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Zinc complexes of hydrazone derivatives bearing 3,4-dihydroquinolin-2(1H)-one nucleus as new anti-tubercular agents
⁎Corresponding author. iycmustapha@gmail.com (Mustapha C. Mandewale)
-
Received: ,
Accepted: ,
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.
Peer review under responsibility of King Saud University.
Abstract
We report synthesis of new hydrazone derivatives bearing 3,4-dihydroquinoline nucleus in a short reaction time with good yield. This synthetic strategy allows for the assimilation of 3,4-dihydroquinoline and quinoline in a single scaffold through an easy way. The Antituberculosis analysis was performed using blue Alamar method to identify the more effective compound. Most of the synthesized compounds show moderate to good antituberculosis properties. Of the compounds studied 6c, 6e and 6h have proven as the efficient antitubercular member Mycobacterium tuberculosis (H37 RV strain) ATCC No.-27294. Subsequently UV and Fluorescence spectral study of the synthesized compounds was performed. This study would pave the way for future development of more effective dihydroquinoline hydrazone analogs for applications in biological and material science.
Abstract
A series of hydrazone derivatives 5a–5i were synthesized through multi-step reactions. The 2-(2-oxo-1,2,3,4-tetrahydroquinoline-7-yloxy)acetohydrazide was prepared from 7-hydroxy-3,4-dihydroquinolin-2(1H)-one as starting material. Then the condensation of 2-(2-oxo-1,2,3,4-tetrahydroquinoline-7-yloxy)acetohydrazide with different o-hydroxyaldehyde derivatives 4a–4i yielded into hydrazone derivatives 5a–5i. These hydrazone ligands were complexed with Zn (II) yielded complexes 6a–6i. The molecular structures of the hydrazones 5a–5i and Zn (II) complexes 6a–6i were characterized by FTIR, 1H and 13C NMR, LCMS, XRD, DSC-TGA, UV–Visible, Fluorescence and elemental analysis. The conductivity experiments showed that all the complexes are non-electrolytes.The Preliminary results of antituberculosis study showed that most of the Zn (II) complexes 6a–6i demonstrated very good antituberculosis activity while the ligands 4a–4i showed moderate activity. Among the tested compounds 6c, 6e and 6h were found to be most active with minimum inhibitory concentration (MIC) of 1.6 μg/mL against Mycobacteriumtuberculosis (H37 RV strain) ATCC No.-27294 which is comparable to ‘‘first and second line’’ drugs used to treat tuberculosis.
Keywords
Hydrazone
Ligand
Metal complex
Anti-tuberculosis
Fluorescence
1 Introduction
The frequency of infectious disease like tuberculosis in humans has increased dramatically because of rising multidrug resistance. The rising clinical importance of drug-resistant bacterial pathogens has impelled additional exigency to investigate more effective agents. Therefore, searching for new antituberculosis agents with specific activity, possibly acting through mechanism, which are different from those of familiar classes is of main interest. The modification in the molecular structure of potential lead compounds is still an organized and ruler approach to widen the vicinity of antimicrobial medicine investigation.
The hydrazone ligands have been studied extensively for years, due to the synthetic flexibilities, selectivity as well as sensitivity toward the transition metal ions (Rao et al., 1997). Among the ligand systems, quinoline hydrazone derivatives are highly important because, these ligands developed due to their diverse chelating ability, structural flexibility and pharmacological activities such as antimicrobial, anti-inflammatory, analgesic, antifungal, antiviral, anticancer and anti-tuberculosis (Uppal et al., 2011; Rollas and Kucukguzel, 2007; West et al., 1993). The transition metal complexes of quinoline hydrazone derivatives have gained increasing attention as antibacterials (Freixas and Span, 1991; Babahan et al., 2013; Banerjee et al., 2009).
Recently it is reported that quinoline hydrazones and their Zn (II) complexes showed significant activity anti-tuberculosis as well as fluorescence properties (Eswaran et al., 2010; Thomas et al., 2011; Vavríkova et al., 2011; Arafa et al., 2013; Hou et al., 2012). Based on these facts, supported by literature and in continuation of our research for new antituberculosis agents (Mandewale et al., 2015a,b, 2016), we have undertaken research studies on synthesis and biological screening of some new quinoline hydrazone derivatives and their Zn (II) complexes as shown in Fig. 1.
2 Experimental
2.1 Materials and methods
The chemicals used were of analytical grade and the solvents were distilled before use according to the standard procedure. The melting points of synthesized compounds were determined in open capillary tubes and are uncorrected. UV–Visible spectra were obtained on Shimadzu UV-1800 spectrophotometer for scan range 200–800 nm. The path length of the measurements was 1.0 cm. The fluorescence spectra were recorded on a spectrofluorophotometer Shimadzu RF-5301pc having 1 cm path length and 3 nm slit width for scan range 220.0–900.0 nm. The concentration of 200 ppm of ligand and metal complexes was prepared in DMF (N,N-dimethylformamide) for study. Infrared spectra were measured with KBr pellet on a FTIR-7600 Lambda Scientific Pty. Ltd., in the range 4000–400 cm−1. LCMS spectra were performed on BRUKER ESQUIRE HCT spectrometer. 1H NMR and 13C NMR spectra were recorded on Bruker AV II 300 spectrometer instrument in DMSO-d6 using tetramethylsilane (TMS) as an internal standard; chemical shifts are reported as δ ppm units. The DSC-TGA was carried out on Universal V4.5A TA instrument. The spectral and elemental analyses were done at the University of Mumbai and SAIF, IIT Mumbai, India.
