Send Orders for Reprints to
[email protected] Letters in Organic Chemistry, 2014, 11, ???-???
1
Synthesis, Characterization and Biological Evaluation Against Influenza Virus Agonists of (N'E,N'"E)-2,2'-[[1,1'-Biphenyl]-4,4'-dihylbis(oxy)]bis (N'-arylmethyleneacetohydrazides) El Sayed H. El Ashrya,b*, Zia Ud Din,a Zahid H. Soomroa, Wajid Rahmana,+, Muhammad Raza Shaha, Yeldez El Kilanyc, Lieve Naesensd and Ahmed T.A. Boraeie a
International Center for Chemical and Biological Sciences, H.E.J Research Institute of Chemistry, University of Karachi, Karachi-75270, Pakistan; bChemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt; cChemistry Department, Faculty of Applied Sciences, Girls Campus, University of Um-Alqura, Makka, Saudi Arabia; dRega Institute, Laboratory of Virology and Chemotherapy, Katholieke Universiteit Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium; eChemistry Department, Faculty of Science, Suez Canal University, Ismailia, Egypt Received July 04, 2013: Revised October 29, 2013: Accepted November 06, 2013
Abstract: N',N"'-[2,2'-[[1,1'-Biphenyl]-4,4'-diylbis(oxy)]bis(acetyl)]di(benzohydrazide) 3 was prepared by reaction of 2,2'-[1,1'-biphenyl]-4,4'-diylbis(oxy)]bisacetohydrazide 2 with benzoyl chloride. A new series of the arylidene 4-15 was prepared by heating 2 with the following aldehydes: 4-flourobenzaldehyde, p-tolualdehyde, 2-hydroxy-3methoxybenzaldehyde, 2-chlorobenzaldehyde, isonicotinaldehyde (4-pyridine carboxaldehyde), benzaldehyde, 4chlorobenzaldehyde, picolinaldehyde (2-pyridine carboxaldehyde), 4-methoxybenzaldehyde (4-anisaldehyde), 3bromobenzaldehyde, 2,4,6-trimethoxybenzaldehyde and 4-hydroxy-3-methoxybenzaldehyde (vaniline). The compounds were evaluated against influenza virus. Two compounds showed moderate activity which means that with more derivatization, better activity could be expected.
Keywords: Aryloxyacetohydrazides, hydrazones, bisphenols, influenza virus. INTRODUCTION Hydrazones possess an azomethine -NHN=CH- residue, and represents a class of compounds with great potential applications [1, 2], such as anticonvulsant [3], antidepressant [4], anti-inflammatory [5, 6], antimalarial [7, 8], antimycobacterial [9, 10], anticancer [11, 12], antimicrobial [13-16], trypanocidal [17], anti-HIV [18] and antiviral [19] activities have been reported in the literature. They are employed in the characterization of various natural and synthetic compounds, particularly low molecular weight aldehydes and ketones and also considered as scaffolds for the design of lead compounds with diverse and novel pharmacological activities [1, 2]. The high bio-potency of hydrazides R-CONH-NH2 and their corresponding arylidene hydrazones RCO-NH-N=CHR, are due to their ability for chelation with transition metal ions to be used as enzyme inhibitors and have increased the interest in the synthesis of these novel hydrazides and hydrazones. Also, several hydrazine derivatives became commercially available as therapeutic drugs, such as isoniazide which has been used for the treatment of tuberculosis [20-27], and iproclozide as monoamine oxidase inhibitor (MAOI). Moreover, the conversion of hydrazones *Address correspondence to this author at the International Center for Chemical and Biological Sciences, H.E.J Research Institute of Chemistry, University of Karachi, Karachi-75270, Pakistan; Tel: +20127430924; Fax: +203 4271360; E-mail:
[email protected] + Present address: Department of Chemistry, Hazara University, Mansehra, Pakistan
1570-1786/14 $58.00+.00
into heterocycles provides different approaches for valuable relevant classes of pharmacological compounds. Thus, substituted 1,3,4-oxadiazolines can be synthesized when hydrazones are heated in the presence of acetic anhydride. Similarly, 2-azetidinones and 4-thiazolidinones can be synthesized when hydrazones are reacted with chloroacetylchloride and thioglycolic acid or thiolactic acid, respectively. The search for fascinating biologically active molecular building blocks based on diverse structural features, easy synthetic roots and the desired functionalities in the molecules attracted our attention to synthesize biaryl systems functionalized with hydrazide residues that could be of interesting biological activity itself or after encompassing it with heterocyclic rings via the hydrazide residue. Thus, a new series of arylidene 2,2'-[biphenyl-4,4'-diylbis(oxy)]bisacetohydrazones has been prepared and their antiviral activity were evaluated, particularly for influenza virus. RESULTS AND DISCUSSION The synthesis of the target hydrazone derivatives 4-15 were accomplished as outlined in (Scheme 1), Simply, by reacting 4,4'-bisphenol with methyl chloroacetate in the presence of a base leads to bisester derivative of 1, followed by reaction with hydrazine hydrate in ethanol provided the novel bishydrazide 2. Treatment of 2 with benzoyl chloride gave 3, while the reaction of 2 with various aromatic aldehydes afforded the corresponding aldimines 4-15 in 65-
© 2014 Bentham Science Publishers
2 Letters in Organic Chemistry, 2014, Vol. 11, No. 3
El Ashry et al.
