A facile synthesis and anticancer activity of some novel thiazoles carrying 1,3,4-thiadiazole moiety
© The Author(s) 2017
Received: 5 January 2017
Accepted: 15 March 2017
Published: 21 March 2017
Thiazoles and 1,3,4-thiadiazoles have been reported to possess various pharmacological activities.
A novel series of thiazoles carrying 1,3,4-thiadiazole core were designed and prepared via the reaction of the 2-(4-methyl-2-phenylthiazole-5-carbonyl)-N-phenylhydrazinecarbo-thioamide with the appropriate hydrazonoyl chlorides. The structures of the newly synthesized compounds were confirmed based on elemental and spectral analysis as well as their alternative syntheses. The cytotoxic potency of the newly synthesized thiadiazoles was evaluated by their growth inhibitory potency in liver HepG2 cancer cell line. Also, the structure activity relationship was studied.
KeywordsThiazoles 1,3,4-Thiadiazoles Hydrazonoyl chlorides Anticancer activity Structure activity relationship
Cancer is the most common life-threatening disease representing a major health problem for many decades. The clinical application of chemotherapy still considered as a major compartment in treating cancer, however, it is often limited by the severity of the side effects and the development of tumor cell resistance to these cytotoxic agents. Clinical administration of high doses of anticancer drugs to overcome resistance leads to severe toxicities . Therefore, the development of novel effective anticancer drugs and strategies is eagerly being pursued.
Also, it was reported that liver cancer is one from the top ten human cancers worldwide and among the top five of cancers in terms of mortality [2, 3]. A literature survey revealed that thiazole derivatives had many biological activities as antihypertension , antifungal , antimicrobial [6, 7], anti-inflammatory , antioxidant , antitubercular , and anticancer [11–14]. Moreover, 1,3,4-thiadiazole derivatives had many biological activities such as antibacterial, antifungal, antituberculosis, anti-hepatitis B viral, antileishmanial, anti-inflammatory, analgesic, CNS depressant, antioxidant, antidiabetic, molluscicidal, antihypertensive, diuretic, analgesic, antimicrobial, antitubercular, anticonvulsant and anticancer [15–24]. These important biological activities encouraged several researchers to find out different methods for synthesis of new thiadiazoles using different synthons, such as thiosemicarbazides, thiocarbazides, dithiocarbazates, thioacylhydrazines, acyl hydrazines, and bithioureas . As a part of our research projects to synthesize new bioactive compounds [26–34], we intended in this research to synthesize a new series of thiazoles carrying 1,3,4-thiadiazole moiety in order to study their anticancer activity against liver carcinoma cell line (HepG2).
Results and discussion
The presence of the thioamide hydrazine moiety as a side chain in compound 3 prompted us to utilize it for constructing 1,3,4-thiadiazole ring through its reaction with many hydrazonoyl chlorides. Thus, treatment of compound 3 with the appropriate hydrazonoyl chlorides 4a–g  led to the formation of the respective 1,3,4-thiadiazoles 6a–g, rather than thiadiazines 7a–g or 1,3-thiazoles 8a–g (Scheme 1). The elemental analysis together with the spectral data are consistent with the proposed structure 6. The IR spectra of products 6 showed in each case the presence of two absorption bands around 1700, 1650 cm−1 for the two carbonyl groups, in addition to another band near v 3350 cm−1 for the NH function. The 1HNMR spectra of 6 showed in each case the presence of broad singlet signals assigned for the NH proton near δ 11.19 ppm, in addition to the expected signals for the two CH3, and the aryl protons. Also, the mass spectrum of each of products 6 revealed the presence of a molecular ion peak (see materials and methods). A suggested mechanism for the synthesis of 1,3,4-thiadiazole derivatives 6 is outlined in Scheme 1.
To explain the synthesis of 1,3,4-thiadiazole 6a–g, we assumed that the reaction started with S-alkylation to afford the non-isolable intermediate 5 followed by intramolecular cyclization and elimination of aniline molecule to give the respective thiadiazole derivatives 6a–g (Scheme 1). The structure of 6 was proved chemically via an alternative method (Scheme 1). Thus, the reaction of 5-(4-methyl-2-phenylthiazol-5-yl)-1,3,4-oxadiazole-2(3H)-thione (9)  with 4a in ethanol in the presence of triethylamine under reflux led to the formation of a product which is identical in all respects (mp, mixed mp, and IR) with compound 6a.