2.2 Preparation of 2-(2-oxo-1,2,3,4-tetrahydroquinoline-7-yloxy)acetohydrazide (3)
The 7-hydroxy-3,4-dihydroquinolin-2(1H)-one (1) (1 mmol) was dissolved in DMF. To this clear solution 1.2 mmol of K2CO3 was added followed by slow addition of 1 mmol of methyl chloroacetate. Resultant solution was stirred at 80–90 °C for 3 h. After completion of the reaction it was poured in ice cold water. Precipitated product was filtered and dried in oven i.e. 2-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yloxy)acetate (2). The compound (2) was dissolved in methanol and 1.1 mmol hydrazine hydrate was added and stirred at room temperature for 1 h. White shiny solid precipitated product was filtered. Finally, the product (3) Fig. 2 was dried in oven.
2.3 Preparation of the hydrazones ligands
The compound (3) (0.01 mol) and appropriate aldehyde derivatives (4a–4i) (0.01 mol) were taken in round bottom flax containing 10 cm3 of ethanol. Reaction mixture was refluxed for 30 min. Completion of reaction was checked with TLC. Upon cooling the reaction mixture a solid product 5a–5i as shown in Fig. 2 and Table 1 was precipitated out, which was filtered, dried and purified by recrystallization from ethanol.
| Entry | Aldehyde (4) | Hydrazone (5) | Yield (%) |
|---|---|---|---|
| a |
|
|
90 |
| b |
|
|
84 |
| c |
|
|
82 |
| d |
|
|
83 |
| e |
|
|
89 |
| f |
|
|
88 |
| g |
|
|
91 |
| h |
|
|
82 |
| i |
|
|
85 |
2.4 Preparation of Zn (II) complexes
A solution of ZnCl2 in methanol was added gradually to a stirred ethanolic solution of the hydrazone ligand (5a–5i) in the molar ratio 1:2. The reaction mixture was further stirred for 2 h at 78 °C. Then it was cooled in ice bath to ensure the complete precipitation of the formed complexes (6a–6i) Fig. 2 and Table 2. The precipitated solid complex was filtered and washed with water. Finally, the complex was washed with diethyl ether and dried in vacuum desiccators over anhydrous CaCl2.
| Entry | Complex | Color | Entry | Complex | Color |
|---|---|---|---|---|---|
| 6a |
|
Yellow | 6f |
|
Yellow |
| 6b |
|
Yellow | 6g |
|
Yellow |
| 6c |
|
Yellow | 6h |
|
Yellow |
| 6d |
|
Yellow | |||
| 6e |
|
Yellow | 6i |
|
Yellow |
2.5 Spectral data
2.5.1 2-[(2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)oxy]acetohydrazide (3)
Bright white solid (MeOH); mp 224–226 °C; IR(KBr, υ, cm−1): 3322 (NH2), 3289 (NH), 3066, 3008 (ArC—H), 2913, 2856 (Aliphatic C—H), 1679 (C⚌O), 1631 (C⚌O), 1598; 1H NMR (DMSO-d6, 300 MHz): δ = 10.04 (s, 1H, —CO—NH—), 9.33 (s, 1H, —NH—NH2), 7.03–7.06 (m, 1H), 6.48–6.50 (m, 2H), 4.40 (s, 2H, —O—CH2), 4.31 (s, 2H, —NH2), 2.75–2.80 (m, 2H, —CO—CH2—CH2—), 2.38–2.43 (m, 2H, —CO—CH2—CH2—); LCMS (98.793%) m/z: 236.00 [M+H] (100); Anal. Calcd. for C11H13N3O3: C. 56.16; H, 5.57; N, 17.86. Found: C, 54.98; H, 5.50; N, 17.93.
2.5.2 N′-[(E)-(2-hydroxyphenyl)methylidene]-2-[(2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)oxy] acetohydrazide (5a)
white spongy solid (EtOH); mp 285–287 °C; IR(KBr, υ, cm−1): 3316 (OH), 3193 (NH), 3077 (ArC—H), 2975, 2944, 2915 (Aliphatic C—H), 1666 (C⚌O), 1621 (—CH⚌N—), 1598; 1H NMR (DMSO-d6, 300 MHz): δ = 12.03 (s, 1H, NH), 11.72 (s, 1H, NH), 10.08 (s, 1H, OH), 8.55 (s, 1H, —CH⚌N), 7.12–7.71 (m, 2H), 6.85–7.52 (m, 3H), 6.47–6.56 (m, 2H), 4.62 (s, 2H, O—CH2), 2.76–2.78 (m, 2H, —CO—CH2—CH2—), 2.39–2.50 (m, 2H, —CO—CH2—CH2—); 13C NMR (DMSO-d6, 75 MHz) δ: 170.34 (C⚌O), 170.30 (C⚌O), 168.22 (C—OH), 156.59 (C—O—CH2), 148.31 (—C⚌N—), 141.51, 131.45, 129.25, 128.40, 126.37, 119.97, 119.23, 118.57, 107.62, 102.12, 101.67, 66.48 (O—CH2), 33.66 (—CO—CH2—CH2—), 23.97 (—CO—CH2—CH2—); EIMS m/z: 340.84 [M+H] (32); 339.36 [M]+ (100); Anal. Calcd. for C18H17N3O4: C, 63.71; H, 5.05; N 12.38. Found: C, 63.63; H, 5.12; N, 12.30.