K2CO3/CH3CN ClCH2COOCH3
OH
HO
O
N2H4.2H2O
H3CO
O NH
HN NH2 R
H2N
2 H
BzCl THF
O
O
O
O
HN N R
O
O
NH N
HN
O NH HN O
O
R
4-15
O
O
NH
R 4
OCH3
1
O
O
O
O
O
O
R
F
10
5 H3C
11
3
Cl
N 12 H3CO
6 H3CO
OH 13
7
Br
Cl 8
N
OCH3
14 H3CO OCH3
9
15
HO H3CO
Scheme 1. Synthesis of hydrazide 2, dibenzoylated derivative 3 and hydrazones 4-15.
92% yields (Scheme 1). The structures of all these new compounds were confirmed by 1H NMR, FTIR and mass spectral analysis. Compound 1 showed two characteristically coupled aromatic signals at 7.46 and 6.95 with coupling constant 8.7 Hz, whereas two OCH3 were displayed at 3.81 as a singlet and two characteristic methylene groups as a singlet at 4.60 ppm. The 1H NMR spectrum of 2,2'-[1,1'biphenyl-4,4'-diylbis(oxy)]bisacetohydrazide (2) revealed characteristic signals at 9.30 ppm for NH protons; also the two NH2 groups were equivalent and appeared as a singlet at 4.30 ppm. The EI-MS spectrum of 2 also showed the
molecular ion peak at m/z 330 which was in close agreement with the calculated molecular weight. The 1H NMR of all these hydrazones 4-15 displayed characteristic peaks for amide protons (2 CONH) in the range of 11.85-11.36 ppm. Similarly, the methylene protons (2 CH2) appeared in the range of 5.20-4.66ppm. The azomethine (2 x N=CH) protons of all the hydrazones appeared as singlets in range of 8.757.97 ppm based on the substituent on aromatic system. In particular, the 2,2'-[[1,1'-biphenyl]-4,4'-dihylbis(oxy)]bis[N'(4-fluorophenyl)methyleneacetohydrazide) (4) displayed the two NH protons at 11.59 and 11.58 ppm, while the two
Synthesis, Characterization and Biological Evaluation
Letters in Organic Chemistry, 2014, Vol. 11, No. 3
3
Table 1. Anti - Influenza Virus Activity and Cytotoxicity in MDCKa Cells EC50 b Against
Cytotoxicity
Compound A/H1N1
A/H3N2
B
MCCc
CC50 d
CPE
MTS
CPE
MTS
CPE
MTS
01
>100
>100
>100
>100
>100
>100
100
>100
02
>100
>100
>100
>100
>100
57
>100
>100
03
36
43
28
34
>100
>100
>100
>100
04
>100
>100
>100
>100
>100
>100
>100
>100
05
>100
>100
>100
>100
>100
>100
>100
>100
06
35
55
9
10
>100
>100
100
>100
07
>100
>100
>100
>100
>100
>100
100
>100
08
29
33
21
26
34
45
>100
>100
09
>100
>100
45
40
>100
>100
>100
>100
10
>100
58
>100
55
>100
>100
20
>100
11
>100
>100
>100
>100
>100
>100
>100
>100
12
33
14
31
16
45
39
>100
>100
13
>100
>100
>100
>100
>100
>100
100
>100
14
>100
>100
>100
>100
>100
>100
>100
>100
15
>100
>100
>100
>100
>100
>100
4
42
Zanamivir
2.3
1.9
2.3
3.7
12
9.5
>100
>100
Ribavirin
10
12
8.9
7.5
10
6.8
100
>100
Amantadine
100
78
0.45
0.50
>500
>500
500
>500
Rimantadine
4.6
5.3
0.014
0.046
>500
>500
500
247
a
MDCK: Madin Darby canine kidney cells. The EC50 represents the compound concentration producing 50% inhibition of virus replication, as estimated by microscopic scoring of the virus-induced cytopathic effect (CPE), or by the spectroscopic MTS cell viability assay. The virus strains used were: A/PR/8/34 (A/H1N1); A/HK/7/87 (A/H3N2), and B/HK/5/72. c The MCC or minimum cytotoxic concentration represents the compound concentration producing minimal alterations in cell morphology, as assessed by microscopy. d The CC50 is the 50% cytotoxic concentration, as determined by the MTS cell viability assay. b
N=CH singlets were observed at 8.34 and 8.01 ppm. In case of 2,2'-[[1,1'-biphenyl]-4,4'-dihylbis(oxy)]bis[N'-(4-methylphenyl)methyleneacetohydrazide) (5), the methyl protons appeared at 2.33 ppm and two singlets for NH protons were observed at 11.53 and 11.51 ppm. Similarly two singlets for N=CH at 8.29 and 7.97 ppm were observed. The two CH 2 singlets resonated at 4.68 and 5.14 ppm. The 1H NMR spectrum of 6 showed OH protons at 10.69 and 9.35 ppm. The spectroscopic behavior of compound 6 was comparable to that of the compounds 7-11, with the appearance of extra signals for the additional groups. The structures of all compounds were further established through FT-IR and mass spectrometric analysis. Biological Studies The synthesized compounds were evaluated for antiinfluenza virus activity and cytotoxicity in a cell-culture based assay in MDCK cells (Table 1) [27]. Three virus strains were included, belonging to the influenza A/H1N1 or A/H3N2 subtype, or the influenza B virus type. Four