Cytotoxic activity of the tested compounds against HepG2
0.72 ± 0.13
9.89 ± 0.19
39.06 ± 0.24
1.29 ± 0.27
64.35 ± 0.14
4.03 ± 0.19
1.88 ± 0.08
1.06 ± 0.12
4.70 ± 0.16
32.4 ± 0.19
0.91 ± 0.20
0.82 ± 0.13
6.79 ± 0.11
1.25 ± 0.18
The ester group (CO2Et) at position 2 of the thiadiazole ring is necessary to have higher antitumor activity than the acetyl and the N-phenyl carboxamide (CONHPh) groups.
The presence of chlorine group (electron-withdrawing group) at the position 2, 4 or 4 in the aryl moiety of the thiadiazole ring increased the cytotoxic activity.
Chlorine at positions 2, 4 or 4 in the aryl moiety had high cytotoxic activity than halogen at position 3.
The compounds containing chlorine had high cytotoxic activity than the compounds containing bromine.
The presence of electron-donating groups such as methyl or methoxy at the position 4 in the aryl moiety as in the compounds 12b, 6b and 6d decreased the cytotoxic activity.
Melting points were measured on an Electrothermal IA 9000 series digital melting point apparatus (Bibby Sci. Lim. Stone, Staffordshire, UK). IR spectra were measured on PyeUnicam SP 3300 and Shimadzu FTIR 8101 PC infrared spectrophotometers (Shimadzu, Tokyo, Japan) in potassium bromide discs. NMR spectra were measured on a Varian Mercury VX-300 NMR spectrometer (Varian, Inc., Karlsruhe, Germany) operating at 300 MHz (1H-NMR) and run in deuterated dimethylsulfoxide (DMSO-d 6 ). Chemical shifts were related to that of the solvent. Mass spectra were recorded on a Shimadzu GCMS-QP1000 EX mass spectrometer (Tokyo, Japan) at 70 eV. Elemental analyses were measured by using a German made Elementar vario LIII CHNS analyzer. Antitumor activity of the products was measured at the Regional Center for Mycology and Biotechnology at Al-Azhar University, Cairo, Egypt. 2-(4-Methyl-2-phenylthiazole-5-carbonyl)-N-phenylhydrazinecarbo-thioamide (3) , 5-(4-methyl-2-phenylthiazol-5-yl)-1,3,4-oxadiazole-2(3H)-thione (9) , hydrazonoyl halides 4a–g, 10a–d and 16a, b , and ethyl 5-hydrazono-4-phenyl-4,5-dihydro-1,3,4-thiadiazole-2-carboxylate (15)  were prepared as reported in the respective literature.
Synthesis of 1,3,4-thiadiazole derivatives (6a–g, 12a–d and 18a, b)
General procedure A mixture of compound 3 (0.368 g, 1 mmol) and the appropriate hydrazonoyl chlorides 4a–g or 10a–d or 16a, b (1 mmol) in ethanol (20 mL), triethylamine (0.1 g, 1 mmol) was added. The mixture was refluxed for 4–6 h. The formed solid product was filtered, washed with methanol, dried and recrystallized from the proper solvents to afford products 6a–g, 10a–d and 18a, b, respectively. The physical constants and spectral data of the obtained products are listed below:
N′-(5-Acetyl-3-phenyl-1,3,4-thiadiazol-2(3H)-ylidene)-4-methyl-2-phenyl thiazole-5-carbohydrazide (6a)
Yellow solid (73%); m.p. 163–165 °C (EtOH); IR (KBr) v 3317 (NH), 3038, 2951 (CH), 1701, 1647 (2C=O), 1593 (C=N) cm−1; 1H-NMR (DMSO-d 6) δ 2.44 (s, 3H, CH3CO), 2.74 (s, 3H, CH3–thiazole), 6.92–8.00 (m, 10H, ArH), 11.19 (s, br, 1H, D2O-exchangeable NH); 13C-NMR (DMSO-d 6): δ 16.9, 24.9 (CH3), 114.8, 117.1, 120.9, 121.9, 123.4, 126.2, 128.9, 129.2, 129.4, 130.9, 138.3, 141.7, 159.4 (Ar–C and C=N), 167.9, 194.0 (C=O); MS m/z (%) 435 (M+, 10), 381 (13), 274 (56), 118 (31), 92 (100), 65 (38). Anal. Calcd. for C21H17N5O2S2 (435.52): C, 57.91; H, 3.93; N, 16.08. Found C, 57.86; H, 3.84; N, 16.00%.
