate the compounds of considerable anticancer specificity, and SI much greater than 1.0 highly selective ones. Therefore, we can conclude that 10 and 17, of the benzocoumarin-chalcone bearing ketoprofen and 6-methyl pyridine scaffolds are excellent selective inhibitors against PCa (PC-3 cell lines) with SI = 3.0 and 4.2, respectively.

In addition, compounds 10 and 12 have been selected for further screening with other cell lines. Compound 10 was tested against breast cancer (HER2 cell lines) and prostate cancer (DU-135 cell lines) with IC50 values of 66.39 and 119.8 μg mL−1, respectively. The cytotoxicity effects of compounds 10 and 12 were further evaluated for their toxicity against normal human liver epithelia (WRL-68) with IC50 = 158.4 and 254.2 μg mL−1, resulting in SI values of 2.4 and 2.1, respectively (SI of doxorubicin = 9 and 14.5, respectively). Compound 12 was tested against breast cancer (MCF-7 cell lines) and noncancer cells WRL68 with IC50 values of 146.8 and 157.4 μg mL−1, respectively, resulting of SI = 1.1 (SI of doxorubicin = 9) (Figures S3, Supplementary information). Therefore, compounds 10 and 12 showed no activity against both breast cancer (MCF-7 and HER2) and prostate cancer (DU-135).

2.3 Computational modeling study

The prostate cancer protein receptor cytochrome P450 17A1 (P450c17) has been exploited as one of the therapeutic target for PCa. In our search for new lead analogs as human CYP450 17A1 inhibitor, we have selected compounds 10 and 17 for molecular docking study. Thus, molecular docking of these two analogs into the three-dimensional P450c17 receptor structure (PDB ID: 3RUK) was performed using the Autodock program [35]. The prospective ligands were ranked according to the highest energy of the best conforms. Thus, the calculated energy scores for compounds 10 and 17 are −6.98 and −9.85, respectively, indicating selectivity and potency profiles of these analogs to bind strongly the cytochrome P450 receptor. Figure 3(A) demonstrated a π-π stacking interaction between the aromatic ring (f) of compound 10 and the pyrrole ring of HEM600. Additionally, it showed the same stacking between the aromatic ring (e) and Asp298. Further, aliphatic hydrophobic interactions with CYP450 17A1 receptors-binding residues including Val482, Met369, Leu370 and Val483 were observed.

Figure 3: The interactions mode of compounds 10 (A) and 17 (B) with the active site amino acids of the human cytochrome P450 17A1 (PDB ID: 3RUK).
Figure 3:

The interactions mode of compounds 10 (A) and 17 (B) with the active site amino acids of the human cytochrome P450 17A1 (PDB ID: 3RUK).

According to the cytochrome CYP450 receptor docking results, Figure 3(B) demonstrated that compound 17 was able to show three π -H interactions, one between the aromatic ring (a) and Ala302, while the other interaction was observed between the pyridine residue and Ala302. The third π−H interaction was displayed between the aromatic ring (c) and Ile205. Moreover, compound 17 showed three C–H interactions of Me group of the pyridine ring with Ala367, Val366 and Val483. In addition, a π -π interaction between pyrrole groups of HEM600 and pyridine ring was observed. Besides these interactions, nonbonding amino acids acid residues were surrounded by compounds 10 and 17 which further enhances their inhibitory activity.

3 Conclusion

In the present work, new benzocoumarin-chalcone bearing substituted ester derivatives 9–12 as well as benzocoumarin-derived arylamide analogs 16–19 have been synthesized. The structures of the new synthesized benzocoumarin analogs were confirmed by the spectral and mass data. The synthesized analogs were evaluated for their activity against prostate cancer (PC-3) and the results showed that 10 and 17 were the most active analogs of the series with IC50 values of 71.35 and 78.25 μg mL−1 (SI = 3.0 and 4.2, respectively, based on the effect of 10 and 17 on the noncancer prostate cells WRL68). Molecular docking simulations showed that analogs 10 and 17 can potentially inhibit protein receptor CYP450. Therefore, these compounds seem to be the most promising antiproliferative agents against protein receptor cytochrome P450 17A1 dependent prostatic cancer cells.

4 Experimental section

4.1 General

Melting points were determined on Stuart SMP3 melting point apparatus and are uncorrected. The IR spectra were recorded, on FT-IR Spectrophotometer (Shimaduz), using KBr discs. 1H and 13C NMR spectra were recorded on Varian 500 (1H) and 125.65 MHz (13C) spectrometers, using DMSO-d6 solvent containing tetramethylsilane as an internal standard (chemical shifts in δ in ppm). Mass spectra (EI, 70 eV, and FAB) were recorded on MAT 8200 spectrometers (Finnegan MAT, USA). The reactions were monitored by thin layer chromatography, (eluent: hexane-EtOAc 4: 1), and the spots were visualized by iodine and U.V.