reference compounds (zanamivir, ribavirin, amantadine and rimantadine) were tested in parallel. The results from two or three independent experiments are shown in (Table 1). Importantly, all the compounds produced minimal, if any, cytotoxicity at 100 g per ml (the highest concentration tested). The only exceptions were compounds 10 and 15, which caused minimal alterations in cell morphology at 20 and 4 g per ml, respectively. Two compounds (8 and 12) were found to have moderate activity against influenza virus, their 50% effective concentrations being in the range of 14 to 45 g per ml. Although their antiviral potency was at the low side, their broad and reproducible activity against influenza A and B virus is remarkable. For three other compounds (3, 6 and 9), the activity was more variable or (sub)typedependent. CONCLUSION Successfully we were able to synthesiz a series of biphenyl hydrazides 2, 3 and hydrazones 4-15 in high yields
4 Letters in Organic Chemistry, 2014, Vol. 11, No. 3
under these coupling conditions. All these newly synthesized compounds were tested for antiviral activity against influenza viruses, and some of them showed moderate activity against influenza A virus and/or influenza B virus. Note that the compound concentrations are expressed in g per ml for the test compounds, and in M for the reference compounds (zanamivir, ribavirin, amantadine and rimantadine). EXPERIMENTAL General All chemicals were purchased from Organics, SigmaAldrich, Acros Chemicals and Fisher Scientific Ltd and used without further purification. The deuterated solvents of Apolo were used for the NMR analysis. Thin layer chromatography was performed with precoated silica gel G25-UV254 plates and detection was carried out at 254 nm under UV, and by ceric sulphate in 10% H2SO4 solution. The FT-IR spectra were recorded on Perkin Elmer spectrophotometers. Mass spectra (EI- and HR-EI-MS) were measured in an electron impact mode on Varian Mat 312 spectrophotometers. The NMR spectra were obtained on a Bruker AMX 400 spectrometer operating at 400.1 MHz. Compounds 1-15 were dissolved in organic solvents at about 10 mg ml1 each and transferred into a 5-mm NMR tube. Chemical shifts (ppm) were measured. Internal lock and tetramethylsilane (TMS) were used as internal reference. Chemistry 2,2'-[1,1'-Biphenyl-4,4'-dihylbis(oxy)]bisacetic Acid Dimethyl Ester (1) A mixture of 4,4'-dihydroxy biphenyl (100 mg, 5. 0.537 mmol), potassium carbonate (0.37 mg, 0.921mmol) and acetone (15 mL) was refluxed for 1h, then methyl chloroacetate (100 g, 1.84 mol) was added and the reflux was maintained for further 3 h.The reaction mixture was cooled to room temperature and filtered. The filtrate was evaporated under reduced pressure and the crude product was collected as white precipitate which was recrystallized from ethanol, to give the product (68% yield); Mp: 185-186 °C. EI-MS: m/z 330 [M+]. HR-MS (FT-ICR): calcd for C18H18O6 330.1103; found 330.1113. IR: n (cm-1) 3517, 2958, 1770, 1606, 1500, 1440, 1278, 1080, 829, 713, 600, 516.1H NMR (300 MHz, CDCl3): 7.46 (4H, d, J = 8.7 Hz, ArH), 6.95 (4H, d, J = 8.7 Hz, ArH), 4.60 (4H, s, 2 x CH2), 3.81 (6H, s, 2 x CH3). 2,2'-[1,1'-Biphenyl-4,4'-diylbis(oxy)]bisacetohydrazide (2) A mixture of 2,2'-[1,1'-biphenyl-4,4'-dihylbis(oxy)] bisacetic acid dimethyl ester (1) (100 mg, 0.303 mmol), hydrazine hydrate (60 mg, 0.881 mmol) and acetone (15 mL) was taken in 100 mL round bottom flask and refluxed for 2 h with vigorous stirring, while white precipitates indicated the formation of hydrazide 2. The content of reaction flask was filtered and the precipitate was washed by cold ethanol. The crude product was collected as white precipitate, and recrystallized from ethanol using few drops of DMF (73% yield). Mp 252-253 °C. EI-MS: m/z 330 330 [M+]. HR-MS
El Ashry et al.
