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| ORIGINAL ARTICLE |
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| Year : 2010 | Volume
: 1
| Issue : 3 | Page : 342-347 |
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Synthesis, characterization, and analgesic activity of novel schiff base of isatin derivatives
Rajaram Prakash Chinnasamy1, Raja Sundararajan2, Saravanan Govindaraj3
1 Department of Pharmaceutical Chemistry, D.C.R.M. Pharmacy College, Inkollu - 523 167 (A.P), India
2 Kamalakshi Pandurangan College of Pharmacy, Ayyampalayam, Thiruvannamalai, (T.N), India
3 Department of Medicinal Chemistry, Medicinal Chemistry Research Laboratory, Bapatla College of Pharmacy, Bapatla - 522 101, (A.P), India
| Date of Web Publication | 10-Nov-2010 |
Correspondence Address:
Rajaram Prakash Chinnasamy
Department of Pharmaceutical Chemistry, D.C.R.M. Pharmacy College, Inkollu - 523 167, (A.P)
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/0110-5558.72428
 Abstract | | |
In the present study, a series of novel Schiff bases of isatin [5a-5l] were synthesized by condensation of imesatin with different aromatic aldehydes. The imesatins were synthesized by the reaction of isatin with p-phenylenediamine. The chemical structures of the synthesized compounds were confirmed by means of Infrared (IR), Mass spectroscopy, and Elemental analysis. These compounds were screened for the analgesic activity by the tail-immersion method at a dose of 200 mg/kg body weight. Among the tested compounds 3-(4-(4-hydroxy-3-methoxylbenzylideneamino) phenylimino) indoline-2-one (5i) exhibited better analgesic activity when compared to standard pentazocine. From the above-mentioned results it may be concluded that compounds containing electron-donating groups exhibit better analgesic activity than the electron-withdrawing groups. Keywords: Analgesic activity, isatin, schiff base
How to cite this article:
Chinnasamy RP, Sundararajan R, Govindaraj S. Synthesis, characterization, and analgesic activity of novel schiff base of isatin derivatives. J Adv Pharm Technol Res 2010;1:342-7 |
How to cite this URL:
Chinnasamy RP, Sundararajan R, Govindaraj S. Synthesis, characterization, and analgesic activity of novel schiff base of isatin derivatives. J Adv Pharm Technol Res [serial online] 2010 [cited 2023 Apr 1];1:342-7. Available from: https://www.japtr.org/text.asp?2010/1/3/342/72428 |
| Introduction | |  |
Isatin (indole-2, 3-dione) is an endogenous compound, widely distributed in mammalian tissues and body fluids. [1] In the brain the highest levels have been found in the hippocampus [2] and an immunocytochemical staining revealed its specific localization within particular cells. In vivo isatin administration causes a range of dose-dependent behavioral effects, [3] including angiogenesis and increased water retention. In vitro, isatin is a potent inhibitor of both atrial natriureticpeptide (ANP)-stimulated, membrane-bound guanylate cyclase and nitric oxide-stimulated soluble guanylate cyclase [4] It is an inhibitor of monoamine oxidase B (IC 50 3-8 lM) and of atrial natriuretic peptide receptor binding (0.4 lM) at levels that may be in the physiological range. [5] Isatin is well known as a pharmacological agent having a range of action in the brain and it is protective against certain types of infections. Isatin derivatives are reported to show other biological activities, such as, anti-bacterial, [6],[7],[8] anti-fungal, [9],[10],[11] anti-viral, [12],[13],[14] anti-HIV, [15],16],[17] anti-protozoal, [18],[19] muscle relaxant, [20] anti-allergic, [21] and anti-inflammatory [22] activities. Schiff bases are used as substrates in the preparation of a number of biologically active compounds. Moreover, Schiff bases derived from various heterocycles have been reported to possess anti-fungal, [23] anti-cancer, [24] cytotoxic, [25] and anti-convulsant activities. [26] The chemistry of isatin and its derivatives is particularly interesting because of their potential application in medicinal chemistry. Schiff bases of isatin derivatives have been reported to demonstrate a variety of biological activities, such as, anti-inflammatory, [27] anti-convulsant, [28] anti-HIV, [29] anti-bacterial, [30] anti-fungal, [31] and anti-depressant [32] activities. These observations have led to the conception that a series of some different novel Schiff bases of isatin were synthesized using different aromatic aldehydes by condensation with imesatin and their chemical structures were confirmed by IR, 1 H-NMR, 13 C-NMR, Mass spectroscopy, and Elemental analysis. These compounds were screened for their analgesic properties. The results of such studies are discussed in this article.
| Materials and Methods | | |
The melting points were taken with the help of an open capillary tube and were uncorrected. The IR spectra of the compounds were recorded on ABB Bomem FT-IR spectrometer MB 104 with KBr pellets. The 1 H (400 MHz) and 13 C-NMR (400 MHz) spectra were recorded on a Bruker 400 NMR spectrometer (with TMS for 1 H and DMSO-d 6 for 13 C as internal references). Mass spectroscopy was recorded on Shimadzu GC MS QP 5000. Microanalyses were obtained with an elemental analyses system GmbH VarioEL V300 element analyzer. The purity of the compounds was checked by TLC on pre-coated SiO 2 gel (HF 254 , 200 mesh) aluminium plates (E-Merck) using ethyl acetate : n-hexane (2 : 3) and visualized in a UV chamber. IR, 1 H-NMR, 13 C-NMR, mass spectroscopy, and elemental analysis were consistent with the assigned structures.
General Method of Synthesis
In the present study, aniline 1 is treated with chloral hydrate to form isonitrosoacetanilide 2. Then this intermediate undergoes cyclization with sulfuric acid to form isatin 3, [33] which is further reacted with p-phenylenediamine, resulting in the formation of imesatin 4. Compound 4 is subjected to reaction with various aromatic aldehydes in the presence of ethanol as a solvent to form Schiff bases (5a-5f, [Figure 1]). All the synthesized compounds are soluble in dimethylformamide.