4.2 General procedure for the synthesis of benzocoumarin-chalcone derivatives (7 and 8)

To a stirred solution of 4 (119 mg, 0.50 mmol) in EtOH (25 mL) was added arylbenzaldehyde (0.50 mmol) and aq. solution of 2 m NaOH (7 mL). After stirring at ambient temperature for 24 h, the mixture was neutralized with 1 M HCl and partitioned with EtOAc (3 × 20 mL). The combined organic extracts were washed with brine, dried over Na2SO4 and evaporated in vacuo. The residue was purified on a short SiO2 column using the eluent hexane-EtOAc (3:2) as eluent to give the desired chalcone.

4.2.1 2-(3-(4-Hydroxyphenyl)acryloyl)-3H-benzozocoumarin-3-one (7)

From 4-hydroxybenzaldeyde 5 (61 mg). Yield: 147 mg, (86%) as orange crystals, m.p.: 270–272 °C, Rf = 0.78. – IR (KBr): ν = 3082 (Ar–H), 2939 (C–Haliphatic), 1730 (C=Olactone), 1680 (C=Ochalcone), 1608, 1552 (C=C) cm−1. – 1H NMR (DMSO-d6): δ = 9.76 (s,1H, C–OH), 8.59 (s, 1H, H-4), 8.48 (d, 1H, J5, 6 = 7.5 Hz, H-5), 8.30 (d, 1H, J7, 8 = 7.5 Hz, H-8), 7.71 (d, 1H, J12, 13 = 15.6 Hz, H-13), 7.80 (m, 1H, H-6), 7.74 (m, 1H, H-7), 7.70–7.35 (m, 4H, H-9+H-10+H-2′+H-6′), 6.97–6.81 (m, 3H, H-12+H-3′+H-5′). – 13C NMR (DMSO-d6): δ = 190.0 (C11=O), 162.1 (C2=O) 155.8 (C–OH), 155.0 (C-10a), 147.1 (C-4), 145.3 (Carom.-3′+C-13), 134.5 (C-3), 131.8 (Carom.-2″+Carom.-6″), 128.1 (C-5a+C-9), 127.8 (C-8a), 127.4 (C-8), 126.2 (Carom.-1″+C-12), 125.7 (Carom.-2′), 122.7 (C-5+C-6), 118.5 (C-7), 116.1 (C-4a+C-10), 115.5 (Carom.-3′+Carom.-5′). – MS ((+)-EI) for C22H14O4: m/z (%) = 342 (85) [M]+.

4.2.2 2-(3-(4-Hydroxy-3-methoxyphenyl)acryloyl)-3H-benzocoumarin-3-one (8)

From vanillin 6 (76 mg). Yield: 147 mg, (79%) as a brown crystals, m.p.: 255–256 °C, Rf = 0.73. – IR (KBr): ν = 3085 (Ar–H), 2942 (C–Haliphatic), 1724 (C=Olactone), 1681 (C=Ochalcone), 1610, 1572 (C=C) cm–1. – 1H NMR (DMSO-d6): δ = 9.72 (s,1H, C–OH), 8.59 (s, 1H, H-4), 8.40 (d, 1H, J5, 6 = 7.4 Hz, H-5), 8.21 (br s, 1H, H-8), 7.85 (d, 1H, J12, 13 = 16.0 Hz, H-13), 7.70 (m, 1H, H-6), 7.65 (m, 1H, H-7), 7.62–7.34 (m, 3H, H-9+H-10+H-2′), 6.88 (m, 3H, H-12+H-5′+H-6′), 3.82 (s, 3H, OMe). – 13C NMR (DMSO-d6): δ = 190.4 (C11=O), 161.1 (C2=O), 154.8 (C-10a), 151.1 (C–OMe), 150.8 (C-4+C-OH), 143.5 (C-13), 132.8 (C-3), 131.2 (C-9), 129.1 (C-5a), 125.2 (C-8a+C-12), 124.3 (C-8+Carom.-1″), 123.1 (C-12+Carom.-6′), 122.7 (C-5+C-6), 117.9 (C-4a+C-7), 116.1 (C-10), 112.7 (Carom.-2′), 45.4 (OMe). – MS ((+)-EI) for C23H16O5: m/z (%) = 373 (90) [M+H]+.