(FT-ICR) calcd for C16H18N4O4 330.1328; found 330.1300. IR: n (cm-1) 3307, 3039, 2844, 1899, 1668, 1498, 1367, 1164, 927, 690, 592, 501. 1H NMR (300 MHz, DMSO-d6): 9.30 (2H, s, 2 x NH), 7.50 (4H, d, J = 8.7 Hz, ArH), 7.10 (4H, d, J = 8.7 Hz, ArH), 4.50 (4H, s, 2 x CH2), 4.30 (4H, s, 2 x NH2). N',N"'-[2,2'-[1,1'-Biphenyl-4,4'-diylbis(oxy)]bis(acetyl)]di (benzohydrazide) (3) 2,2'-[1,1'-Biphenyl-4,4'-diylbis(oxy)]bisacetohydrazide (2) (50 mg, 0.151 mmol) in THF (10 mL) was refluxed with benzoyl chloride (40.5 mL, 0.349 mol) for 3 h. The content of flask was cooled and filtered by normal filtration setup using filter paper and the precipitate was collected and washed by ethanol and recrystallized from ethanol with drops of DMF (73% yield). Mp: 264-265 °C. EI-MS: m/z 538 [M+]. HR-MS (FT-ICR) calcd for C30H26N4O6 538.1852; found 538.1842. IR: n (cm-1) 3408, 3232, 2908, 1699, 1502, 1434, 1242, 1074, 902, 819, 790, 690, 582, 505. 1H NMR (300 MHz, DMSO-d6): 10.40 (2H, s, NH), 10.20 (2H, s, NH), 7.60x (4H, m, ArH), 7.10(14H, m, 14ArH), 4.70 (4H, s, 2 x CH2). (N'E,N'"E)-2,2'-[[1,1'-biphenyl]-4,4'-dihylbis(oxy)]bis(N'arylmethylene)acetohydrazides 4-15 A mixture of 2 (50 mg, 0.151 mmol) in 10 mL of ethanol was refluxed with aromatic aldehydes (0.350 mmol) with few drops of acetic acid for 16 h. The precipitate was filtered after cooling. The crude product was washed with ethanol and recrystallized from ethanol and drops of DMF to give the respective hydrazones 4-15. (N'E,N'"E)-2,2'-[[1,1'-Biphenyl]-4,4'-dihylbis(oxy)]bis[N'(4-fluorophenylmethylene)acetohydrazide) (4) Yield 50%. Mp: 270 °C. EI-MS: m/z 542 [M+]. HR-MS (FT-ICR): calculated for C30H24F2N4O4: 542.1766; found 542.1912. IR: n (cm-1) 3556, 3409, 2821, 1679, 1602, 1500, 1440, 1234, 1089, 991, 835, 621, 516. 1H NMR (DMSO-d6, 400 MHz): 11.59 (1H, s, CONH), 11.58 (1H, s, CONH) 8.34 (1H, s, N=CH), 8.01 (1H, s, N=CH), 7.77 (4H, m, ArH), 7.56 (4H, m, ArH), 7.29 (4H, d, J = 8.0 Hz, ArH), 7.05 (4H, dd, J = 8.4 and 8.0 Hz, ArH), 5.16 (2H, s, CH2), 4.69 (2H, s, CH2). (N'E,N'"E)-2,2'-[[1,1'-Biphenyl]-4,4'-dihylbis(oxy)]bis[N'(4-methylphenylmethylene)acetohydrazide) (5) Yield 69%. Mp 288-289 °C. EI-MS: m/z 534 [M+]. HRMS (FT-ICR) calculated for C32H30N4O4: 534.2267; found 534.1704. IR: n (cm-1) 3332, 2908, 1679, 1494, 1371, 1234, 1070, 977, 815, 698, 557, 503. 1H NMR (DMSO-d6, 300 MHz): 11.53 (1H, s, CONH), 11.51 (1H, s, CONH), 8.29 (1H, s, N=CH), 7.97 (1H, s, N=CH), 7.60 (8H, m, ArH), 7.26 (4H, d, J = 7.5 Hz, ArH), 7.06 (4H, t, J = 8.4 Hz, ArH), 5.14 (2H, s, CH2), 4.68 (2H, s, CH2), 2.33 (6H, s, 2 x CH3). (N'E,N'"E)-2,2'-[[1,1'-Biphenyl]-4,4'-dihylbis(oxy)]bis[N'(2-hydroxy-3-methoxyphenyl)methyleneacetohydrazide] (6) Yield 69%. Mp 285-286 °C. EI-MS: m/z 598 [M+]. HRMS (FT-ICR) calcd for C32H30N4O8: 598.2064; found 598.2085. IR: n (cm-1) 3606, 2906, 1705, 1666, 1498, 1398,
Synthesis, Characterization and Biological Evaluation