Equimolar quantities of (0.01 mol) isatin and p-phenylenediamine were dissolved in a sufficient quantity of methanol (30 mL) in the presence of acetic acid and refluxed for one hour, and then kept for two hours at room temperature (37 0 C). The product that separated out was filtered, dried in a vacuum, and recrystallized from absolute ethanol. Equimolar quantities (0.01 mol) of imesatin 4 and various aromatic aldehydes were dissolved in ethanol and refluxed for eight hours. After standing for one-to-two days at room temperature, the product of different substituted derivatives of isatin (5a-5f) separated out as a mixture of E and Z isomers, which was filtered, dried, and recrystallized from absolute ethanol. In the present study a novel series of various three-substituted isatin compounds were synthesized. The target compounds 5a-5f were synthesized according to [Figure 1]. Aniline and chloral hydrate were used as starting materials to produce the Schiff bases of substituted isatin via the intermediate imesatin (4) through a condensation reaction.
The condensation proceeds selectively on the carbonyl group in position 3 of the isatin ring. Reactions of imesatin with different aromatic aldehydes have been carried out in ethanol in the presence of glacial acetic acid, and a variety of Schiff base derivatives have been isolated according to the synthetic [Figure 1]. The method used for the preparation and isolation of the compounds has given materials of good purity, as evidenced by their spectral analyses and thin layer chromatography. The Schiff base derivatives are found to be soluble in chloroform, dimethyl sulfoxide, and dimethylformamide.
Pharmacological Screening
Animals
The animals used in the present study were Swiss albino mice weighing 20 - 25 gm, which were procured from the C. L. Baid Metha College of Pharmacy, Chennai, India. The animals were maintained in colony cages at 25±2 o C, with relative humidity of 45 - 55%, under 12 hours light and dark cycle, and were fed with the standard animal feed and water ad libitum. The animals were maintained under standard conditions in an animal house approved by the committee for the purpose of control and supervision of experiments on animals (CPCSEA). The Institutional Animal Ethics Committee approved the experimental protocol. All the animals were acclimatized for a week before use.
Acute Toxicity Studies
The Acute toxicity test was performed for the entire synthesized compound, to ascertain the LD 50 values as per OECD guidelines. [34] The experimental dose was selected between the minimum effective dose and maximal non-lethal dose.
Analgesic Activity (Tail Immersion Method in Mice)
The analgesic activity [35] was determined by the tail-immersion method. Swiss mice (n = 6) of either sex, selected by the random sampling technique, were used for the study. Pentazocine at a dose of 10 mg/kg (i.p.) was administered as a standard drug for comparison, to check the centrally acting analgesic activity of the synthesized compounds. Pentazocine would produce excellent centrally acting analgesic action compared to other analgesic standards. Moreover, pentazocine is a synthetically prepared compound and known to act as an opioid-mixed agonist and antagonist. [36] The test compounds at 200 mg/kg dose level were administered orally. The animals were held in position by a suitable restrainer with the tail extending out and the tail (up to 5 cm) was taken, dipped in a beaker of water maintained at 55±0.5oC. The time in seconds taken to withdraw the tail clearly out of water was taken as the reaction time. The first reading (0 minute) was taken immediately after the administration of the test compound and subsequent the reaction time was recorded at 30, 60, 120, and 180 minutes after the administration of the compounds. A cut-off point of 15 seconds was observed to prevent tail damage. The percentage analgesic activity was calculated using the following formula, and the results are presented in [Table 1].
PAA = [(T 2 -T 1 )/T 2 ] X 100
Where, T 1 and T 2 are the reaction times (in seconds) before and after treatment, respectively; PAA is the percentage analgesic activity.
| Results and Discussion | | |
Chemistry
IR, 1 H-NMR, 13 C-NMR, Mass spectra, and Elemental analysis were consistent with the assigned structures.
3-(4-(benzylideneamino) phenylimino) indoline-2-one [5a]
Bright yellow crystals; Yield: 80%; mp. 322 - 324°C; IR: 3177 (N-H), 3050 (Ar-CH), 1690 (C=O), 1597 (C=N), 1580 (C=C) cm -1 ; 1H-NMR (DMSO): δ 8.29 (s, 1H,-N=CH -), 8.02 (s, 1H, -N H -), 7.01-7.68 (m, 13H, H-4, H-5 , H-6, H-7, H-2', H-3', H-5 ' , H-6', H-2'', H-3 '' , H-4'', H-5'', H-6'', Ar-H); 13C-NMR (DMSO): δ 167.2 (C-2), 163.5 (C-3), 160.3 (-N=C H-), 151.6 (C-1 ' and C-4'), 133.5 (C-9 ' ), 132.5 (C-6), 130.4 (C-8), 131.2 (C-4''), 129.5 (C-4), 129.2 (C-2'' and C-6''), 129.2 (C-5), 128.7 (C-3'' and C-5''), 126.4(C-1''), 123.4 (C-2', C-3', C-5 ' and C-6'), 121.9 (C-7); EI-MS (m/z, %): 325(M + , 21), 235(14), 120(100), 105(24), 69(44); (Calcd. for C 21 H 15 N 3 O: 325.36); Anal. Calcd. for C 21 H 15 N 3 O: C, 74.35; H, 4.82; N, 11.82; Found: C, 74.30; H, 4.84; N, 11.78.
3-(4-(4-chlorobenzylideneamino) phenylimino) indoline-2-one [5b]
Pale yellow crystals; Yield: 75%; mp. 346 - 348°C; IR: 3130 (N-H), 2988 (Ar-CH), 1613 (C=N), 1700 (C=O), 1599 (C=C), 744 (C-Cl) cm -1 ; 1 H-NMR (DMSO): δ 8.25 (s, 1H, -N=CH -), 7.92 (s, 1H, -N H -), 7.03-7.60 (m, 12H, H-4, H-5 , H-6, H-7, H-2', H-3', H-5 ' , H-6', H-2'', H-3 '' , H-5'', H-6'', Ar-H); 13C-NMR (DMSO): δ 166.9 (C-2), 164.2 (C-3), 160.1 (-N=C H-), 151.2 (C-1 ' and C-4'), 136.2 (C-4''), 133.5 (C-9), 131.2 (C-6), 130.6 (C-8), 130.5 (C-2'' and C-6''),129.8 (C-4), 129.1 (C-3'' and C-5''), 126.6 (C-1''), 124.4 (C-5), 123.1 (C-2',C-3',C-5 ' and C-6'), 121.6 (C-7); EI-MS (m/z, %): 362(M + 2), 360(M + , 20), 264(22), 91(100), 77(22), 69(44); (Calcd. for C 21 H 14 ClN 3 O: 359.80); Anal. Calcd. for C 21 H 14 ClN 3 O: C, 70.10; H, 3.92; N, 11.68; Found: C, 70.15; H, 3.95; N, 11.72.