4.3 General procedure for the synthesis of benzocoumarin-chalcone bearing aryl ester derivatives (9–12)

To a mixture of 7 or 8 (0.60 mmol) and suitable carboxylic acid (0.5 mmol) in CH2Cl2 (10 mL) containing Et3N (101 mg, 1.2 mmol) were added POCl3 (77 mg, 0.5 mmol) and DMAP (19 mg, 0.15 mmol) and the mixture was stirred at room temperature for 2–3 h. After completion the reaction via monitoring by TLC, the mixture was evaporated to dryness and the residue was partitioned between CHCl3 (3 × 10 mL) and water (10 mL). The combined organic extracts were dried (Na2SO4), filtered and evaporated to dryness. The residue was poured on a short column of silica gel (5 g), using hexane-EtOAc (3:2) as eluent to give the pure desired ester

4.3.1 2-Methoxy-4-(3-oxo-3-(3-oxo-3H-benzocoumarin-2-yl)prop-1-en-1-yl)phenyl-2-(2-fluoro-[1,1′-biphenyl]-4-yl)propanoate (9)

From 8 (171 mg) and flurbiprofen (122 mg). Yield: 239 mg, (80%) as a purple powder, m.p.: 73–75 °C, Rf = 0.49. – IR (KBr): ν = 3061 (Ar–H), 2987 (C–Haliphatic), 1722 (C=Oester), 1699 (C=Olactone), 1656 (C=Ochalcone), 1606, 1514 (C=C), 1419 (C–F) cm−1. – 1H NMR (DMSO-d6): δ = 8.71 (s, 1H, H-4), 8.45 (d, 1H, J5, 6 = 7.5 Hz, H-5), 8.25 (m, 1H, H-8), 7.78 (d, 1H, J12, 13 = 16.0 Hz, H-13), 7.72–7.18 (m, 17H, Ar–H+H-12), 3.82 (s, 3H, OMe), 2.91 (br s, 1H, H-16), 1.47 (br s, 3H, Me). – 13C NMR (DMSO-d6): δ = 192.1 (C11=O), 175.3 (C15=O), 159.0 (C2=O), 158.1 (d, JC, F = 270 Hz, C–F), 154.3 (C-10a), 151.1 (C3′-OMe), 144.5 (C-4+C-13), 139.8 (Carom.-4′), 135.0 (C-3+Carom.-1″+Carom.-1‴), 130.9 (C-5a+C-9+Carom.-1′), 129.0, 128.5, 128.0, 127.6 (Carom.+C-6+C-8+C-8a), 125.9 (C-12+Carom.-5′+Carom.-6″), 122.5 (C-5+C-7+Carom.-6′), 116.3 (C4a + C-10+Carom.-4″), 113.0 (Carom.-2′), 47.1 (OMe), 44.3 (C-16), 18.8 (Me-17). – MS ((+)-EI) for C39H27FO7: m/z (%) = 597/599 (95) [M]+.

4.3.2 3-Methoxy-4-(3-oxo-3-(3-oxo-3H-benzocoumarin-2-yl)prop-1-en-1-yl)phenyl-2-(3-benzoyl phenyl)propanoate (10)

From 8 (171 mg) and ketoprofen (127 mg). Yield: 228 mg, (75%) as a purpule powder, m.p.: 65–66 °C, Rf = 0.57. – IR (KBr): ν = 2937 (C–Haliphatic), 1722 (C=Oester), 1656 (C=Olactone), 1657 (C=Ochalcone), 1600, 1512 (C=C) cm−1. – 1H NMR (DMSO-d6): δ = 8.74 (s, 1H, H-4), 8.50 (br s, 1H, H-5), 8.34 (br s, 1H, H-8), 7.80–7.20 (m, 19H, Ar–H+H-12+H-13), 3.92 (br s, 3H, OMe+H-16), 1.49 (br s, 3H, Me-17). – 13C NMR (DMSO-d6): δ = 197.4 (C17=O), 191.8 (C11=O), 175.6 (C15=O), 160.5 (C2=O), 153.8 (C-10a), 150.3 (C-OMe), 147.1 (C-4), 143.4 (C-13+Carom.-4′), 138.8 (C-3+Carom.-1″+Carom.-4″+Carom.-1‴), 131.8 (C-5a+C-9+Carom.-1′), 130.6, 130.1, 129.4, 128.4, 126.3 (Carom.+C-6+C-8+C-8a), 125.3 (C-12+Carom.-5′+Carom.-6″), 122.2 (C-5+C-7+Carom.-6′), 117.4 (C4a + C-10), 114.3 (Carom.-2′), 47.3 (OMe), 45.1 (C-16), 18.5 (Me-17). – MS ((+)-EI) for C39H28O7: m/z (%) = 607 (65) [M+H]+.