1242, 1078, 999, 825, 732, 599, 507. 1H (DMSO-d6, 300 MHz): 11.78 (1H, s, CONH), 11.53 (1H, s, CONH), 10.69 (1H, s, OH), 9.35 (1H, s, OH), 8.57 (1H, s, N=CH), 8.34 (1H, s, N=CH), 7.59 (4H, m, ArH), 7.32 (2H, d, J = 7.6 Hz, ArH), 7.13 (6H, m, ArH), 6.86 (2H, m, ArH), 5.13 (2H, s, CH2), 4.72 (2H, s, CH2), 3.81 (6H, s, 2 x OCH3). (N'E,N'"E)-2,2'-[[1,1'-Biphenyl]-4,4'-dihylbis(oxy)]bis[N'(2-chlorophenylmethylene)acetohydrazide] (7) Yield 70%. Mp: 253-255 °C. EI-MS: m/z 574 [M+]. HRMS (FT-ICR) calcd for C30H24Cl2N4O4: 574.1175; found 574.1269. IR: n (cm-1) 3199, 3049, 1674, 1544, 1494, 1436, 1230, 1070, 825, 756, 574, 513. 1H NMR (DMSO-d6, 300 MHz): 11.85 (1H, s, CONH), 11.78 (1H, s, CONH), 8.75 (1H, s, N=CH), 8.39 (1H, s, N=CH), 8.04 (2H, m, ArH), 7.55 (10H, m, ArH), 7.06 (4H, t, J = 8.4 Hz, ArH), 5.18 (2H, s, CH2), 4.71 (2H, s, CH2). (N'E,N'"E)-2,2'-[[1,1'-Biphenyl]-4,4'-dihylbis(oxy)]bis[N'(pyridin-4-ylmethylene]acetohydrazide) (8) Yield 58%. Mp: 257-259 °C. EI-MS: m/z 508 [M+]. HRMS (FT-ICR) calcd for C28H24N6O4: 508.1859; found 508.1859. IR: n (cm-1) 3558, 3415, 2910, 1681, 1583, 1498, 1234, 1101, 993, 812, 617, 511, 405. 1H NMR (DMSO-d6, 300 MHz): 11.87 (2H, s, 2 x CONH), 8.64 (4H, d, J = 5.7 Hz, ArH), 8.34 (1H, s, N=CH), 8.01 (1H, s, N=CH), 7.64 (8H, m, ArH), 7.03 (4H, t, J = 8.7 Hz, ArH), 5.20 (2H, s, CH2), 4.73 (2H, s, CH2). (N'E,N'"E)-2,2'-[[1,1'-Biphenyl]-4,4'-dihylbis(oxy)]bis[N'benzylideneacetohydrazide] (9) Yield 70%. Mp: 263-266 °C. EI-MS: m/z 506 [M+]. HRMS (FT-ICR) calculated for C30H26N4O4: 506.1954; found 506.1945. IR: n (cm-1) 3558, 3411, 2868, 1678, 1498, 1442, 1240, 1099, 989, 815, 754, 688, 615, 507. 1H NMR (DMSOd6, 300 MHz): 11.85 (1H, s, CONH), 11.78 (1H, s, CONH), 8.75 (1H, s, N=CH), 8.39 (1H, s, N=CH), 8.04 (4H, m, ArH), 7.55 (10H, m, ArH), 7.06 (4H, dd, J = 8.7 and 8.4 Hz, ArH), 5.18 (2H, s, CH2), 4.71 (2H, s, CH2). (N'E,N'"E)-2,2'-[[1,1'-Biphenyl]-4,4'-dihylbis(oxy)]bis[N'(4-chlorophenylmethylene)acetohydrazide] (10) Yield 64%. Mp: 267-268 °C. EI-MS: m/z 574 [M+]. HRMS (FT-ICR) calcd for C30H24Cl2N4O4: 574.1175; found 574.1213. IR: n (cm-1) 3552, 3222, 3076, 2906, 1699, 1652, 1496, 1244, 1089, 1012, 821, 690, 511. 1H NMR (DMSO-d6, 300 MHz): 11.71 (2H, s, 2 x CONH), 8.30 (1H, s, N=CH), 8.02 (1H, s, N=CH), 7.70 (4H, t, Hz, ArH), 7.5 x (8H, m, ArH), 7.00 (4H, t, J = 8.7 Hz, ArH), 6.90 (4H, d, J = 8.7 Hz, ArH), 4.70 (4H, s, 2 x CH2). (N'E,N'"E)-2,2'-[[1,1'-Biphenyl]-4,4'-dihylbis(oxy)]bis[N'(pyridin-2-yl)methyleneacetohydrazide (11) Yield 60%. Mp: 278-280 °C. EI-MS: m/z 508 [M+]. HRMS (FT-ICR) calculated for C28H24N6O4: 508.1859; found 508.1955. IR: n (cm-1) 3392, 3087, 2827, 1697, 1608, 1498, 1396, 1226, 1082, 817, 704, 630, 561, 511. 1H NMR (DMSO-d6, 300 MHz): 11.75 (2H, s, 2 x CONH), 8.87 (2H, d, J = 11.5 Hz, ArH), 8.59 (1H, s, N=CH), 8.39 (1H, s,
Letters in Organic Chemistry, 2014, Vol. 11, No. 3
5