2.5.3 N′-[(E)-(5-chloro-2-hydroxyphenyl)methylidene]-2-[(2-oxo-1,2,3,4-tetrahydroquinolin-7-yl) oxy]acetohydrazide (5b)
white solid (EtOH); mp 284–286 °C; IR(KBr, υ, cm−1): 3195 (OH), 3112 (NH), 3056 (ArC—H), 2979, 2892, 2844 (Aliphatic C—H), 1675 (C⚌O), 1627 (—CH⚌N—), 1598; 1H NMR (DMSO-d6, 300 MHz): δ = 12.03 (s, 1H, NH), 11.72 (s, 1H, NH), 9.97 (s, 1H, OH), 8.57 (s, 1H, —CH⚌N), 8.42–8.48 (m, 1H), 7.76–7.91 (m, 1H), 7.04–7.83 (m, 4H), 4.60 (s, 2H, O—CH2), 2.78 (m, 2H, —CO—CH2—CH2—), 2.50 (m, 2H, —CO—CH2—CH2—); LCMS (98.712%) m/z: 374.20 [M+H] (100); Anal. Calcd. for C18H16ClN3O4: C, 57.84%; H, 4.31; N, 11.24. Found: C, 57.78; H, 4.35; N, 11.17.
2.5.4 N′-[(E)-(5-bromo-2-hydroxyphenyl)methylidene]-2-[(2-oxo-1,2,3,4-tetrahydroquinolin-7-yl) oxy]acetohydrazide (5c)
white solid (EtOH); mp 278–280 °C; IR(KBr, υ, cm−1): 3191 (OH), 3106 (NH), 3052, 2977 (ArC—H), 2892, 2840 (Aliphatic C—H), 1677 (C⚌O), 1629 (—CH⚌N—), 1598; 1H NMR (DMSO-d6, 300 MHz) δ: 11.56 (s, 2H, NH), 10.04 (s, 1H, OH), 8.51 (s, 1H, —CH⚌N), 7.74–7.81 (m, 2H), 7.36–7.43 (m, 2H), 7.03–7.09 (m, 2H), 4.61 (s, 2H, O—CH2), 2.79 (m, 2H, —CO—CH2—CH2—), 2.50 (m, 2H, —CO—CH2—CH2—); 13C NMR (75 MHz, DMSO-d6) δ: 170.31 (C⚌O), 168.86 (C⚌O), 164.35 (C—OH), 157.42 (C—O—CH2), 145.67 (—C⚌N—), 139.06, 133.40, 130.21, 128.24, 122.43, 121.18, 118.62, 116.52, 110.42, 107.62, 102.12, 101.77, 66.43 (O—CH2), 30.67 (—CO—CH2—CH2—), 23.97 (—CO—CH2—CH2—); LCMS (98.205%) m/z: 418.05 [M+H] (100); Anal. Calcd. For C18H16BrN3O4: C, 51.69; H, 3.86; N, 10.05. Found: C, 51.60; H, 3.94; N, 10.12.
2.5.5 N′-[(E)-(1-hydroxynaphthalen-2-yl)methylidene]-2-[(2-oxo-1,2,3,4-tetrahydroquinolin-7-yl) oxy]acetohydrazide (5d)
white solid (EtOH); mp 279–281 °C; IR(KBr, υ, cm−1): 3212 (OH), 3092 (NH), 3048 (ArC—H), 2971, 2900 (Aliphatic C—H), 1666 (C⚌O), 1623 (—CH⚌N—), 1598; 1H NMR (300 MHz, DMSO-d6) δ: 12.58 (s, 1H, NH), 11.88 (s, 1H, NH), 10.12 (s, 1H, OH), 8.90 (s, 1H, —CH⚌N), 8.21–8.24 (m, 1H), 7.83–7.93 (m, 2H), 7.04–7.61 (m, 4H), 6.51–6.62 (m, 2H), 4.70 (s, 2H, O—CH2), 2.79 (m, 2H, —CO—CH2—CH2—), 2.50 (m, 2H, —CO—CH2—CH2—); EIMS m/z: 390.23 [M+H] (80); Anal. Calcd. For C22H19N3O4: C, 67.86; H, 4.92; N, 10.79. Found: C, 67.90; H, 5.02; N, 10.87.