N′-(5-Acetyl-3-(p-tolyl)-1,3,4-thiadiazol-2(3H)-ylidene)-4-methyl-2-phenyl thiazole-5-carbohydrazide (6b)
Yellow solid (75%); m.p. 149–151 °C (EtOH); IR (KBr) v 3334 (NH), 3019, 2920 (CH), 1699, 1648 (2C=O), 1597 (C=N) cm−1; 1H-NMR (DMSO-d 6) δ 2.31 (s, 3H, CH3-Ar), 2.44 (s, 3H, CH3CO), 2.73 (s, 3H, CH3–thiazole), 6.98–7.89 (m, 9H, ArH), 11.18 (s, br, 1H, D2O-exchangeable NH); 13C-NMR (DMSO-d 6): δ 16.0, 17.7, 19.4 (CH3), 116.0, 118.0, 120.8, 125.1, 126.7, 127.3, 128.1, 129.8, 131.9, 132.7, 138.2, 152.6, 159.4 (Ar–C and C=N), 166.5, 194.7 (C=O); MS m/z (%) 449 (M+, 45), 372 (54), 200 (27), 104 (36), 80 (100), 64 (35). Anal. Calcd. for C22H19N5O2S2 (449.55): C, 58.78; H, 4.26; N, 15.58. Found C, 58.65; H, 4.17; N, 15.46%.
Brown solid (75%); m.p. 171–173 °C (EtOH); IR (KBr) v 3325 (NH), 3013, 2926 (CH), 1698, 1655 (2C=O), 1594 (C=N) cm−1; 1H-NMR (DMSO-d 6) δ 2.45 (s, 3H, CH3CO), 2.76 (s, 3H, CH3–thiazole), 6.93–7.96 (m, 9H, ArH), 11.25 (s, br, 1H, D2O-exchangeable NH); 13C-NMR (DMSO-d 6): δ 16.8, 24.9 (CH3), 115.1, 119.4, 120.2, 122.9, 123.8, 127.3, 128.3, 128.7, 129.0, 133.5, 138.3, 140.2, 157.9 (Ar–C and C=N), 167.8, 194.3 (C=O); MS m/z (%) 471 (M++2, 14), 469 (M+, 45), 396 (57), 200 (17), 80 (100), 64 (89). Anal. Calcd. for C21H16ClN5O2S2 (469.97): C, 53.67; H, 3.43; N, 14.90. Found C, 53.52; H, 3.37; N, 14.82%.
Brown solid (68%); m.p. 143–145 °C (EtOH); IR (KBr) v 3328 (NH), 3031, 2923 (CH), 1697, 1653 (2C=O), 1596 (C=N) cm−1; 1H-NMR (DMSO-d 6) δ 2.45 (s, 3H, CH3CO), 2.75 (s, 3H, CH3–thiazole), 3.76 (s, 3H, OCH3), 6.99–7.99 (m, 9H, ArH), 11.29 (s, br, 1H, D2O-exchangeable NH); 13C-NMR (DMSO-d 6): δ 16.5, 17.9, 54.2 (CH3), 116.2, 117.9, 120.7, 124.8, 126.3, 127.0, 127.7, 129.3, 131.9, 132.4, 137.6, 150.2, 159.0 (Ar–C and C=N), 166.2, 194.6 (C=O); MS m/z (%) 465 (M+, 39), 334 (87), 200 (63), 122 (80), 77 (100), 64 (45). Anal. Calcd. for C22H19N5O3S2 (465.55): C, 56.76; H, 4.11; N, 15.04. Found C, 56.63; H, 4.04; N, 14.95%.
Yellow solid (70%); m.p. 166–168 °C (EtOH); IR (KBr) v 3431(NH), 3025, 2932 (CH), 1698, 1659 (2C=O), 1593 (C=N) cm−1; 1H-NMR (DMSO-d 6) δ 2.44 (s, 3H, CH3CO), 2.66 (s, 3H, CH3–thiazole), 6.98–7.90 (m, 9H, ArH), 11.23 (s, br, 1H, D2O-exchangeable NH); MS m/z (%) 471 (M++2, 10), 469 (M+, 34), 334 (46), 200 (28), 132 (48), 80 (100), 64 (68). Anal. Calcd. for C21H16ClN5O2S2 (469.97): C, 53.67; H, 3.43; N, 14.90. Found C, 53.60; H, 3.36; N, 14.79%.