N=CH), 8.15-7.54 (8H, m, ArH), 7.06 (4H, dd, J = 8.4 and 8.1 Hz, ArH), 5.19 (2H, s, CH2), 4.70 (2H, s, CH2). (N'E,N'"E)-2,2'-[[1,1'-Biphenyl]-4,4'-dihylbis(oxy)]bis[N'(4-methoxyphenylmethylene)acetohydrazide] (12) Yield 50%. Mp: 288-289 °C. EI-MS: m/z 566 [M+]. HRMS (FT-ICR) calcd for C32H30N4O6: 566.2165; found 566.2069. IR: n (cm-1) 3219, 3068, 1670, 1498, 1240, 1172, 1085, 823, 705, 590, 526, 408.1H NMR (DMSO-d6, 400 MHz): 11.45 (1H, s, CONH), 11.41 (1H, s, CONH), 8.28 (1H, s, N=CH), 7.89 (1H, s, N=CH), 7.64 (8H, m, ArH), 7.52 (8H, m, ArH), 5.14 (2H, s, CH2), 4.67 (2H, s, CH2), 3.79 (6H, s, 2 x OCH3). (N'E,N'"E)-2,2'-[[1,1'-Biphenyl]-4,4'-dihylbis(oxy)]bis[N'(3-bromophenylmethylene)acetohydrazide] (13) Yield 50%. Mp: 273-276 °C. EI-MS: m/z 662 [M+]. HRMS (FT-ICR) calculated for C30H24Br2N4O4: 662.0164; found 662.0141. IR: n (cm-1) 3433, 3064, 2962, 1681, 1606, 1498, 1404, 1220, 1082, 813, 786, 813, 680, 565, 484. 1 H NMR (DMSO-d6, 400 MHz): 11.72 (1H, s, CONH), 11.69 (1H, s, CONH), 8.30 (1H, s, N=CH), 7.98 (1H, s, N=CH), 7.93 (2H, d, J = 12.6 Hz, ArH), 7.67-7.51 (8H, m, ArH), 7.05 (4H, dd, J = 8.4 and 8.7 Hz, ArH), 5.19 (2H, s, CH2), 4.70 (2H, s, CH2). (N'E,N'"E)-2,2'-[[1,1'-Biphenyl]-4,4'-dihylbis(oxy)]bis[N'(2,4,6-trimethoxyphenylmethylene)acetohydrazide] (14) Yield 50%. Mp: 262-264 °C. EI-MS: m/z 686 [M+]. HRMS (FT-ICR) calcd for C36H38N4O10: 686.2588; found 686.2501. IR: n (cm-1) 3197, 3070, 2841, 1670, 1595, 1496, 1461, 1242, 1095, 1043, 997, 812, 725, 617, 513, 476. 1 H NMR (DMSO-d6, 400 MHz): 11.53 (1H, s, CONH), 11.47 (1H, s, CONH), 8.50 (1H, s, N=CH), 8.19 (1H, s, N=CH), 7.56 (6H, m, ArH), 7.06 (2H, d, J = 8.4 Hz, ArH), 6.98 (4H, m, ArH), 5.13 (2H, s, CH2), 4.66 (2H, s, CH2), 3.83 (18H, m, 6 x OCH3). (N'E,N'"E)-2,2'-[[1,1'-Biphenyl]-4,4'-dihylbis(oxy)]bis[N'(4-hydroxy-3-methoxyphenylmethylene)acetohydrazide] (15) Yield 50%. Mp: 288-289 °C. EI-MS: m/z 598 [M+]. HRMS (FT-ICR) calculated for C32H30N4O8: 598.2064; found 598.1214. IR: n (cm-1) 3473, 3060, 1678, 1496, 1278, 1172, 1082, 821, 756, 621, 516, 482. 1H NMR (DMSO-d6, 400 MHz): 11.42 (1H, s, CONH), 11.36 (1H, s, CONH), 9.51 (1H, s, OH), 9.46 (1H, s, OH), 8.21 (1H, s, N=CH), 7.89 (1H, s, N=CH), 7.56 (4H, t, ArH), 7.27 (2H, s, ArH), 7.09 (6H, m, ArH), 6.82 (2H, t, ArH), 5.14 (2H, s, CH2), 4.66 (2H, s, CH2), 3.80 (6H,2 s, 2 x OCH3). Biological Experiments To determine the compound- activity against influenza virus, a 96-well plate assay in Madin-Darby canine kidney (MDCK) cells was used, as fully described in reference [27]. Briefly, the influenza virus was added together with serially diluted compound to MDCK cell, and after 3 days incubation at 37°C, microscopy was performed to score the cytopathic effect of the virus as well as the cytotoxic activity of the test
6 Letters in Organic Chemistry, 2014, Vol. 11, No. 3
compound. These data were confirmed by a subsequent spectroscopic MTS cell viability assay.
El Ashry et al.
[12]
CONFLICT OF INTEREST The authors confirm that this article content has no conflict of interest.
[13]
[14]