2.5.6 N′-[(E)-(2-hydroxyquinolin-3-yl)methylidene]-2-[(2-oxo-1,2,3,4-tetrahydroquinolin-7-yl) oxy]acetohydrazide (5e)
Yellow solid (EtOH); mp 297–299 °C; IR(KBr, υ, cm−1): 3268 (OH), 3153 (NH), 3102 (NH), 3006 (ArC—H), 2964, 2900 (Aliphatic C—H), 2857, 1650 (C⚌O), 1600 (—CH⚌N—), 1521; 1H NMR (300 MHz, DMSO-d6) δ: 11.89 (s, 1H, NH), 11.59 (s, 1H, NH), 11.08 (s, 1H, OH), 8.52 (s, 1H, —CH⚌N), 8.25 (s, 1H), 7.62–7.71 (m, 2H), 7.25–7.33 (m, 2H), 7.03–7.09 (m, 3H), 4.62 (s, 2H, O—CH2), 2.79 (m, 2H, —CO—CH2—CH2—), 2.50 (m, 2H, —CO—CH2—CH2—); 13C NMR (75 MHz, DMSO-d6) δ: 175.69 (C⚌O), 170.26 (C⚌O), 168.86 (C—OH), 164.33 (C—O—CH2), 155.92, 145.89 (—C⚌N—), 139.41, 130.55, 128.23, 127.39, 124.99, 122.97, 121.90, 120.59, 118.18, 115.81, 107.60, 102.14, 66.48 (O—CH2), 30.68 (—CO—CH2—CH2—), 23.99 (—CO—CH2—CH2—); LCMS (96.637%) m/z: 391.05 [M+H] (100); Anal. Calcd. For C21H18N4O4: C, 64.61; H, 4.65; N, 14.35. Found: C, 64.56; H, 4.70; N, 14.43.
2.5.7 N′-[(E)-(6-fluoro-2-hydroxyquinolin-3-yl)methylidene]-2-[(2-oxo-1,2,3,4-tetrahydroquin olin-7-yl)oxy]acetohydrazide (5f)
Yellow solid (EtOH); mp above 300 °C; IR(KBr, υ, cm−1): 3438 (OH), 3191 (NH), 3031, 2898 (ArC—H), 2854 (Aliphatic C—H), 1662 (C⚌O), 1610 (—CH⚌N—), 1596; 1H NMR (300 MHz, DMSO-d6) δ: 12.12 (s, 1H, NH), 11.78 (s, 1H, NH), 10.23 (s, 1H, OH), 8.55 (s, 1H, —CH⚌N), 8.24–8.47 (m, 1H), 7.62–7.75 (m, 1H), 7.32–7.47 (m, 2H), 7.04–7.09 (m, 1H), 6.48–6.54 (m, 2H), 4.60 (s, 2H, O—CH2), 2.79–2.81 (m, 2H, —CO—CH2—CH2—), 2.39–2.44 (m, 2H, —CO—CH2—CH2—); 13C NMR (75 MHz, DMSO-d6) δ: 170.30 (C⚌O), 169.08 (C⚌O), 164.35 (C—OH), 160.58 (C—O—CH2), 157.39 (C—F), 156.95 (—C⚌N—), 139.08, 138.47, 135.65, 133.80, 128.30, 126.19, 119.70, 115.86, 113.37, 107.66, 102.05, 101.74, 66.40 (O—CH2), 30.65 (—CO—CH2—CH2—), 23.95 (—CO—CH2—CH2—); LCMS (97.592%) m/z: 409.10 [M+H] (100); Anal. Calcd. For C21H17FN4O4: C, 61.76; H, 4.20; N, 13.72. Found: C, 61.89; H, 4.13; N, 13.70.
2.5.8 N′-[(E)-(6-chloro-2-hydroxyquinolin-3-yl)methylidene]-2-[(2-oxo-1,2,3,4-tetrahydroquin olin-7-yl)oxy]acetohydrazide (5g)
Yellow solid (EtOH); mp above 300 °C; IR(KBr, υ, cm−1): 3505 (OH), 3450 (NH), 3197 (NH), 3029, 2906 (ArC—H), 1643 (C⚌O, —CH⚌N—), 1596; 1H NMR (300 MHz, DMSO-d6) δ: 12.18 (s, 1H, NH), 11.80 (s, 1H, NH), 10.23 (s, 1H, OH), 8.55 (s, 1H, —CH⚌N), 8.23–8.49 (m, 1H), 7.91–8.07 (m, 2H), 7.05–7.59 (m, 2H), 6.48–6.54 (m, 2H), 4.48 (s, 2H, O—CH2), 2.80 (m, 2H, —CO—CH2—CH2—), 2.30 (m, 2H, —CO—CH2—CH2—); 13C NMR (75 MHz, DMSO-d6) δ: 170.29 (C⚌O), 170.25 (C⚌O), 169.03 (C—OH), 161.38 (C—O—CH2), 160.88, 156.99, 142.80 (—C⚌N—), 141.10, 138.84, 134.66, 133.61, 129.02, 125.05, 122.33, 118.96, 115.12, 107.69, 101.74, 66.45 (O—CH2), 30.68 (—CO—CH2—CH2—), 23.98 (—CO—CH2—CH2—); LCMS (99.405%) m/z: 425.10 [M+H]; Anal. Calcd. For C21H17ClN4O4: C, 59.37; H, 4.03; N, 13.19. Found: C, 59.44; H, 4.07; N, 13.11.