4.3.3 2-Methoxy-4-(3-oxo-3-(3-oxo-3H-benzocoumarin-2-yl)prop-1-en-1-yl)phenyl-2-(4-isobutyl phenyl)propanoate (11)

From 8 (171 mg) and ibuprofen (103 mg) Yield: 218 mg, (78%) as a purple powder, m.p.: 60–62 °C, Rf = 0.50. – IR (KBr): ν = 3018 (Ar–H), 2955 (C–Haliphatic), 1732 (C=Oester), 1720 (C=Olactone), 1656 (C=Ochalcone), 1606, 1514 (C=C) cm−1. – 1H NMR (DMSO-d6): δ = 8.68 (s, 1H, H-4), 8.39 (br s, 2H, H-5+H-8), 7.85 (d, 1H, J12, 13 = 15.5 Hz, H-13), 7.75–7.13 (m, 12H, Ar–H+H-12), 3.72 (m, 4H, OMe+H-16), 2.95 (m, 2H, CH2-18), 1.78 (m, 1H, H-19), 1.48 (br s, 3H, Me-17), 0.88 (br s, 6H, Me-20+Me-21). – 13C NMR (DMSO-d6): δ = 192.0 (C11=O), 175.8 (C15=O), 159.8 (C2=O), 152.5 (C-10a+C3′-OMe), 147.0 (C-4), 143.4 (C-13), 141.5 (Carom.-4′), 138.7 (C-3+Carom.-4″), 129.6, 128.5, 125.8 (Carom.+C-5a + C-6+C-8+C-8a + C-9+Carom.-1′), 124.7 (C-12), 122.9 (C-5+C-7+Carom.-6′), 115.8 (C4a + C-10+Carom.-3′+Carom.-5′), 113.7 (Carom.-2′), 50.8 (OMe), 45.1 (C-16+C-18), 30.2 (C-19), 22.8 (Me-20+Me-21), 18.9 (Me-17). – MS ((+)-EI) for C36H38O6: m/z (%) = 560 (75) [M]+.

4.3.4 4-(3-Oxo-3-(3-oxo-3H-benzocoumarin-2-yl)prop-1-yl)phenyl-2-(4-isobutylphenyl) propianoate (12)

From 7 (171 mg) and ibuprofen (103 mg). Yield: 212 mg (80%) as a purpule powder, m.p.: 84–86 °C, Rf = 0.53. – IR (KBr): ν = 3061 (Ar–H), 2987 (C–Haliphatic), 1722 (C=Oester), 1699 (C=Olactone), 1656 (C=Ochalcone), 1606, 1514 (C=C), 1419 (C–F) cm−1. – 1H NMR (DMSO-d6): δ = 8.68 (s, 1H, H-4), 8.39 (br s, 2H, H-5+H-8), 7.85 (d, 1H, J12, 13 = 15.5 Hz, H-13), 7.75–7.13 (m, 12H, Ar–H+H-12), 3.72 (m, 3H, H-16), 2.95 (m, 2H, CH2-18), 1.78 (m, 3H, H-19), 1.48 (br s, 3H, Me-17), 0.88 (br s, 3H, Me-20+Me-21). – 13C NMR (DMSO-d6): δ = 191.4 (C11=O), 175.7 (C15=O), 158.8 (C2=O), 152.9 (C-10a+C-4′), 147.6 (C-4), 140.5 (C-13), 139.5 (Carom.-4″), 133.2 (C-3+Carom.-1′+Carom.-1″), 129.5, 128.6, 127.2, 126.5, 124.1, (Carom.), 117.8 (C4a + C-10), 113.9 (Carom.-2′), 45.0 (C-16+C-18), 30.1 (C-19), 22.7 (Me-20+Me-21), 18.9 (Me-17). – MS ((+)-EI) for C35H30O5: m/z (%) = 531 (95) [M+H]+.

4.4 Ethyl 3-oxo-3H-benzocoumarin-2-carboxylate (15)

This compound was prepared previously following Knoevenagel condensation reaction by refluxing 2-hydroxy-1-naphthaldehyde (13) (172 mg, 1.0 mmol) and dimethyl malonate (14) (160 mg, 1.0 mmol) in EtOH (10 mL) in the presence of piperidine to furnish after work-up the ester 15 (227 mg, 80%). Mp and mixed melting point (114–116 °C) together with the other spectral data were identical with those of the authentic sample prepared previously [32].

4.5 General procedure for synthesis benzocoumarin-chalcone-derived substituted amide derivatives (16–19)

To a mixture of 15 (268 mg, 1.0 mmol) and arylamine (1.0 mmol) in THF (20 mL) was added potassium tert-butoxide (224 mg, 2.0 eq) and the mixture was stirred at room temperature for 30–60 min in the presence of air. The reaction progress was monitored by TLC. After the completion of reaction, the solution was filtered and evaporated to dryness. The residue was portioned between CHCl3 (3 × 15 mL) and water (15 mL) and the combined extracts were dried (Na2SO4), filtered and evaporated to dryness. The residue was purified on a short column of silica gel (5 g), using hexane-EtOAc 2:1 to give the pure desired amide.