N′-(5-Acetyl-3-(4-bromophenyl)-1,3,4-thiadiazol-2(3H)-ylidene)-4-methyl-2-phenyl thiazole-5-carbohydrazide (6f)
Brown solid (73%); m.p. 160–162 °C (EtOH); IR (KBr) v 3429 (NH), 3012, 2924 (CH), 1696, 1654 (2C=O), 1594 (C=N) cm−1; 1H-NMR (DMSO-d 6) δ 2.44 (s, 3H, CH3CO), 2.65 (s, 3H, CH3–thiazole), 6.95–7.94 (m, 9H, ArH), 11.25 (s, br, 1H, D2O-exchangeable NH); 13C-NMR (DMSO-d 6): δ 16.9, 24.8 (CH3), 114.8, 120.3, 122.0, 122.6, 123.8, 127.2, 127.9, 128.3, 130.2, 132.5, 136.9, 140.0, 157.5 (Ar–C and C=N), 167.6, 194.1 (C=O); MS m/z (%) 516 (51), 514 (M+, 53), 325 (76), 172 (44), 91 (80), 80 (100), 64 (47). Anal. Calcd. for C21H16BrN5O2S2 (514.42): C, 49.03; H, 3.14; N, 13.61. Found C, 48.93; H, 3.12; N, 13.53%.
N′-(5-Acetyl-3-(2,4-dichlorophenyl)-1,3,4-thiadiazol-2(3H)-ylidene)-4-methyl-2-phenyl thiazole-5-carbohydrazide (6g)
Brown solid (77%); m.p. 181–183 °C (EtOH/dioxane); IR (KBr) v 3318 (NH), 3088, 2926 (CH), 1699, 1671 (2C=O), 1597 (C=N) cm−1; 1H-NMR (DMSO-d 6) δ 2.47 (s, 3H, CH3CO), 2.67 (s, 3H, CH3–thiazole), 6.97–8.07 (m, 8H, ArH), 11.19 (s, br, 1H, D2O-exchangeable NH); MS m/z (%) 504 (M+, 14), 407 (33), 161 (14), 80 (99), 64 (100). Anal. Calcd. for C21H15Cl2N5O2S2 (504.41): C, 50.00; H, 3.00; N, 13.88. Found C, 49.88; H, 2.92; N, 13.75%.
Ethyl 5-(2-(4-methyl-2-phenylthiazole-5-carbonyl)hydrazono)-4-phenyl-4,5-dihydro-1,3,4-thiadiazole-2-carboxylate (12a)
Yellow solid (71%); m.p. 137–139 °C (EtOH); IR (KBr) v 3432 (NH), 3035, 2923 (CH), 1749, 1659 (2C=O), 1597 (C = N) cm−1; 1H-NMR (DMSO-d 6) δ 1.20 (t, 3H, J = 7.1 Hz, CH2CH 3 ), 2.74 (s, 3H, CH3–thiazole), 4.21 (q, 2H, J = 7.1 Hz, CH 2 CH3),7.00–8.01 (m, 10H, ArH), 10.72 (s, br, 1H, D2O-exchangeable NH); 13C-NMR (DMSO-d 6): δ 13.7, 16.8 (CH3), 61.2 (CH2), 115.8, 117.3, 118.4, 120.9, 122.4, 126.0, 128.5, 128.9, 130.0, 132.6, 135.6, 139.6, 159.1 (Ar–C and C=N), 163.4, 166.8 (C=O); MS m/z (%): 465 (M+, 27), 334 (50), 200 (34), 104 (40), 80 (100), 64 (37). Anal. Calcd. for C22H19N5O3S2 (465.55): C, 56.76; H, 4.11; N, 15.04. Found C, 56.69; H, 4.03; N, 15.01%.