2.5.9 N′-[(E)-(6-bromo-2-hydroxyquinolin-3-yl)methylidene]-2-[(2-oxo-1,2,3,4-tetrahydroquin olin-7-yl)oxy]acetohydrazide (5h)
Yellow solid (EtOH); mp above 300 °C; IR(KBr, υ, cm−1): 3513 (OH), 3436 (NH), 3193 (NH), 3027 (ArC—H), 2906 (Aliphatic C—H), 1643 (C⚌O), 1612 (—CH⚌N—), 1598; 1H NMR (300 MHz, DMSO-d6) δ: 12.17 (s, 1H, NH), 11.80 (s, 1H, NH), 10.22 (s, 1H, OH), 8.55 (s, 1H, —CH⚌N), 8.04–8.23 (m, 2H), 7.66–7.69 (m, 1H), 7.05–7.29 (m, 2H), 6.48–6.54 (m, 2H), 4.60 (s, 2H, O—CH2), 2.77–2.81 (m, 2H, —CO—CH2—CH2—), 2.39–2.44 (m, 2H, —CO—CH2—CH2—); EIMS m/z: 469.28 [M]+ (100), 471.78 [M+2] (90); Anal. Calcd. For C21H17BrN4O4: C, 53.75; H, 3.65; N, 11.94. Found: C, 53.69; H, 3.61; N, 11.91.
2.5.10 (E)-N′-((2-hydroxybenzo[h]quinolin-3-yl)methylene)-2-(2-oxo-1,2,3,4-tetrahydroquino lin-7-yloxy)acetohydrazide (5i)
Faint yellow solid (EtOH); mp above 300 °C; IR(KBr, υ, cm−1): 3322 (OH), 3220 (NH), 3056 (ArC—H), 2908 (Aliphatic C—H), 1667 (C⚌O), 1629 (—CH⚌N—), 1598; 1H NMR (300 MHz, DMSO-d6) δ: 12.06 (s, 1H, NH), 11.67 (s, 1H, NH), 10.45 (s, 1H, OH), 8.86–9.07 (m, 2H), 8.50 (s, 1H, —CH⚌N), 7.80–8.14 (m, 4H), 7.04–7.12 (m, 2H), 6.42–6.58 (m, 2H), 4.67 (s, 2H, O—CH2), 2.78–2.80 (m, 2H, —CO—CH2—CH2—), 2.41–2.43 (m, 2H, —CO—CH2—CH2—); EIMS m/z: 441.56 [M+H] (100); Anal. Calcd. For C25H20N4O4: C, 68.17; H, 4.58; N, 12.72. Found: C, 68.12; H, 4.49; N 12.78.
2.5.11 Zn (II) complex of N′-[(E)-(5-bromo-2-hydroxyphenyl)methylidene]-2-[(2-oxo-1,2,3,4-tetrahydroquinolin-7-yl) oxy]acetohydrazide (6c)
Yellow solid (MeOH), IR(KBr, υ, cm−1): 3448 (lattice water), 1623 (imine —HC⚌N), 1469 (C—O), 636 (M—N), 462 (M—O), 1H NMR (300 MHz, DMSO-d6) δ: 12.03 (s, 2H, NH), 11.72 (s, 2H, NH), 8.57 (s, 2H, —CH⚌N), 8.42–8.48 (m, 2H), 7.76–7.91 (m, 2H), 7.04–7.83 (m, 8H), 4.60 (s, 4H, O—CH2), 2.78 (m, 4H, —CO—CH2—CH2—), 2.50 (m, 4H, —CO—CH2—CH2—), EIMS m/z: 900.00 [M+H] (100); Molar conductance Λm: 10.2 Ω−1 mol−1 cm2, Anal. Calcd. For C36H30Br2N6O8Zn: Zn, 6.99. Found: 7.04.
3 Results and discussion
3.1 Chemistry
The hydrazone derivatives 5a–5i have been synthesized by condensation reaction of equimolar amounts of 2-(2-oxo-1,2,3,4-tetrahydroquinoline-7-yloxy)acetohydrazide and 2-hydroxy-aldehyde derivatives 4a–4i in warming ethanol at 70 °C. The required 2-(2-oxo-1,2,3,4-tetrahydroquinoline-7-yloxy)acetohydrazide was prepared from 7-hydroxy-3,4-dihydroquinolin-2(1H)-one as starting material. Finally, hydrazone derivatives 5a–5i were refluxed with ZnCl2 in ethanol with molar ratio 2:1 to offer Zn (II) complexes 6a–6i.
All the synthesized hydrazone ligands and their Zn (II) complexes are stable at room temperature and are non-hygroscopic in nature. The Zn (II) complexes are insoluble in H2O but are soluble in DMF and DMSO. The spectral characterizations (FT-IR, 1H and 13C NMR, MS, UV–Visible and Fluorescence) of synthesized compounds confirm the suggested structures of the hydrazones as well as their Zn (II) complexes. The elemental analysis, physical properties and spectral data of the ligand and complexes are summarized below.