3-(4-(4-hydroxybenzylideneamino) phenylimino) indoline-2-one [5c]
Pale yellow solid; Yield: 68%; mp. 334 - 336°C; IR: 3529 (Ar-OH), 3130 (N-H), 3011 (Ar-CH), 1680 (C=O), 1615 (C=C), 1591 (C=N) cm -1 ; 1H-NMR (DMSO): δ 8.28 (s, 1H, -N=CH -), 8.01 (s, 1H, -N H -), 7.01-7.48 (m, 8H, H-4, H-5 , H-6, H-7, H-2', H-3', H-5 ' , H-6', Ar-H), 7.42 (d, J=7.2 Hz, 1H, C-2'' Ar-H), 7.47 (d, J=6.5 Hz , 1H, C-6'' Ar-H), 6.62 (d, J=5.9 Hz , 1H, C-3'' Ar-H), 6.67 (d, J=7.8 Hz , 1H, H-5'' Ar-H), 5.14 (s, 1H, Ar -O H ); 13C-NMR (DMSO): δ 166.9 (C-2), 163.2 (C-3), 160.8 (C-4''), 160.1(-N=C H-), 151.4 (C-1 ' and C-4'), 133.4 (C-9), 132.0 (C-6), 130.5 (C-2'' and C-6''), 130.3 (C-8), 129.4 (C-4), 126.4 (C-1''), 124.5 (C-5), 123.5 (C-2',C-3',C-5 ' and C-6'), 121.7 (C-7), 116 (C-3'' and C-5''); EI-MS (m/z, %): 341(M + , 26), 222(66), 149(74), 121(100), 57(74), 69(44); (Calcd. for C 21 H 15 N 3 O 2 : 341.36); Anal. Calcd. for C 21 H 15 N 3 O 2 : C, 73.89; H, 4.43; N, 12.31; Found: C, 73.91; H, 4.46; N, 12.28.
3-(4-(4-methoxybenzylideneamino) phenylimino) indoline-2-one [5d]
Lemon yellow crystals; Yield: 79%; mp. 326 - 328°C; IR: 3146 (N-H), 3079 (Ar-CH), 1688 (C=O), 1647 (C=C), 1567 (C=N), 1270 (C-O-C) cm -1 ; 1H-NMR (DMSO): δ 8.39 (s, 1H, -N=CH -), 8.01(s, 1H, -N H -), 7.51(d, J=6.3 H Z, 1H, C-6'' Ar-H), 7.47 (d, J=5.9 Hz , 1H, C-2'' Ar-H), 6.99-7.31 (m, 8H, H-4, H-5 , H-6, H-7, H-2', H-3', H-5 ' , H-6' Ar-H), 6.81 (d, J=7.2 Hz , 1H, H-5'' Ar-H), 6.77(d, J=6.5 Hz, 1H, H-3'' Ar-H), 3.70 (s, 3H, -OC H 3 ); 13 C-NMR (DMSO): δ 167.6 (C-2), 163.5 (C-3), 163.1 (C-4''), 160.5(-N= C H-), 151.64 (C-1 ' and C-4'), 133.6 (C-9), 132.0 (C-6), 130.6 (C-8), 130.2 (C-2'' and C-6''), 129.4 (C-4), 126.1 (C-1''), 124.5 (C-5), 123.6 (C-2',C-3',C-5 ' and C-6'), 121.5 (C-7), 114.3 (C-3'' and C-5''), 55.8 (-O C H 3 ); EI-MS (m/z, %): 355(M + , 18), 282(20), 121(100), 91(42), 55(94); (Calcd. for C 22 H 17 N 3 O 2 : 355.38); Anal. Calcd. for C 22 H 17 N 3 O 2 : C, 74.35; H, 4.82; N, 11.82; Found: C, 74.36; H, 4.80; N, 11.78.
3-(4-(4-nitrobenzylideneamino) phenylimino) indoline-2-one [5e]
Creamy crystals; Yield: 68%; mp. 338 - 340°C; IR: 3132 (N-H), 3012 (Ar-CH), 1690 (C=O), 1603 (C=C), 1590 (C=N), 1515 and 1310 (N=O) cm -1 ; 1H-NMR (DMSO): δ 8.29 (s, 1H, -N=CH -), 8.21 (d, J=7.1 Hz , 1H, H-5'' Ar-H), 8.17 (d, J=6.8 Hz , 1H, H-3'' Ar-H), 8.10 (s, 1H, -N H -), 7.77(d, J=7.5 Hz, 1H, H-2' Ar-H), 7.69 (d, J=6.2 Hz , 1H, H-6'' Ar-H), 6.99-7.70 (m, 8H, H-4, H-5 , H-6, H-7, H-2', H-3', H-5 ' , H-6' Ar-H); 13C-NMR (DMSO): δ 166.7 (C-2), 162.9 (C-3), 159.6 (-N=C H-), 151.6 (C-1' and C-4'), 150.2 (C-4''), 139.6 (C-1''), 133.1 (C-9), 131.2 (C-6), 130.2 (C-8), 130.0 (C-2'' and C-6''), 128.3 (C-4), 124.6 (C-5), 123.4 (C-2', C-3', C-5 ' and C-6'), 121.7 (C-7), 121.23 (C-3'' and C-5''); EI-MS (m/z, %): 370(M + , 58), 324(18), 235(100), 120(18), 77(42). (Calcd. for C 21 H 14 N 4 O 3 : 370.36); Anal. Calcd. for C 21 H 14 N 4 O 3 : C, 68.10; H, 3.81; N, 15.13; Found: C, 68.12; H, 3.78; N, 15.15.