Ethyl 5-(2-(4-methyl-2-phenylthiazole-5-carbonyl)hydrazono)-4-(p-tolyl)-4,5-dihydro-1,3,4-thiadiazole-2-carboxylate (12b)
Yellow solid (70%); m.p. 147–149 °C (EtOH); IR (KBr) v 3424 (NH), 3058, 2925 (CH), 1749, 1674 (2C=O), 1595 (C=N) cm−1; 1H-NMR (DMSO-d 6) δ 1.20 (t, 3H, J = 7.1 Hz, CH2CH 3 ), 2.26 (s, 3H, CH3–Ar), 2.76 (s, 3H, CH3–thiazole), 4.19 (q, 2H, J = 7.1 Hz, CH 2 CH3), 7.00–8.02 (m, 9H, ArH), 10.73 (s, br, 1H, D2O-exchangeable NH); 13C-NMR (DMSO-d 6): δ 13.9, 16.8, 20.1 (CH3), 61.5 (CH2), 114.5, 115.8, 117.1, 120.9, 121.9, 126.2, 128.1, 129.6, 130.8, 131.8, 138.3, 140.0, 159.4 (Ar–C and C=N), 163.0, 166.5 (C=O); MS m/z (%) 479 (M+, 20), 367 (25), 251 (18), 80 (85), 64 (100). Anal. Calcd. for C23H21N5O3S2 (479.57): C, 57.60; H, 4.41; N, 14.60. Found C, 57.49; H, 4.33; N, 14.51%.
Ethyl 4-(4-chlorophenyl)-5-(2-(4-methyl-2-phenylthiazole-5-carbonyl) hydrazono)-4,5-dihydro-1,3,4-thiadiazole-2-carboxylate (12c)
Yellow solid (73%); m.p. 167–169 °C (EtOH/dioxane); IR (KBr) v 3340 (NH), 3050, 2927 (CH), 1748, 1670 (2C=O), 1599 (C=N) cm−1; 1H-NMR (DMSO-d 6) δ 1.23 (t, 3H, J = 7.1 Hz, CH2CH 3 ), 2.75 (s, 3H, CH3–thiazole), 4.22 (q, 2H, J = 7.1 Hz, CH 2 CH3),7.02–7.96 (m, 9H, ArH), 10.77 (s, br, 1H, D2O-exchangeable NH); 13C-NMR (DMSO-d 6): δ 13.4, 16.9 (CH3), 61.4 (CH2), 116.2, 117.0, 119.5, 120.9, 122.3, 127.2, 128.2, 129.4, 131.4, 132.2, 137.0, 139.4, 158.6 (Ar–C and C=N), 163.8, 167.2 (C=O); MS m/z (%) 501 (M++2, 13), 499 (M+, 45), 363 (39), 334 (100), 200 (35), 104 (30), 77 (50). Anal. Calcd. for C22H18ClN5O3S2 (499.99): C, 52.85; H, 3.63; N, 14.01. Found C, 52.79; H, 3.60; N, 13.87%.
Ethyl 4-(2,4-dichlorophenyl)-5-(2-(4-methyl-2-phenylthiazole-5-carbonyl) hydrazono)-4,5-dihydro-1,3,4-thiadiazole-2-carboxylate (12d)
Brown solid (75%); m.p. 173–175 °C (EtOH/dioxane); IR (KBr) v 3221 (NH), 3079, 2926 (CH), 1749, 1671 (2C=O), 1599 (C=N) cm−1; 1H-NMR (DMSO-d 6) δ 1.24 (t, 3H, J = 7.1 Hz, CH2CH 3 ), 2.77 (s, 3H, CH3-thiazole), 4.23 (q, 2H, J = 7.1 Hz, CH 2 CH3),7.08–8.13 (m, 8H, ArH), 10.77 (s, br, 1H, D2O-exchangeable NH); MS m/z (%) 534 (M+, 19), 449 (78), 223 (100), 200 (54), 104 (58), 80 (85). Anal. Calcd. for C22H17Cl2N5O3S2 (534.44): C, 49.44; H, 3.21; N, 13.10. Found C, 49.29; H, 3.16; N, 13.02%.
Brown solid (76%); m.p. 176–178 °C (EtOH/dioxane); IR (KBr) v 3427, 3343 (2NH), 1672, 1653 (2C=O), 1597 (C=N) cm−1; 1H-NMR (DMSO-d 6) δ 2.75 (s, 3H, CH3–thiazole), 7.02–7.78 (m, 15H, ArH), 10.18 (s, br, 1H, D2O-exchangeable NH), 11.72 (s, br, 1H, D2O-exchangeable NH); 13C-NMR (DMSO-d 6): δ 17.2 (CH3), 114.6, 117.3, 118.4, 120.9, 122.6, 122.8, 124.0, 126.5, 128.5, 129.1, 130.0, 130.6, 131.9, 132.6, 138.2, 142.1, 159.2 (Ar–C and C=N), 162.6, 166.0 (C=O); MS m/z (%) 512 (M+, 8), 401 (00), 282 (10), 150 (22), 92 (26), 65 (29). Anal. Calcd. For C26H20N6O2S2 (512.61): C, 60.92; H, 3.93; N, 16.39. Found C, 60.78; H, 3.85; N, 16.32%.