The FT-IR spectrum of hydrazone 5c, as a representative example, showed strong absorption bands at 1677 and 1629 cm−1 due to conjugated C⚌N and C⚌O functions, respectively. The broad peak at 3191 cm−1 is attributed to hydroxyl group, which is present at 2nd position of quinoline ring. The important IR peaks and their assignments are listed in Table 3. Its 1H NMR spectrum revealed, in addition to expected aromatic signals, three singlets at δ 8.51, 10.04, 11.56 ppm are assignable to the azomethine proton (—CH⚌N—), hydroxyl proton (—OH) and amide proton (—NH—C⚌O), respectively. In addition, the 13C NMR spectrum of 5c displayed three characteristic peaks at δ 145.67, 164.35, 168.86 and 170.31 ppm assignable to imine carbon, carbon linked to hydroxyl group of quinoline, carbonyl carbon of acyclic amide and carbonyl carbon of cyclic amide, respectively. Moreover the LCMS spectrum of 5c revealed molecular ion peak at m/z 418.05 (M+H) corresponding to the molecular formula [C21H18BrN3O3] with 98.205% purity. In a similar manner, compounds 5a–5i were prepared and characterized.
| Compound | Amidea —NH— | Amideb —NH— | Phenolic —OH | Imine —CH⚌N— | ||||
|---|---|---|---|---|---|---|---|---|
| 1H NMR δ | FTIR (cm−1) | 1H NMR δ | FTIR (cm−1) | 1H NMR δ | FTIR (cm−1) | 1H NMR δ | FTIR (cm−1) | |
| 5a | 12.03 | 3193 | 11.72 | 3193 | 10.08 | 3316 | 8.55 | 1621 |
| 5b | 12.03 | 3112 | 11.72 | 3112 | 9.97 | 3195 | 8.57 | 1627 |
| 5c | 11.56 | 3106 | 11.56 | 3106 | 10.04 | 3191 | 8.51 | 1629 |
| 5d | 12.58 | 3092 | 11.88 | 3092 | 10.12 | 3212 | 8.90 | 1623 |
| 5e | 11.89 | 3153 | 11.59 | 3102 | 11.08 | 3268 | 8.52 | 1600 |
| 5f | 12.12 | 3191 | 11.78 | 3191 | 10.23 | 3438 | 8.55 | 1610 |
| 5g | 12.18 | 3450 | 11.80 | 3197 | 10.23 | 3505 | 8.55 | 1643 |
| 5h | 12.17 | 3436 | 11.80 | 3193 | 10.22 | 3513 | 8.55 | 1612 |
| 5i | 1206 | 3220 | 11.67 | 3220 | 10.45 | 3322 | 8.50 | 1629 |
FTIR spectra of all the zinc complexes show broad peak in the region of 3330–3517 cm−1 due to coordinated water molecules. The FTIR spectral study is useful to explain the coordination mode of hydrazone with central metal ion Table 4. The phenolic —OH band appears at 3139–3488 cm−1 which disappears in IR spectra of the metal complexes; however, new broad peaks observed at 3330–3517 cm−1 indicate coordinated water molecules which confirms the coordination of hydrazones with Zn (II) through phenolic —OH. The IR spectra also show new bands at 935–950 cm−1 and 645–650 cm−1, which are attributed to ρ(H2O) and ω(H2O) which indicate the presence of coordinated water molecules. The low frequency region of the FTIR spectra showed the presence of two new mediums to strong intensity bands at about 443–485 cm−1 due to υM—O vibrations. The IR spectra of all the metal complexes show prominent band at about 501–620 cm−1 due to υM—N stretching. It was observed that the azomethine proton in zinc complex 6c appeared at 8.57 ppm after complexation with zinc metal. This chemical shift was altered significantly downfield due to deshielding effect exerted by zinc metal atom. Aromatic protons of coumarin ring were observed at 7.04–8.42 ppm due to the electron withdrawing mesomeric effect exerted by central zinc metal atom.
| Entry | FT-IR bands | Molar conductance Λm (Ω−1 mol−1 cm2) | % Zn observed (calculated) | ||||
|---|---|---|---|---|---|---|---|
| Lattice water υ(OH) (cm−1) | Imine υ(C⚌N) (cm−1) | υ(C—O) (cm−1) | υ(M—N) (cm−1) | υ(M—O) (cm−1) | |||
| 6a | 3387 | 1623 | 1444 | 590 | 470 | 11.3 | 8.48 (8.40) |
| 6b | 3407 | 1625 | 1473 | 649 | 470 | 7.4 | 7.70 (7.72) |
| 6c | 3448 | 1623 | 1469 | 636 | 462 | 10.2 | 7.04 (6.99) |
| 6d | 3340 | 1623 | 1461 | 646 | 472 | 6.4 | 7.40 (7.45) |
| 6e | 3376 | 1617 | 1444 | 640 | 469 | 5.9 | 7.41 (7.43) |
| 6f | 3361 | 1623 | 1417 | 617 | 462 | 7.8 | 7.20 (7.14) |
| 6g | 3392 | 1627 | 1427 | 630 | 470 | 4.2 | 6.80 (6.89) |
| 6h | 3390 | 1623 | 1411 | 642 | 445 | 8.7 | 6.27 (6.30) |
| 6i | 3380 | 1627 | 1438 | 638 | 453 | 9.8 | 6.63 (6.67) |
The DSC-TGA was carried out to explain the thermal stability of the complexes. The thermal behavior of the metal complex 6c was studied in temperature range of 25–1000 °C. The TG-DTA studies of complex 6c Fig. 3 show that the decomposition occurs in three steps. The first stage involves weight loss below 100 °C due to the removal of the lattice cell water in the complexes. Second step involves weight loss in the temperature range 110–160 °C is due to elimination of coordinated water. A plateau was observed above 600 °C corresponding to the formation of ZnO. From the elemental analysis of Zn (II) complexes 6a–6i, it is clear that observed percentage of Zn content is in good agreement with the theoretical values as shown in Table 4.