4.5.1 N-(4-Bromophenyl)-3-oxo-3H-benzocoumarin-2-carboxamide (16)

From 4-bromoaniline (172 mg). Yield: 315 mg (80%) as a greenish-white solid, m.p.: 92–94 °C, Rf = 0.44. – IR (KBr): ν = 3452 (NHamide), 3063 (Ar–H), 2978 (C–Haliphatic), 1768, 1689 (C=Olactone+C=Oamide), 1610, 1562 (C=C), 1030 (C–Br) cm−1. – 1H NMR (DMSO-d6): δ = 10.70 (s, 1H, NH), 8.92 (s, 1H, H-4), 8.78 (br s, 1H, H-5), 8.65 (br s, 1H, H-8), 8.29–7.69 (m, 7H, Ar–H), 7.35 (br s, 1H, H-10). – 13C NMR (DMSO-d6): δ = 163.6 (C11=O), 157.2 (C2=O), 149.0 (C-10a), 142.5 (C-4), 135.0 (Carom.-1′), 133.4 (C-3), 130.8 (C-3+C-5a+C-9+Carom.-3′+Carom.-5′), 127.3 (C-6+C-8+C-8a), 125.1 (C-5+C-7), 120.9 (C-Br), 119.2 (Carom.-2′+Carom.-6′), 117.5 (C4a), 116.6 (C-10). – MS ((+)-FAB) for C20H12BrNO3: m/z (%) = 416/418 (90) [M+Na]+.

4.5.2 N-(6-Methylpyridin-2-yl)-3-oxo-3H-benzocoumarin-2-carboxamide (17)

From 2-amino-6-methylpyridine (108 mg). Yield: 244 mg (74%) as a colorless solid, m.p.: 87–89 °C, Rf = 0.42. – IR (KBr): ν = 3380 (NHamide), 3063 (Ar–H), 2961 (C–Haliphatic), 1743, 1699 (C=Olactone+C=Oamide), 1610, 1564 (C=C), 1296 (CN) cm−1. – 1H NMR (DMSO-d6): δ = 10.92 (s, 1H, NH), 8.82 (s, 1H, H-4), 7.98 (br s, 2H, H-5), 7.83 (br s, 1H, H-8), 7.25 (m, 7H, Ar–H), 6.70 (br s, 1H, Hpyridine-5′), 2.15 (Me). – 13C NMR (DMSO-d6) δ 163.2 (C11=O), 157.0 (C2=O), 155.0 (Cpyridine-2′), 151.9 (Cpyridine-6′), 148.4 (C-10a), 146.0 (Cpyridine-4′+C-4), 134.0 (C-3), 131.8 (C-9+C-5a), 125.1 (C-6+C-8), 123.2 (C-8a), 120.1 (C-5+C-7), 118.0 (C-4a), 116.6 (Cpyridine-3′), 114.7 (C-10), 112.5 (Cpyridine-5′). – MS ((+)-EI) for C20H14N2O3: m/z (%) = 331 (80) [M+H]+.

4.5.3 N-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-3-oxo-3H-benzocoumarin-2-carboxamide (18)

From 4-amino-1,5-dimethyl-2-phenyl-pyrazole-3-one (amino-antipyrine) (203 mg). Yield: 255 mg (60%) as a colorless solid, m.p.: 125–126 °C, Rf = 0.48. – IR (KBr): ν = 3433 (NHamide), 3064 (Ar–H), 2980 (C–Haliphatic), 1774 (C=Oantipyrine), 1763 (C=Oamide), 1682, 1562 (C=Olactone), 1610, 1562 (C=C) cm−1. – 1H NMR (DMSO-d6): δ = 9.68 (s, 1H, NH), 8.72 (s, 1H, H-4), 7.89 (br s,1H, H-5), 7.68 (br s, 1H, H-8), 7.48 (m, 4H, Ar–H). – 13C NMR (DMSO-d6): δ = 163.6 (C11=O), 162.2 (Cpyrazole-3′), 156.8 (C2=O), 149.0 (C-10a), 136.5 (C-4), 134.5 (C-3+Carom.-1″), 130.9 (C-5a+C-9+Carom.-3″+Carom.-5″), 129.1 (C-8+C-8a), 125.1 (C-6), 123.5 (C-5+C-7), 121.8 (Carom.-2″+Carom.-4″+Carom.-6″), 117.0 (C-4a), 115.3 (C-10), 103.4 (Cpyrazol-4′), 35.1 (N1′-Me), 14.9 (Cpyrazol-Me). – MS ((+)-EI) for C25H19N3O4: m/z (%) = 425 (78) [M+H]+.