4-(2,4-Dichlorophenyl)-5-(2-(4-methyl-2-phenylthiazole-5-carbonyl) hydrazono)-N-phenyl-4,5-dihydro-1,3,4-thiadiazole-2-carboxamide (18b)
Brown solid (77%); m.p. 186–188 °C (Dioxane); IR (KBr) v 3429, 3337 (2NH), 1692, 1656 (2C=O), 1591 (C=N) cm−1; 1H-NMR (DMSO-d 6) δ 2.76 (s, 3H, CH3–thiazole), 7.13–7.83 (m, 13H, ArH), 10.19 (s, br, 1H, D2O-exchangeable NH), 11.77 (s, br, 1H, D2O-exchangeable NH); MS m/z (%) 581 (M+, 38), 473 (64), 334 (72), 200 (35), 119 (65), 64 (100). Anal. Calcd. for C26H18Cl2N6O2S2 (581.50): C, 53.70; H, 3.12; N, 14.45. Found C, 53.62; H, 3.03; N, 14.32%.
Alternate synthesis of thiadiazole derivatives 6a and 18a
To a mixture of 5-(4-methyl-2-phenylthiazol-5-yl)-1,3,4-oxadiazole-2(3H)-thione (9) (0.275 g, 1 mmol) and hydrazonoyl chloride 4a or 16a (1 mmol) in absolute EtOH (25 mL), was added triethylamine (0.1 g, 0.14 mL, 1 mmol). The reaction mixture was stirred at room temperature till methyl mercaptan ceased to evolve (3 h). The solvent was evaporated and the residue was treated with ice/HCl mixture. The solid product was collected by filtration, washed with EtOH, dried, and recrystallized to give the respective compounds 6a and 18a, that was identical in all respects (m.p., mixed m.p. and IR spectra) with that obtained from the reaction of 4a or 16a with 3.
Alternate synthesis of 12a
A mixture of ethyl 4-methyl-2-phenylthiazole-5-carboxylate (1) (0.247 g, 1 mmol) and ethyl 5-hydrazono-4-phenyl-4,5-dihydro-1,3,4-thiadiazole-2-carboxylate (15) (0.264 g, 1 mmol) was refluxed in ethanol for 4 h. The solid product that separated was filtered off, washed with water and finally recrystallized to give the corresponding product, 12a which was identical in all aspects (m.p., mixed m.p. and IR spectra) with those obtained from the reaction of 3 with 10a.
Evaluation of the antitumor activity using Viability assay
Human hepatocellular carcinoma (HepG2) cell line was obtained from the American Type Culture Collection (ATCC, Rockville, MD). The detailed procedure for the in vitro antitumor assay is presented in Additional file 1.
A series of novel thiazoles carrying 1,3,4-thiadiazole ring were synthesized. The structure of the newly prepared compounds was established based on both elemental analysis and spectroscopic data and by an alternative method wherever possible. All the synthesized compounds were evaluated for their anti-cancer activity against the human hepatocellular carcinoma (HepG2) cell line. The results showed that the thiazole derivatives 12d, 12c, 6g,18b, 6c and 6f having IC50 values 0.82, 0.91, 1.06, 1.25, 1.29 and 1.88 µM, respectively, were found to be the highly active compounds of the prepared series. Based on the experimental results of the antitumor activity, the structure–activity relationships were discussed.
human hepatocellular carcinoma
structure activity relationship
American Type Culture Collection
thin layer chromatography
SMG designed research; SMG, MRA and NAK performed research and analyzed the data; SMG, NAK, YNM and AMA wrote and approved the final manuscript. All authors read and approved the final manuscript.
The authors extend their sincere appreciation to the Deanship of Scientific Research at the King Saud University for its funding this Prolific Research group (PRG-1437-29).
The authors declare that they have no competing interests.
Samples of the compounds are available from the authors.
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