The X-ray powder diffraction data provide vital structural information of materials which do not yield single crystals of good quality. Single crystals of the complexes under study could not be prepared; thus, the powder diffraction data were acquired for structural description (Bayoumi et al., 2013). The X-ray diffractogram of the ligand and the complexes was measured in the range of 5–70° 2θ values, which are shown in Fig. 4. The XRD pattern indicates that complex 6c has well defined crystalline patterns, with various degrees of crystallinity. The average crystallite size of the complex was calculated using Scherer’s formula. The Zn (II) complex 6c has an average crystallite size of 76 nm (see Fig. 5).
From the mathematical relation Λm = K/C the molar conductance of the metal complexes (Λm) can be calculated by dissolving in a proper solvent where, C is the molar concentration (Mohamed et al., 2006). The solutions (10−3 M) of Zn (II) complexes 6a–6i were prepared in DMF. The molar conductivities were measured at 25 ± 2 °C. The study shows negligible molar conductance values for metal complexes 6a–6i (4.2–11.3 Ω−1 mol−1 cm2), indicating that the complexes are non-electrolytes. The results are represented in Table 4. From the experimental study, it is clear that practical observations are in good agreement with the theoretical values calculated for 1:2 ratio of metal:ligand stoichiometry. From the above explanation of the results of various spectroscopic studies, it may be concluded that the proposed geometry for the Zn (II) complexes with general formula ZnL2⋅2H2O is octahedral for Zn (II) complexes. The proposed structures are represented in Table 2.
3.2 Biological evaluation (anti-tuberculosis activity)
The anti-microbial effects of the new hydrazones and their Zinc complexes against Mycobacterium tuberculosis (H37 RV strain) ATCC No.-27294, were evaluated at the Department of Microbiology, Maratha Mandal’s NGH Institute of Dental Sciences and Research Centre, Belgaum-590010, India. The method applied is similar to that reported by Maria and Lourenco (Lourenco et al., 2007). Ciprofloxacin (MIC 3.12 μg/mL), Pyrazinamide (MIC 3.12 μg/mL) and Streptomycin (MIC 6.25 μg/mL) were used as references to evaluate the potency of the synthesized compounds.
All the studied samples are showing different potency due to the effective barrier of an outer cell wall membrane of M. tuberculosis for entry of external substances like test compounds under this study. However, hydrazone ligands 5a–5i showed less activity than their Zn (II) complexes 6a–6i. As shown in Table 5, complex 6c, 6e and 6h has unpredictable high anti-tuberculosis activity against M. tuberculosis as their MIC value is 1.6 μg/mL. This could be as a result of the metal chelates, which bear polar and nonpolar properties together; this makes them suitable for permeation to the bacterial cell. This finding indicates that complex formation enhanced the amphiphilic properties and solubility and hence, the penetration of complex 6c, 6e and 6h into the cell wall of the M. tuberculosis, which translated into better activity. According to the Molecular Theory of Coordination metal orbital overlap with ligand orbitals this decreases the positive charge on the metal ion by accepting the electrons from donor groups of the hydrazone ligand (Kralova et al., 2004; Parekh et al., 2005). Thus, the donation of the electrons from ligand to metal also favors the increased delocalization of the π-electrons through entire coordinating rings. This results in increased lipophilicity of the metal complexes. This finding indicates that complex formation enhanced the physical properties such as solubility and amphiphilicity and hence, the penetration of complex 6c, 6e and 6h into the cell wall of the M. tuberculosis, which translated into better activity (Vaghasia et al., 2004).
| Entry | Compound | % of inhibition at various concentrationsa | |||||||
|---|---|---|---|---|---|---|---|---|---|
| 0.80 μg/mL | 1.60 μg/mL | 3.12 μg/mL | 6.25 μg/mL | 12.5 μg/mL | 25 μg/mL | 50 μg/mL | 100 μg/mL | ||
| 01 | 5a | 0.0 | 0.0 | 4.5 | 22.6 | 45.3 | 66.2 | 79.1 | 93.5 |
| 02 | 5b | 0.0 | 0.0 | 18.1 | 48.2 | 68.7 | 81.3 | 90.0 | 98.7 |
| 03 | 5c | 0.0 | 0.0 | 20.4 | 50.3 | 77.6 | 84.5 | 91.6 | 99.2 |
| 04 | 5d | 0.0 | 0.0 | 2.6 | 67.5 | 75.3 | 92.3 | 96.5 | 100 |
| 05 | 5e | 0.0 | 0.0 | 6.8 | 25.7 | 78.9 | 81.6 | 89.4 | 97.4 |
| 06 | 5f | 0.0 | 0.0 | 3.5 | 18.2 | 58.1 | 89.3 | 92.1 | 98.3 |
| 07 | 5g | 0.0 | 0.0 | 2.5 | 21.3 | 45.3 | 88.7 | 93.2 | 98.8 |
| 08 | 5h | 0.0 | 0.0 | 2.2 | 8.4 | 20.9 | 70.7 | 86.6 | 99.4 |
| 09 | 5i | 0.0 | 0.0 | 0.0 | 2.4 | 23.5 | 86.4 | 97.4 | 98.8 |