3-(4-(2-hydroxybenzylideneamino) phenylimino) indoline-2-one [5f]
Creamy crystals; Yield: 73%; mp. 318 - 320°C; IR: 3467(Ar-OH), 3210 (N-H), 3065 (Ar-CH), 1678 (C=O), 1649 (C=C), 1575 (C=N) cm -1 ; 1H-NMR (DMSO): δ 8.22 (s, 1H, -N=CH -), 7.06-7.67 (m, 8H, H-4, H-5 , H-6, H-7, H-2', H-3', H-5 ' , H-6' Ar-H), 6.75-7.40 (m, 4H, H-3'', H-4'', H-5'' and H-6'' Ar-H), 6.01 (s, 1H, -N H -), 5.20 (s,1H, Ar-OH); 13C-NMR (DMSO): δ 167.2 (C-2), 163.2 (C-3), 161.2 (C-2''), 160.2 (-N= C H-), 151.7 (C-1 ' and C-4'), 133.8 (C-9), 132.3 (C-4''), 131.4 (C-6), 130.1 (C-8), 130.5 (C-6''), 129.3 (C-4), 126.2(C-1''), 124.5 (C-5), 123.5 (C-2', C-3', C-5 ' and C-6'), 121.5 (C-7), 121.3 (C-5''), 116.0 (C-3''). EI-MS (m/z, %): 341(M + , 36), 282(6), 242(34), 131(100), 89(26), 77(30). (Calcd. for C 21 H 15 N 3 O 2 : 341.36); Anal. Calcd. for C 21 H 15 N 3 O 2 : C, 73.89; H, 4.43; N, 12.31; Found: C, 73.91; H, 4.45; N, 12.35.
3-(4-(4-methylbenzylideneamino) phenylimino) indoline-2-one [5g]
Pale yellow crystals; Yield: 77%; mp. 320 - 322°C; IR: 3198 (N-H), 3144 (Ar-CH), 1696 (C=O), 1618 (C=C), 1518 (C=N) cm -1 ; 1H-NMR(DMSO): δ 8.21 (s, 1H, -N=CH -), 8.01 (s, 1H, -N H -), 7.01-7.50 (m, 12H, H-4, H-5, H-6, H-7, H-2', H-3', H-5', H-6', H-2'',H-3'', H-5'', H-6'' Ar-H), 2.30 (s, 3H, -C H 3 ); 13C-NMR (DMSO): δ 166.2 (C-2), 163.2 (C-3), 159.6 (-N=C H-), 151.2 (C-1 ' and C-4'), 140.6 (C-4 '' ), 133.2 (C-9), 131.2 (C-6), 130.9 (C-8), 130.8 (C-1 '' ), 129.5 (C-4), 129.3 (C-3'' and C-5''), 129.1 (C-2'' and C-6''), 124.6 (C-5), 123.5 (C-2', C-3', C-5' and C-6'), 121.6 (C-7), 24.1 (-CH 3 ); EI-MS (m/z, %): 339(M + , 28), 235(40), 222(80), 104(92), 55(100). (Calcd. for C 22 H 17 N 3 O: 339.38); Anal. Calcd. for C 22 H 17 N 3 O: C, 77.86; H, 5.05; N, 12.38; Found: C, 77.84; H, 5.09; N, 12.34.
3-(4-(3, 4, 5,-trimethoxy benzylideneamino) phenylimino) indoline-2-one [5h]
Pale yellow powders; Yield: 71%; mp. 316 - 318°C; IR: 3186 (N-H), 3061 (Ar-CH), 1682 (C=O), 1672 (C=C), 1574 (C=N), 1283 (C-O-C) cm -1 ; 1H-NMR(DMSO): δ 8.35 (s, 1H,-N=CH -), 7.99 (s, 1H, -N H -), 6.99-7.29 (m, 8H, H-4, H-5, H-6, H-7, H-2', H-3', H-5', H-6' Ar-H), 6.51 (s, 1H, H-2'' Ar-H), 6.58 (s, 1H, H-6 '' Ar-H), 3.70 (s, 9H, [OC H 3 ] 3 ); 13 C-NMR (DMSO): δ 167.2 (C-2), 163.2 (C-3), 160.2 (-N= C H-), 151.6 (C-1 ' and C-4 ' ), 150.5 (C-3 '' and C-5 '' ), 141.3 (C-4''), 132.9 (C-9), 131.2 (C-6), 131.0 (C-8), 129.4 (C-4), 128.1 (C-1''), 124.5 (C-5), 123.5 (C-2', C-3', C-5' and C-6'), 121.9(C-7), 106.6 (C-2'' and C-6''), 56.3 ([O C H 3 ] 3 ); EI-MS (m/z, %): 415(M + , 28), 324(18), 263(8), 167(100), 125(58), 69(30); (Calcd. for C 24 H 21 N 3 O 4 : 415.44); Anal. Calcd. for C 24 H 21 N 3 O 4 : C, 69.39; H, 5.10; N, 10.11; Found: C, 69.41; H, 5.12; N, 10.14.
3-(4-(4-hydroxy-3-methoxylbenzylideneamino) phenylimino) indoline-2-one [5i]
Yellow crystals; Yield: 65%; mp. 340 - 342°C; IR: 3523 (Ar-OH), 3210 (N-H), 3023 (Ar-CH), 1698 (C=O), 1631 (C=C), 1595 (C=N), 1127 (C-O-C) cm -1 ; 1H-NMR(DMSO): δ 8.29 (s, 1H, -N=CH -), 8.02 (s, 1H, -N H -), 7.03-7.68 (m, 8H, H-4, H-5, H-6, H-7, H-2', H-3', H-5' , H-6' Ar-H), 7.00 (d, J=7.8 Hz 1H, H-6'' Ar-H), 6.95-6.97 (s, 1H, H-2'' Ar-H), 6.64 (d, J=6.6 Hz 1H, H-5'' Ar-H), 5.06 (s, 1H, Ar-OH), 3.73 (s, 3H, OC H 3 ); 13 C-NMR (DMSO): δ 167.2 (C-2), 162.3 (C-3), 160.6 (-N= C H-), 151.6 (C-1' and C-4'), 151.6 (C-3''), 148.5 (C-4''), 133.3 (C-9), 132.3 (C-8), 132.2 (C-6), 129.4 (C-4), 126.8 (C-1''), 124.6 (C-5), 123.6 (C-2', C-3', C-5' and C-6'), 122.9 (C-6''), 121.6 (C-7), 117.0 (C-5''), 114.6 (C-2''), 56.8 (-O C H 3 ); EI-MS (m/z, %): 371(M + , 72), 324(8), 242(28), 235(100), 177(28), 95(12); (Calcd. for C 22 H 17 N 3 O 3 : 371.38); Anal. Calcd. for C 22 H 17 N 3 O 3 : C, 71.15; H, 4.61; N, 11.31; Found: C, 71.19; H, 4.59; N, 11.36.