ACKNOWLEDGEMENTS We appreciate the support of the Higher Education Commission of Pakistan to perform this study through the Project No. 20-697/R&D/06/38 from HEC. REFERENCES [1] [2]
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
Rollas, S.; Küçükgüzel, S. G. Biological activities of hydrazone derivatives. Molecules, 2007, 12, 1910-1939. Scior, T.; Garcés-Eisele, S. J. Isoniazid is not a lead compound for its pyridyl ring derivatives, isonicotinoyl amides, hydrazides, and hydrazones: a critical review. Curr. Med. Chem., 2006, 13, 22052219. Ragavendran, J. V.; Sriram, D.; Patel, S. K.; Reddy, I. V.; Bharathwajan, N.; Stables, J.; Yogeeswari, P. Design and synthesis of anticonvulsants from a combined phthalimide-GABA-anilide and hydrazone pharmacophore. Eur. J. Med. Chem., 2007, 42, 146151. Ergenç, N.; Günay, N. S.; Demirdamar, R. Synthesis and antidepressant evaluation of new 3-phenyl-5-sulfonamidoindole derivatives. Eur. J. Med. Chem., 1998, 33, 143-148. Todeschini, A. R.; de Miranda, A. L. P.; da Silva, K. C. M.; Parrini, S. C.; Barreiro, E. J. Synthesis and evaluation of analgesic, antiinflammatory and antiplatelet properties of new 2pyridylarylhydrazone derivatives. Eur. J. Med. Chem., 1998, 33, 189-199. Radwan, M. A. A.; Ragab, E. A.; Sabry, N. M.; El-Shenawy, S. M. Synthesis and biological evaluation of new 3-substituted indole derivatives as potential anti-inflammatory and analgesic agents. Bioorg. Med. Chem., 2007, 15, 3832-3841. Gemma, S.; Kukreja, G.; Fattorusso, C.; Persico, M.; Romano, M. P.; Altarelli, M.; Savini, L.; Campiani, G.; Fattorusso, E.; Basilico, N.; Taramelli, D.; Yardley, V.; Butini, S. Synthesis of N1arylidene-N2-quinolyl- and N2-acrydinylhydrazones as potent antimalarial agents active against CQ-resistant P. falciparum strains. Bioorg. Med. Chem. Lett., 2006, 16, 5384-5388. Sahu, N.K; Sharma, M.; Mourya, V.; Kohli, D. V. QSAR study of some substituted 4-quinolinyl and 9-acridinyl hydrazones as antimalaria agents. Acta Poloniae Pharmaceutica, Drug Research, 2012, 69,1153-1165 Bijev, A. New heterocyclic hydrazones in the search for antitubercular agents: synthesis and in vitro evaluations. Lett. Drug Des. Discov., 2006, 3, 506-512. Nayyar, A.; Monga, V.; Malde, A.; Coutinho, E.; Jain, R. Synthesis, anti-tuberculosis activity, and 3D-QSAR study of 4(adamantan-1-yl)-2-substituted quinolines. Bioorg. Med. Chem., 2007, 15, 626-640. Gürsoy, E.; Güzeldemirci, N. U. Synthesis and primary
[15] [16]
[17]
[18]
[19]
[20]
[21]
[22] [23]
[24] [25]
[26] [27]