| 10 | 6a | 10.3 | 24.5 | 87.4 | 99.2 | 100 | 100 | 100 | 100 |
| 11 | 6b | 9.5 | 31.2 | 90.2 | 98.7 | 100 | 100 | 100 | 100 |
| 12 | 6c | 12.5 | 88.7 | 98.2 | 100 | 100 | 100 | 100 | 100 |
| 13 | 6d | 6.1 | 22.6 | 84.1 | 95.4 | 99.2 | 100 | 100 | 100 |
| 14 | 6e | 9.1 | 78.4 | 97.2 | 100 | 100 | 100 | 100 | 100 |
| 15 | 6f | 6.4 | 16.3 | 69.5 | 91.2 | 97.4 | 99.2 | 100 | 100 |
| 16 | 6g | 7.3 | 15.8 | 31.3 | 82.7 | 90.5 | 95.4 | 100 | 100 |
| 17 | 6h | 15.4 | 91.2 | 97.4 | 100 | 100 | 100 | 100 | 100 |
| 18 | 6i | 5.6 | 17.1 | 28.9 | 81.0 | 89.6 | 98.1 | 100 | 100 |
In addition, these metal complexes disturb the respiration process of the cell and thereby restrict the synthesis of proteins. If the synthesis of proteins is blocked then formation bacterial cell wall is not possible which ultimately results in cell death and therefore restricts further growth and infection of the bacteria (Raman, 2005). According to one more probable mechanism, these complexes might be interacting with the DNA gyrase enzyme, which is necessary for DNA multiplication step. The DNA gyrase is inhibited by metal complexes, which alters the multiplication of bacterial cells, eventually resulting in death of the bacteria (Galm et al., 2004; Alvarez et al., 1997). The observed results of the test compounds indicate the future potential for the development of metal coordination complexes to solve the limitations due to currently existing anti-tuberculosis agents to treat multiple drug resistant Tuberculosis.
3.3 Fluorescence study
The UV–Visible and fluorescence study was done at room temperature. The spectra of the ligands 5a–5i exhibit bands around 280–384 nm as represented in Fig. 6 and Table. 6. This broad, intense band in the ligands can be assigned to intra ligand n → p∗ transition associated with the azomethine linkage. Table 6 and Fig. 7 show this band experiences red shift in all the complexes 6a–6i. The bands at around 286–404 nm are attributed to the L → M charge transfer transitions.
| Hydrazone | Absorption λmax (intensity) | Emission λmax (intensity) | Complex | Absorption λmax (intensity) | Emission λmax (intensity) |
|---|---|---|---|---|---|
| 5a | 280 (2.83) | 422 (24.76) | 6a | 296 (0.86) | 480 (427.26) |
| 5b | 281 (2.65) | 380 (55.76) | 6b | 296 (1.01) | 485 (489.54) |
| 5c | 282 (2.20) | 429 (26.44) | 6c | 395 (1.15) | 464 (237.45) |
| 5d | 322 (1.70) | 446 (82.08) | 6d | 295 (0.77) | 467 (241.00) |
| 5e | 320 (2.82) | 442 (135.51) | 6e | 404 (0.87) | 488 (332.04) |
| 5f | 307 (1.44) | 451 (254.51) | 6f | 335 (0.73) | 466 (146.01) |
| 5g | 384 (1.62) | 449 (333.86) | 6g | 386 (1.28) | 475 (111.13) |
| 5h | 379 (1.85) | 443 (395.51) | 6h | 393 (0.75) | 451 (471.86) |
| 5i | 319 (0.92) | 411 (322.87) | 6i | 286 (1.18) | 412 (352.36) |
The emission spectra of compounds 5a–5i Fig. 8 showed the emission band in the range of 380–457 nm and complexes 6a–6i Fig. 9 and Table 6 showed emission band in the range of 412–488 nm. Complex formation of hydrazones induces the marked hyperchromic and bathochromic shifts. The Zn (II) complexes demonstrated intense fluorescent properties as compared to their parent ligands. The incorporation of Zn (II) effectively increases the conformational rigidity of the hydrazones and increases the fluorescence intensities of the complexes 6a–6i, which shows that it is a good material in photochemical applications of these complexes.
4 Conclusion
In conclusion, new hydrazone derivatives bearing 3,4-dihydroquinoline nucleus have been synthesized in a short reaction time with good yield. This synthetic strategy allows for the assimilation of 3,4-dihydroquinoline and quinoline in a single scaffold through an easy way. The Antituberculosis analysis was performed using blue Alamar method to identify the more effective compound. Most of the synthesized compounds show moderate to good antituberculosis properties. Of the compounds studied 6c, 6e and 6h have proven as the efficient antitubercular member. Subsequently UV and Fluorescence spectral study of the synthesized compounds was performed. It indicates that Zn (II) complexes are more emissive than their parent ligands. This study would pave the way for future development of more effective dihydroquinoline hydrazone analogs for applications in biological and material science.
Acknowledgment
The authors thank Principal and Head, Department of Chemistry, Government of Maharashtra, Ismail Yusuf Arts, Science and Commerce College for providing research and library facilities. The authors also thank Dr. Kishore Bhat of Governmental Dental College, Belgaum, for facilitating anti-TB assays and providing the procedure for the same.
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