3-(4-(3-nitrobenzylideneamino) phenylimino) indoline-2-one [5j]
Creamy solid; Yield: 72%; mp. 314 - 316°C; IR: 3175 (N-H), 3055 (Ar-CH), 1686 (C=O), 1650 (C=N), 1652 (C=C), 1491 and 1373 (C-NO 2 ) cm -1 ; 1HNMR(DMSO): δ 8.55 (s,1H, H-2'' Ar-H), 8.23(d, J=8.1 Hz, 1H, H-4'' Ar-H), 8.19(s,1H, -N=CH -), 8.10 (s, 1H, -N H -), 8.03 (d, J=6.5 Hz, 1H, H-6'' Ar-H), 7.54 (dd, J=7.3, Hz, 1H, H-5'' Ar-H), 7.01-7.30(m, 8H, H-4, H-5, H-6, H-7, H-2', H-3', H-5', H-6' Ar-H); 13C-NMR (DMSO): δ 167.2 (C-2), 164.1 (C-3), 160.4 (-N=C H-), 151.5 (C-1'and C-4'), 148.2 (C-3''), 135.3 (C-6''), 134.6 (C-1''), 133.8 (C-9), 131.3 (C-6), 130.9 (C-8), 129.7 (C-5''), 129.4 (C-4), 124.6 (C-5), 124.1(C-2''), 123.7 (C-2', C-3', C-5' and C-6'), 123.4 (C-4''), 121.6 (C-7); EI-MS (m/z, %): 370(M + , 40), 324(16), 242(38), 173(72), 122(100), 77(22); (Calcd. for C 21 H 14 N 4 O 3 : 370.36); Anal. Calcd. C 21 H 14 N 4 O 3 : C, 68.10; H, 3.81; N, 15.13; Found: C, 68.12; H, 3.83; N, 15.10.
3-(4-(4-dimethylaminobenzylideneamino) phenylimino) indoline-2-one [5k]
Yellow crystals; Yield: 80%; mp. 322 - 324°C; IR: 3150 (N-H), 3055 (Ar-CH), 3019 (C-H), 1698 (C=O), 1613 (C=C), 1568 (C=N) cm -1 ; 1H-NMR(DMSO): δ 8.21 (s, 1H, -N=CH -), 8.02 (s, 1H, -N H -), 7.42 (dd, J=5.9 Hz, 2H, H-2'' and H-6'' Ar-H), 7.03-7.68 (m, 8H, H-4, H-5, H-6, H-7, H-2', H-3', H-5', H-6' Ar-H), 6.61 (dd, J=7.2 Hz, 2H, H-3'' , H-5'' Ar-H), 2.85 (s, 6H, -N[C H 3 ] 2 ); 13C-NMR (DMSO): δ 168.1 (C-2), 162.9 (C-3), 160.2 (-N=C H-), 151.9 (C-4''), 151.7 (C-1' and C-4'), 133.5 (C-9), 131.3 (C-6), 131.0 (C-8), 130.2 (C-2'' and C-6''), 129.3 (C-4), 124.6 (C-5), 123.6 (C-2', C-3', C-5' and C-6'), 123.3 (C-1''), 121.7 (C-7), 114.3 (C-3'' and C-5''), 40.2 (-N[ C H 3 ] 2 ); EI-MS (m/z, %): 368(M + , 6), 324(14), 242(38), 133(100), 91(20). (Calcd. for C 23 H 20 N 4 O: 368.43); Anal. Calcd. C 23 H 20 N 4 O: C, 74.98: H, 5.47; N, 15.21; Found: C, 74.95; H, 5.49; N, 15.22.
3-(4-(3-phenylallylideneamino) phenylimino) indoline-2-one [5l]
Creamy crystals; Yield: 67%; mp. 310 - 312°C; IR: 3168 (N-H), 3090 (Ar-CH), 1700 (C=O), 1591 (C=N), 1498 (C=C) cm -1 ; 1H-NMR (DMSO): δ 8.01 (s, 1H, -NH -), 7.51 (s, 1H, -N=C H -), 6.99-7.32 (m, 13H, H-4, H-5, H-6, H-7, H-2', H-3', H-5', H-6' , H-2'', H-3'', H-4'', H-5'', H-6'' Ar-H), 6.62 (d, 1H, J=7.1 Hz; C 6 H 5 -C H =CH-), 5.63 (d, 1H, J=8.2 Hz, C 6 H 5 -CH=C H -); 13C-NMR (DMSO): δ 167.2 (C-2), 163.7(-N= C H-), 163.3 (C-3), 151.6 (C-1'), 147.6 (C-4'), 138.4 (C 6 H 5 - C H=CH-), 135.2 (C-1''), 133.3(C-9), 131.3(C-6), 131.2(C-8), 129.3(C-4), 128.7 (C-5'' and C-6''), 128.0 (C-4''), 126.4 (C-2'' and C-6''), 124.6 (C-5), 123.4 (C-2', C-3', C-5' and C-6'), 119.8 (C 6 H 5 -CH= C H-), 121.7 (C-7); EI-MS (m/z, %): 351(M + ,26), 300(24), 243(10), 221(8), 179(18), 109(100), 60(32); (Calcd. for C 23 H 17 N 3 O: 351.40); Anal. Calcd. for C 23 H 17 N 3 O: C, 78.61; H, 4.88; N, 11.96; Found: C, 78.59; H, 4.85; N, 11.90.