cytotoxicity evaluation of new imidazo[2,1-b]thiazole derivatives. Eur. J. Med. Chem., 2007, 42, 320-326. Sztanke, K.; Tuzimski, T.; Rzymowska, J.; Pasternak, K.; Kandefer-Szersze , M. Synthesis, determination of the lipophilicity, anticancer and antimicrobial properties of some fused 1,2,4-triazole derivatives. Eur. J. Med. Chem., 2008, 43, 404-419. Masunari, A.; Costa Tavares, L. A new class of nifuroxazide analogues: Synthesis of 5-nitrothiophene derivatives with antimicrobial activity against multidrug-resistant Staphylococcus aureus. Bioorg. Med. Chem., 2007, 15, 4229-4236. Loncle, C.; Brunel, J. M.; Vidal, N.; Dherbomez, M.; Letourneux, Y. Synthesis and antifungal activity of cholesterol-hydrazone derivatives. Eur. J. Med. Chem., 2004, 39, 1067-1071. Güniz Küçükgüzel, S.; Mazi, A.; Sahin, F.; Öztürk, S.; Stables, J. Synthesis and biological activities of diflunisal hydrazidehydrazones. Eur. J. Med. Chem., 2003, 38, 1005-1013. Vicini, P.; Zani, F.; Cozzini, P.; Doytchinova, I. Hydrazones of 1,2benzisothiazole hydrazides: synthesis, antimicrobial activity and QSAR investigations. Eur. J. Med. Chem., 2002, 37, 553-564. Lima Leite, A. C.; Souza de Lima, R.; de M. Moreira, D. R.; de O. Cardoso, M. V.; Gouveia de Brito, A. C.; Farias dos Santos, L. M.; Zaldini Hernandes, M.; Costa Kiperstok, A.; Santana de Lima, R.; Soares, M. B. P. Synthesis, docking, and in vitro activity of thiosemicarbazones, aminoacyl-thiosemicarbazides and acylthiazolidones against Trypanosoma cruzi. Bioorg. Med. Chem., 2006, 14, 3749-3757. Al-Mawsawi, L. Q.; Dayam, R.; Taheri, L.; Witvrouw, M.; Debyser, Z.; Neamati, N. Discovery of novel non-cytotoxic salicylhydrazide containing HIV-1 integrase inhibitors. Bioorg. Med. Chem. Lett., 2007, 17, 6472-6475. Abdel-Aal, M. T.; El-Sayed, W. A.; El-Ashry, E.-S. H. Synthesis and antiviral evaluation of some sugar arylglycinoylhydrazones and their oxadiazoline derivatives. Arch. Pharm. Chem. Life Sci., 2006, 339, 656-663. Nayyar, A.; Jain, R. Recent Advances in New Structural Classes of Anti-Tuberculosis Agents. Curr. Med. Chem., 2005, 12, 18731886. Scior, T.; Garcés-Eisele, S. J. Isoniazid is Not a Lead Compound for its Pyridyl Ring Derivatives,Isonicotinoyl Amides, Hydrazides, and Hydrazones: A Critical Review Curr. Med. Chem., 2006, 13, 2205-2219. Janin, Y. L. Antituberculosis drugs: ten years of research. Bioorg. Med. Chem., 2007, 15, 2479-2513. Koçyiit-Kaymakçiolu, B.; Oruç, E.; Unsalan, S.; Kandemirli, F.; Shvets, N.; Rollas, S.; Dimoglo, A. Synthesis and characterization of novel hydrazide-hydrazones and the study of their structureantitubercolosis activity. Eur. J. Med. Chem., 2006, 41, 1253-1261. Sah, P. P. T.; Peoples, S. A. Isonicotinoylhydrazones as antitubercular agents and derivatives for identification of aldehydes and ketones. J. Am. Pharm. Assoc., 1954, 43, 513-524. Bavin, E. M.; Drain, D. J.; Seiler, M.; Seymour, D. E. Further studies on tuberculostatic compounds. J. Pharm. Pharmacol., 1952, 4, 844-854. Buu-Hoï, P. H.; Xuong, D.; Nam, H.; Binon, F.; Royer , R. Tuberculostatic hydrazides and their derivatives. J. Chem. Soc., 1953, 1358-1364. Vanderlinden, E.; Gökta, F.; Cesur, Z.; Froeyen, M.; Reed, M. L.; Russell, C. J.; Cesur, N.; Naesens, L. Novel Inhibitors of Influenza Virus Fusion: Structure-Activity Relationship and Interaction with the Viral Hemagglutinin. J. Virol. 2010, 84, 4277-4288.