4.5.4 N-(5-Nitrothiazol-2-yl)-3-oxo-3H-benzocoumarin-2-carboxamide (19)

From 2-amino-5-nitrothiazole (145 mg). Yield: 238 mg (65%) as an orange solid, m.p.: 95–97 °C, Rf = 0.40. – IR (KBr): ν = 3456 (NHamide), 3064 (Ar–H), 2980 (C–Haliphatic), 1764 (C=Oamide), 1693 (C=Olactone), 1610, 1562 (C=C), 1492 (NO2) cm−1. – 1H NMR (DMSO-d6): δ = 11.89 (s, 1H, NH), 9.46 (s, 1H, Hthiazole-4′), 8.74 (s, 1H, H-4), 7.91 (br s, 1H, H-5), 7.69 (br s, 1H, H-8), 7.48 (m, 4H, Ar–H). – 13C NMR (DMSO-d6): δ = 163.5 (C11=O), 161.4 (Cthiazole-2′), 156.7 (C2=O), 149.2 (C-10a), 144.0 (Cthiazole-4′), 135.1 (C-3+C-4+Cthiazole-NO2), 131.8 (C-5a + C-9), 129.0 (C-8+C-8a), 124.1 (C-6), 122.0 (C-7), 120.7 (C-5), 117.1 (C-4a), 115.8 (C-10). – MS ((+)-FAB) for C17H9N3O5S: m/z (%) = 390 (90) [M+Na]+.

4.6 Cytotoxicity assay

Ninety µL containing 1.0 × 104 cells of cell line suspension (PC-3, MCF-7, HER2, DU-135 and WRL68 cells) were seeded into wells of a 96-well plate. After 24 h of incubation, 10 µL of crude extracts dissolved in 0.01% ethanol were added to final concentration 500 or 1,000 μg mL−1 and incubated for another 48 h. The cytotoxicity test was determined by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay [34]. In brief, 50 µL of MTT was added to the wells, the cells were cultured for additional 4 h at 37 °C. Then 100 µL of 10% SDS was added to the wells. The solubilized formazan was measured at 595 nm using microplate spectrophotometer. Each treatment was assayed in triplicate. Three independent preparations of the synthesized ligand and MTT assays were performed. Doxorubicin and 0.01% ethanol (vehicle control) were used as positive and negative controls, respectively. The cytotoxicity of the new ligands was expressed as IC50 value (concentration exhibited 50% cytotoxicity).

4.7 Dock and virtual screening

4.7.1 Preparations of ligands and proteins

The structures of ligands 10 and 17 were prepared by Avogadro (v. 1.0.1) [36] software and saved as PDB file formate. Then, the two ligands were prepared selecting torsions and the structures which were converted from PDB formate to PDBQT. The PDBQT files for the proteins and the ligands, united atom Kollman charges, fragmental volumes, and solvation parameters were performed by the MGLTools software. Ligand structures were energy minimized with the MMFF94 force field. The native ligands and crystallographic water molecules were removed from the PDB structures and the polar hydrogens were added before docking.

4.7.2 Grid map calculations

Autodock grid maps were calculated for each compound using AutoGrid4, based on the active site coordinates of each protein crystal structure. The size of all grid boxes 60 × 60 × 60 xyz points with a grid spacing of 0.375 Å. The grid center dimensions were 26.18, −5.07, and 38.31 for x, y and z, respectively. Maps were calculated for each atom type in each ligand along with an electrostatic and desolavation map using dielectric value of −0.1465.

4.7.3 Molecular docking simulations

Molecular docking simulations were undertaken using the program Autodock [35]. Protein structures were prepared using UCSF Chimera 1.15 [37]. In Autodock program, the Lamarkian Genetic Algorithm (LGA) was used for pose sampling and the number of energy simulations was set to 2500000. The default scoring function was used for calculating the docking scores. Autogrid was used to prepare the maps. The results of molecular docking were visualized in BioviaDiscoveryStudio 2020 [38] and then analyzing the docking results. All docking simulations performed to validate the method, using the ligands present in crystal structures, were able to reproduce the ligand-protein interaction geometries. The image of the native ligand for 3RUK against the redocked native ligand with Autodock is shown in Figure S7 (Supplementary information), meanwhile the root-mean-square deviation of atomic positions (RMSD) was 0.405 Å.

5 Supplementary information

Cytotoxic effects of 9, 10, 12 and 16–19 on both PC-3 and WRL-68 cells (Figure S1), cytotoxic effects of 9–12 and 16–19 and doxorubicin on PC-3 cells (Figure S2), cytotoxic effects of 9 on the prostate cancer (DU-135) and breast cancer (HER2) cells as well as 12 on the breast cancer (MCF-7) cells (Figure S3) together with the image of the native ligand for 3RUK against the redocked native ligand (Figure S4) and other supporting data (1H and 13C NMR spectra of compounds 7 (Figure S5, S6), 8 (Figure S7–9), 10 (Figure S12, S13), 11 (Figure S14, S15), 12 (Figure S17), 16 (Figure S18, S19), 17 (Figure S20, S21), 18 (Figure S22, S23) and 19 (Figure S24, S25) associated with this article can be found as supplementary material in the online version (https://doi.org/10.1515/znb-2020-0204).