Pharmacological Screening
The synthesized compounds were evaluated for analgesic activity by the tail-immersion method. The activity was studied at 200 mg/kg b.w. (p.o) and their effects were measured at time intervals of 30, 60, 120, and 180 minutes. Most of the synthesized compounds showed significant analgesic activity. The highest analgesic activity was observed at 120 mintes for all the compounds. When compared with the standard drug (Pentazocine, 10 mg/kg, i.p), compounds bearing the electron donating hydroxyl and tri-methoxy substituent such as 3-(4-(4-hydroxy-3-methoxylbenzylidene amino) phenylimino) indoline-2-one [5i] and 3-(4-(3, 4, 5,-trimethoxy benzylideneamino) phenylimino) indoline-2-one [5h], exhibited comparable analgesic activity at 200 mg/kg b.w. Compounds 3-(4-(4-dimethylaminobenzylideneamino) phenylimino) indoline-2-one [5k] and 3-(4-(4-methoxybenzylideneamino) phenylimino) indoline-2-one [5d] exhibited moderate analgesic activity. Among the compounds synthesized, the compound-bearing, electron-withdrawing, nitro-substituent, such as 3-(4-(4-nitrobenzylideneamino) phenylimino) indoline-2-one [5e] exhibited the lowest analgesic activity. From the above-mentioned results it may be concluded that compounds containing the electron-donating groups exhibit better analgesic activity than the electron-withdrawing groups.
| Conclusion | | |
It is known that the heterocyclic compounds containing both Schiff base and isatin rings have diverse pharmacological properties. [27],[28],[29],[30],[31],[32] A general and convenient method was established for the synthesis of new heterocyclic compounds of isatin containing Schiff bases. Thus 12 new Schiff base derivatives having unsubstituted, substituted with electron-donating and electron-withdrawing groups were synthesized in good yield. The analgesic activity results showed that Schiff bases bearing electron-donating substituents produced potent results, and therefore, might serve as lead molecules to obtain more clinically useful, novel entities in the future.
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[Figure 1]
[Table 1]
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| Moumita Saha,Asish R. Das | | Current Green Chemistry. 2020; 7(1): 53 | | [Pubmed] | [DOI] | | | 36 |
Synthesis, Conformational Analysis, Infrared, Raman and UV-Visible Spectra of Novel Schiff Bases compiled with DFT Calculations |
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| Samy M. Ahmed,Ibrahim A. Shaaban,Elsayed H. El-Mossalamy,Tarek A. Mohamed | | Combinatorial Chemistry & High Throughput Screening. 2020; 23(7): 568 | | [Pubmed] | [DOI] | | | 37 |
Synthesis, quantum chemical calculations and molecular docking studies of 2-ethoxy-4[(2-trifluromethyl-phenylimino)methyl]phenol |
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| Towseef Ahmad Hajam,H. Saleem,M. Syed Ali Padhusha,K. K. Mohammed Ameen | | Molecular Physics. 2020; : 1 | | [Pubmed] | [DOI] | | | 38 |
Synthesis of 2,5-disubstituted-1,3,4-thiadiazole derivatives from (2S)-3-(benzyloxy)-2-[(tert-butoxycarbonyl) amino] propanoic acid and evaluation of anti-microbial activity |
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| Amit A. Pund,Shweta S. Saboo,Gajanan M. Sonawane,Amol C. Dukale,Baban K. Magare | | Synthetic Communications. 2020; : 1 | | [Pubmed] | [DOI] | | | 39 |
Eco-friendly synthesis of isatin-thiazolidine hybrid using graphene oxide catalyst in deep eutectic solvent and further evaluated for antibacterial, anticancer and cytotoxic agents |
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| Md Afroz Bakht | | Sustainable Chemistry and Pharmacy. 2020; 16: 100252 | | [Pubmed] | [DOI] | | | 40 |
Synthesis of potentially new Schiff bases of N-substituted-2-quinolonylacetohydrazides as anti-Covid-19 |
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| Mohammed B Alshammari,Mohamed Ramadan,Ashraf A Aly,Essmat M. El-Sheref,Md Afroz Bakht,Mahmoud A.A. Ibrahim,hmed M. Shawky | | Journal of Molecular Structure. 2020; : 129649 | | [Pubmed] | [DOI] | | | 41 |
Synthesis, characterization, and applications of novel Co(II)-pyridoxal phosphate-Schiff base/SBA-15 as a nanocatalyst for the green synthesis of benzothiazole heterocycles |
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| Hassan Yari,Rahebeh A. Dehkharghani,Ghasem R. Bardajee,Niloufar Akbarzadeh-T | | Journal of the Chinese Chemical Society. 2020; | | [Pubmed] | [DOI] | | | 42 |
Biological Evaluation of Synthesized Schiff Base-Metal Complexes Derived from Sulfisomidine |
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| Amina Mumtaz,Tariq Mahmud,Maryam Khalid,Huma Khan,Aatika Sadia,Malka M. Samra,Muhammad Asim Raza Basra | | Journal of Pharmaceutical Innovation. 2020; | | [Pubmed] | [DOI] | | | 43 |
Synthesis of Symmetrical bis-Schiff base-Disulfide Hybrids as Highly Effective anti-leishmanial Agents |
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| Muhammad Taha,Amyra Amat Sain,Muhammad Ali,El Hassane Anoure,Fazal Rahim,Nor Hadiani Ismail,Mohd Ilham Adenan,Syahrul Imran,Ahmed Al-Harrasi,Fasial Nawaz,Naveed Iqbal,Khalid Mohammed Khan | | Bioorganic Chemistry. 2020; : 103819 | | [Pubmed] | [DOI] | | | 44 |
Synthesis, characterization and antimicrobial activity of a novel chitosan Schiff bases based on heterocyclic moieties |
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| Amira A. Hamed,Ismail A. Abdelhamid,Gamal R. Saad,Nadia A. Elkady,Maher Z. Elsabee | | International Journal of Biological Macromolecules. 2020; | | [Pubmed] | [DOI] | | | 45 |