Corresponding author: Najim A. Al-Masoudi, Department of Chemistry, College of Science, University of Basrah, Basrah, Iraq; and Am Tannenhof 8, 78464 Konstanz, Germany, E-mail:

Acknowledgment

The authors thank the Department of Chemistry, College of Education, University of Al-Qadisiyah for providing necessary facilities.

  1. Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

  2. Research funding: None declared.

  3. Conflict of interest statement: The authors declare no conflicts of interest regarding this article.

References

1. Sashidhara, K. V., Kumar, M., Modukuri, R. K., Srivastava, A., Puri, A. Bioorg. Med. Chem. Lett. 2011, 21, 6709–6713.10.1016/j.bmcl.2011.09.053Search in Google Scholar PubMed

2. Sashidhara, K. V., Rosaiah, J. N., Kumar, A., Bhatia, G., Khanna, A. K. Bioorg. Med. Chem. Lett. 2010, 20, 3065–3069.10.1016/j.bmcl.2010.03.103Search in Google Scholar PubMed

3. Sashidhara, K. V., Rosaiah, J. N., Bhatia, G., Saxena, J. K. Eur. J. Med. Chem. 2008, 43, 2592–2596.10.1016/j.ejmech.2007.10.029Search in Google Scholar PubMed

4. Ezzatzadeh, E., Hossaini, Z. Mol. Divers. 2020, 24, 81–91.10.1007/s11030-019-09935-6Search in Google Scholar PubMed

5. Salem, M. A. I., Marzouk, M. I., El-Kazak, A. M. Molecules 2016, 21, 249–269.10.3390/molecules21020249Search in Google Scholar PubMed PubMed Central

6. Lv, H.-N., Wang, S., Zeng, K.-W., Li, J., Guo, X.-Y., Ferreria, D., Zjawiony, J. K., Tu, P.-F., Jiang, Y. J. Nat. Prod. 2015, 78, 279–285.10.1021/np500861uSearch in Google Scholar PubMed

7. Gohil, N. N., Kundaliya, K. N., Brahmbhatt, D. I. Int. Lett. Chem. Phys. Astron. 2016, 70, 1–11.10.18052/www.scipress.com/ILCPA.70.1Search in Google Scholar

8. Zaki, R. M., El-Ossaily, Y. A., EL-Dean, A. M. K. Russ. J. Bioorg. Chem. 2012, 38, 639–646.10.1134/S1068162012040152Search in Google Scholar

9. Melad, R., EL-Ossaily, Y. A., El-Dean, A. M. K. Bioorg. Khim. 2012, 38, 721–728.Search in Google Scholar

10. Sashidhara, K. V., Kumar, A., Kumar, N., Sigh, S., Jain, M., Kikshit, M. Bioorg. Med. Chem. Lett 2011, 21, 7034–7040.10.1016/j.bmcl.2011.09.100Search in Google Scholar PubMed

11. Reddy, D. S., Hosamani, K. M., Devarajegowda, H. C. Eur. J. Med. Chem. 2015, 101, 705–715.10.1016/j.ejmech.2015.06.056Search in Google Scholar PubMed

12. Abdel-Aziem, A., Rashdan, H. R. M., Ahmed, E. M., Shabaan, S. N. Green Chem. Lett. Rev. 2019, 12, 9–18.10.1080/17518253.2018.1556743Search in Google Scholar

13. El-Agrody, A. M., Abd El-Mawgoud, H. K., Fouda, A. M., Khattab, E. S. A. E. H. Chem. Pap. 2016, 70, 1279–1292.10.1515/chempap-2016-0049Search in Google Scholar

14. Channar, P. A., Irum, H., Mahmood, A., Shabir, G., Zaib, S., Saeed, A., Ashraf, Z., Larik, F. A., Lecka, J., Sévigny, J., Iqbal, J. Bioorg. Chem. 2019, 91, 103137.10.1016/j.bioorg.2019.103137Search in Google Scholar PubMed

15. Pavurala, S., Vaarla, K., Hesharwani, R., Liekens, S., Vedula, R. R. Synth. Commun. 2018, 48, 1494–1503.10.1080/00397911.2018.1455871Search in Google Scholar

16. Hassan, M. Z., Osman, H., Ali, M. A., Ahsan, M. J. Eur. J. Med. Chem. 2016, 123, 236–255.10.1016/j.ejmech.2016.07.056Search in Google Scholar PubMed PubMed Central

17. Hussain, M. K., Singh, D. K., Singh, A., Asad, M., Ansari, M. I., Shameem, M., Krishna, S., Valicherla, G. R., Makadia, V., Meena, S., Deshmukh, A. L., Gayen, J. R., Siddiqi, M. I., Datta, D., Hajela, K., Banerjee, D. Sci. Rep. 2017, 7, 10715.10.1038/s41598-017-10864-3Search in Google Scholar PubMed PubMed Central

18. Osman, H. M. Y., Osman, M. Y. J. High Inst. Public Health 2008, 38, 723–733.10.21608/jhiph.2008.20960Search in Google Scholar

19. Stypuła-Trębas, S., Minta, M., Radko, L., Jedziniak, P., Posyniak, A. Environ. Toxicol. Pharmacol. 2017, 55, 208–211.10.1016/j.etap.2017.08.036Search in Google Scholar PubMed

20. Grover, S., Lawrence, C. B. Int. J. Mol. Sci. 2017, 18, 18.10.5958/2319-1198.2017.00003.3Search in Google Scholar

21. Wang, J., Peng, T., Zhang, X., Sanlei, X., Zheng, P., Yao, K., Ke, Y., Wang, Z., Jaing, H. J. Mol. Recogn. 2019, 32, e2776; https://doi.org/10.1002/jmr.2776.Search in Google Scholar

22. Wu, Q., Merchant, F. A., Castleman, K. R. Microscope Image Processing; Academic Press: New York, 2008.Search in Google Scholar

23. Al-Masoudi, N. A., Al-Salihi, N. J., Marich, Y. A., Markus, T. J. Fluoresc. 2015, 25, 1847–1854.10.1007/s10895-015-1677-zSearch in Google Scholar PubMed

24. Murata, C., Masuda, T., Kamochi, Y., Todoroki, K., Yoshida, H., Nohta, H., Yamaguchi, M., Takadate, A. Chem. Pharm. Bull. 2005, 53, 750–758.10.1248/cpb.53.750Search in Google Scholar PubMed

25. Rajesha, G., Kumar, H. C. K., Naik, H. S. B., Mahadevan, K. M. S. Afr. J. Chem. 2011, 64, 88–94.Search in Google Scholar

26. Albuquerque, H. M. T., Santos, C. M. M., Cavaleiro, J. A. S., Silva, A. M. S. Curr. Org. Chem. 2014, 18, 2750–2775.10.2174/1385272819666141013224253Search in Google Scholar

27. Das, M., Manna, K. J. Toxicol. 2016, 2016, 7651047.10.1155/2016/8606410Search in Google Scholar

28. Gao, F., Huang, G., Xiao, J. Med. Res. Rev. 2020, 40, 2049–2084.10.1002/med.21698Search in Google Scholar

29. Lawrence, N. J., Rennison, D., McGown, A. T., Hadfield, J. A. Bioorg. Med. Chem. Lett. 2003, 13, 3759–3763.10.1016/j.bmcl.2003.07.003Search in Google Scholar

30. Murthi, G. S. S., Basak, M. J. Indian Chem. Soc. 1993, 70, 170–171.Search in Google Scholar

31. Chen, H., Xu, X., Liu, L., Tang, G., Zhao, Y. RSC Adv. 2013, 3, 16247–250.10.1039/C3RA42887GSearch in Google Scholar

32. Vahini, M. V., Devarajegowda, H. C., Mahadevan, K. M., Meenakshid, T. G., Arunkashi, H. K. Acta Crystallogr. 2010, E66, o2658.10.1107/S1600536810037840Search in Google Scholar

33. Kim, B. O., Lee, H.-G., Kang, S.-B., Yoon, Y.-J. Synthesis 2012, 44, 42–50.10.1055/s-0031-1289622Search in Google Scholar

34. Mosmann, T. J. Immunol. Methods 1993, 65, 55–63.10.1016/0022-1759(83)90303-4Search in Google Scholar

35. Morris, G. M., Huey, R., Lindstrom, W., Sanner, M. F., Belew, R. K., Goodsell, D. S., Olson, A. J. J. Comput. Chem. 2009, 16, 2785–2791.10.1002/jcc.21256Search in Google Scholar PubMed PubMed Central

36. Hanwell, M. D., Curtis, D. E., Lonie, D. C., Vandermeersch, T., Zurek, E., Hutchison, G. R. J. Cheminf. 2012, 4, 17.10.1186/1758-2946-4-17Search in Google Scholar PubMed PubMed Central

37. Pettersen, E. F., Goddard, T. D., Huang, C. C., Couch, G. S., Greenblatt, D. M., Meng, E. C., Ferrin, T. E. J. Comput. Chem. 2004, 13, 1605–612.10.1002/jcc.20084Search in Google Scholar PubMed

38. Biovia Discovery Studio. Discovery Studio Modeling Environment; Dassault Systȇmes: San Diego (USA), 2020.Search in Google Scholar

Supplementary Material

The online version of this article offers supplementary material (https://doi.org/10.1515/znb-2020-0204).

Received: 2020-12-19
Accepted: 2021-03-01
Published Online: 2021-04-03
Published in Print: 2021-04-27

© 2021 Walter de Gruyter GmbH, Berlin/Boston

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https://doi.org/10.1515/znb-2020-0204
Keywords for this article
amide analogs; benzocoumarin; breast cancer; cytotoxicity; ester derivatives; molecular docking study

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