Spectral elucidation with molecular docking study between isatin analogous and bovine serum albumin |
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| Shilpa R. Patil,Sonali M. Salunkhe,Saubai B. Wakshe,Kshipra S. Karnik,Aniket P. Sarkate,Ajinkya A. Patrawale,Prashant V. Anbhule,Govind B. Kolekar | | Chemical Data Collections. 2019; 22: 100254 | | [Pubmed] | [DOI] | | | 46 |
Stannous chloride catalyzed synthesis of Schiff bases from hydroxybenzaldehydes and determination of their antioxidant activity by ABTS and DPPH assay |
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| Gyanashree Bora,Dipankoj Gogoi,Subhasmita Saikia,Archana Pareek,Jyotirekha G Handique | | Journal of Chemical Sciences. 2019; 131(8) | | [Pubmed] | [DOI] | | | 47 |
Synthesis, spectroscopic characterization, crystal structure, interaction with DNA, CTAB as well as evaluation of biological potency, docking and Molecular Dynamics studies of N-(3,4,5-trimethoxybenzylidene)-2, 3-dimethylbenzenamine |
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| Mehwish Tahir,Muhammad Sirajuddin,Ali Haider,Saqib Ali,Akhtar Nadhman,Corrado Rizzoli | | Journal of Molecular Structure. 2019; 1178: 29 | | [Pubmed] | [DOI] | | | 48 |
Synthesis, experimental and theoretical characterizations of a 1,2,4-triazole Schiff base and its nickel(II) complex |
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| Hamide Raouf,S. Ali Beyramabadi,Sadegh Allameh,Ali Morsali | | Journal of Molecular Structure. 2019; 1179: 779 | | [Pubmed] | [DOI] | | | 49 |
Synthesis and Spectral Studies of Schiff Base Receptor for Fluorescence Detection of Hg(II) |
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| Chinnadurai Anbuselvan | | Asian Journal of Chemistry. 2019; 31(3): 527 | | [Pubmed] | [DOI] | | | 50 |
Protective effects of isatin and its synthetic derivatives against iron, copper and lead toxicity |
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| Hamid Moghimi Benhangi,Sheida Ahmadi,Mohammad Hakimi,Azam Molafilabi,Habibollah Faraji,Baratali Mashkani | | Toxicology in Vitro. 2018; | | [Pubmed] | [DOI] | | | 51 |
Schiff Bases: Multipurpose Pharmacophores with Extensive Biological Applications |
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| Khurram Shahzad Munawar, Shah Muhammad Haroon, Syed Ammar Hussain , Hamid Raza | | Journal of Basic & Applied Sciences. 2018; 14: 217 | | [Pubmed] | [DOI] | | | 52 |
Synthesis, characterization, spectroscopic studies and antimicrobial activity of three new Schiff bases derived from Heterocyclic moiety |
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| Mounira Mesbah,Tahar Douadi,Farida Sahli,Saifi Issaadi,Soraya Boukazoula,Salah Chafaa | | Journal of Molecular Structure. 2018; 1151: 41 | | [Pubmed] | [DOI] | | | 53 |
Synthetic, XRD, non-covalent interactions and solvent dependent nonlinear optical studies of Sulfadiazine-Ortho-Vanillin Schiff base: (E)-4-((2-hydroxy-3-methoxy- benzylidene) amino)- N -(pyrimidin-2-yl)benzene-sulfonamide |
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| Muhammad Shahid,Muhammad Salim,Muhammad Khalid,Muhammad Nawaz Tahir,Muhammad Usman Khan,Ataualpa Albert Carmo Braga | | Journal of Molecular Structure. 2018; 1161: 66 | | [Pubmed] | [DOI] | | | 54 |
Synthesis of t -butyl 2-(4-hydroxy-3-methoxybenzylidene)hydrazine carboxylate: Experimental and theoretical investigations of its properties |
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| Muzzaffar A. Bhat,Shabir H. Lone,Muzzaffar A. Mir,Sheikh A. Majid,Haroon Mohi-ud-din Bhat,Raymond J. Butcher,Sanjay K. Srivastava | | Journal of Molecular Structure. 2018; 1164: 516 | | [Pubmed] | [DOI] | | | 55 |
Molecular docking and dynamics of Nickel-Schiff base complexes for inhibiting ß-lactamase of Mycobacterium tuberculosis |
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| Md. Junaid,Md. Jahangir Alam,Md. Kamal Hossain,Mohammad A. Halim,M. Obayed Ullah | | In Silico Pharmacology. 2018; 6(1) | | [Pubmed] | [DOI] | | | 56 |
Efficient Synthesis, Antimicrobial, Antioxidant Assessments and Geometric Optimization Calculations of Azoles- Incorporating Quinoline Moiety |
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| Wafaa S. Hamama,Mona E. Ibrahim,Ayaa A. Gooda,Hanafi H. Zoorob | | Journal of Heterocyclic Chemistry. 2018; | | [Pubmed] | [DOI] | | | 57 |
DFT and TDDFT investigation of the Schiff base formed by tacrine and saccharin |
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| Nursel Acar,Cenk Selçuki,Emine Coskun | | Journal of Molecular Modeling. 2017; 23(1) | | [Pubmed] | [DOI] | | | 58 |
3,4-Dimethoxybenzohydrazide derivatives as antiulcer: Molecular modeling and density functional studies |
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| Muhammad Taha,Nor Hadiani Ismail,Hamizah Mohd Zaki,Abdul Wadood,El Hassane Anouar,Syahrul Imran,Bohari M. Yamin,Fazal Rahim,Muhammad Ali,Khalid Mohammed Khan | | Bioorganic Chemistry. 2017; 75: 235 | | [Pubmed] | [DOI] | | | 59 |
Macrocyclic Schiff Base Metal Complexes Derived from Isatin: Structural Activity Relationship and DFT Calculations |
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| M. Muthukkumar,R. Rajavel,G. Venkatesh,P. Vennila | | Tenside Surfactants Detergents. 2017; 54(3): 248 | | [Pubmed] | [DOI] | | | 60 |
Synthesis, characterization and biological studies of Schiff bases derived from heterocyclic moiety |
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| Angamaly Antony Shanty,Jessica Elizabeth Philip,Eeettinilkunnathil Jose Sneha,Maliyeckal R. Prathapachandra Kurup,Sreedharannair Balachandran,Puzhavoorparambil Velayudhan Mohanan | | Bioorganic Chemistry. 2016; | | [Pubmed] | [DOI] | | | 61 |
Synthesis, biological activity, DNA binding and anion sensors, molecular structure and quantum chemical studies of a novel bidentate Schiff base derived from 3,5-bis(triflouromethyl)aniline and salicylaldehyde |
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| Mustafa Yildiz,Özge Karpuz,Celal Tugrul Zeyrek,Bahadir Boyacioglu,Hakan Dal,Neslihan Demir,Nuray Yildirim,Hüseyin Ünver | | Journal of Molecular Structure. 2015; 1094: 148 | | [Pubmed] | [DOI] | | | 62 |
Investigation on Effects of Schiff Base Complex to Hydroxyapatite Bioceramics |
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| F. Çaliskan,M. Tuna,S.G. Akça | | Acta Physica Polonica A. 2015; 127(4): 1393 | | [Pubmed] | [DOI] | | | 63 |
Synthesis and spectral, antimicrobial, anion sensing, and DNA binding properties of Schiff base podands and their metal complexes |
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| M. Yildiz,E. Tan,N. Demir,N. Yildirim,H. Ünver,A. Kiraz,B. Mestav | | Russian Journal of General Chemistry. 2015; 85(9): 2149 | | [Pubmed] | [DOI] | | | 64 |
Synthesis of Quinazolinone Based Schiff Bases as Potential Anti-inflammatory and Analgesic Agents |
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| Rashmi Arora,N.S. Gill,Ashish Kapoor | | Journal of Pharmacy and Allied Health Sciences. 2014; 4(1): 15 | | [Pubmed] | [DOI] | | | 65 |
First X-ray structural characterization of isatin Schiff base derivative. NMR and theoretical conformational studies |
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| Pavel Davidovich,Daria Novikova,Vyacheslav Tribulovich,Sergey Smirnov,Vlad Gurzhiy,Gerry Melino,Alexander Garabadzhiu | | Journal of Molecular Structure. 2014; 1075: 450 | | [Pubmed] | [DOI] | | | 66 |
Schiff Bases: A Versatile Pharmacophore |
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| Anu Kajal,Suman Bala,Sunil Kamboj,Neha Sharma,Vipin Saini | | Journal of Catalysts. 2013; 2013: 1 | | [Pubmed] | [DOI] | | | 67 |
Synthesis, spectroscopic characterization and biological activities of N4O2 Schiff base ligand and its metal complexes of Co(II), Ni(II), Cu(II) and Zn(II) |
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| Saud I. Al-Resayes,Mohammad Shakir,Ambreen Abbasi,Kr. Mohammad Yusuf Amin,Abdul Lateef | | Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy. 2012; 93: 86 | | [Pubmed] | [DOI] | | | 68 |
Synthesis, characterization andin vitroantimicrobial evaluation of new compounds incorporating oxindole nucleus |
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| Nadia G. Kandile,Howida T. Zaky,Mansoura I. Mohamed,Hind M. Ismaeel,Nashwa A. Ahmed | | Journal of Enzyme Inhibition and Medicinal Chemistry. 2012; 27(4): 599 | | [Pubmed] | [DOI] | | | 69 |
Biological evaluation of potent antioxidant, lipoxygenase inhibitor and antibacterial: A comparative study |
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| Muhammad Aslam,Itrat Anis,Nighat Afza,Lubna Iqbal,Samina Iqbal,Ajaz Hussain,Rashad Mehmood,Muhammad Tahir Hussain,Muhammad Khalid,Haq Nawaz | | Journal of Saudi Chemical Society. 2012; | | [Pubmed] | [DOI] | | | 70 |
Synthesis, spectroscopic characterization and biological activities of N 4O 2 Schiff base ligand and its metal complexes of Co(II), Ni(II), Cu(II) and Zn(II) |
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| Al-Resayes SI, Shakir M, Abbasi A, Amin KM, Lateef A. | | Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy. 2012; 93: 86-94 | | [Pubmed] | | | 71 |
In vivo anticancer activity of vanillin semicarbazone |
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| Shaikh M Mohsin Ali*, M Abul Kalam Azad, Mele Jesmin, Shamim Ahsan, M Mijanur Rahman, Jahan Ara Khanam, M Nazrul Islam, Sha M Shahan Shahriar | | Asian Pacific Journal of Tropical Biomedicine. 2012; : 1-5 | | [Pubmed] | | | 72 |
Synthesis, characterization and in vitro antimicrobial evaluation of new compounds incorporating oxindole nucleus |
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| Kandile NG, Zaky HT, Mohamed MI, Ismaeel HM, Ahmed NA. | | Journal of Enzyme Inhibition and Medicinal Chemistry. 2012; 27(4): 599-608 | | [Pubmed] | | | 73 |
In vivo anticancer activities of Benzophenone semicarbazone against Ehrlich Ascites Carcinoma cells in Swiss albino mice |
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| Islam K, Ali SM, Jesmin M, Khanam JA. | | Cancer Biology and Medicine. 2012; 9(4): 242-247 | | [Pubmed] | | | 74 |
Design, synthesis, and antimicrobial screening of novel pyridyl-2-amidrazone incorporated isatin mannich bases |
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| N Saravana Kumar, T Pradeep, G Jani, Divya Silpa, B Vijaya Kumar | | J Adv Pharm Tech Res. 2012; 3(1): 57-61 | | [Pubmed] | | | 75 |
1.Synthesis, characterization and in vitro antimicrobial evaluation of new compounds incorporating oxindole nucleus |
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| Nadia G. Kandile, Howida T. Zaky, Mansoura I. Mohamed, Hind M. Ismaeel, and Nashwa A. Ahmed | | Journal of Enzyme Inhibition and Medicinal Chemistry. 2011; : 1-10 | | [Pubmed] | |
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