SYNTHESIS AND EVALUATION OF NOVEL THIOSEMICARBAZONE DERIVATIVES AS ANTICANCER AGENTS
HTML Full TextSYNTHESIS AND EVALUATION OF NOVEL THIOSEMICARBAZONE DERIVATIVES AS ANTICANCER AGENTS
Niharika Gokhale 1* and Sanjay Jain 2
Department of Pharmaceutical Sciences, Gyan vihar University 1, Jaipur Rajasthan, India
Smriti College of Pharmaceutical Education 2, Indore Madhya Pradesh, India
ABSTRACT: Thiosemicarbazobes are the compounds that possess wide range of biological activities. Presently the areas in which thiosemicarbazones receiving more attention is its use against cancer. Reports from the SAR studies confirms that the thiosemicarbazones with heterocyclic moiety shows carcinogenic potency. These are potent ribonucleotide reductase inhibitor. Adamantyl derivatives is also having interesting biological properties and most promising towards anticancer activity. The value of adamantyl group in drug design is multidimensional. A novel series of compounds of thiosemicarbazones were prepared by conjugating adamantyl group and using aromatic substitution. The various substitutions on thiosemicarbazones were reported as anti cancer activity and adamantyl group also show antiproliferative activity against some cell lines, so in present work 20 compounds were prepared on the basis of best results of QSAR studies and they were screened for anticancer activity using cell line studies. The results were compared with standard drug doxorubicin, 3 compounds show more inhibitory action than standard drug.
Keywords: |
Adamantyl, Thiosemicarbazones
Antiproliferative, Ribonucleotide Reductase.
INTRODUCTION: The cancer is one of the leading cause of deaths worldwide, in developing countries it is second leading cause of death while in developed countries it is leading cause of death. Till 2030 one among eight peoples of world will suffer from this disease1. The cancerous cells have property to proliferate uncontrollably and defensive apoptosis due to inactivation of tumor suppressive genes. The cells of cancer also invade easily and ability to metastasize in normal tissues 2-3. Cancer is a complex disease with various genetic and epigenetic alterations. The all alteration also having much difference which is a challenge for synthesizing new analogues as anticancer agent 4. Thiosemicarbazones is rapidly investigated compounds with different pharmacological actions 5. The fused thiosemicarbazones show potential anticancer effects.
The groups like benzopyridine, acetyl pyridine, metals like palladium, platinum and nickel when fused with thiosemicarbazone then they show cytotoxic activity against various solid cell tumors 6-9.
The substitution of adamantane and its derivative have been known for antiviral effect 10-14, anti microbial effect 15-18 and as anti inflammatory agent 17-21. Substitution on thiopyrimidine, caboxamide and acetamide 22-24 shows potential cytotoxic effects.
So in the present work a novel series of compounds of thiosemicarbazones were prepared by conjugating Adamantyl Group and using aromatic Substitution.
Experimental work:
Synthesis of Compounds:
For synthesis of aromatic/heterocyclic substituted thiosemicarbazone derivatives two step reaction was performed. Amantadine (0.01 mol), ethanolic solution of potassium hydroxide (1.68 gm 0.03 mol) were mixed together. The mixture was cooled below 10oC and Carbon disulphide (1.8mL, 0.03mol) was added gradually with constant stirring d till CS2 had completely dissolved. After standing for overnight, thioglycolic acid was obtained. It was shaked with a solution of sodium chloroacetate (1.0 mol) followed by hydrazine hydrate (5 ml, 100%) and was refluxed for two hours with continuous strirring. The filtrate was concentrated to half its initial volume and allowed to stand overnight, at 0oC. Dry ether (20mL) was added and the yellow ppt. was filtered, washed with ether and dried and recrystallized from ethanol. (Compound 1)
Scheme:
A mixture of carboxaldehyde (0.5mmol), thiosemicarbazide (0.55mmol) andconc. sulfuric acid (0.4mL) in 5mL of ethanol was heated under reflux for 4 h. The mixture was then cooled to room temperature, filtered and rinsed with cold solution of 50 % aqueous ethanol and diethyl ether respectively. By this scheme Compounds 2 Tsc-1 to Tsc-20 were prepared. (Table 1)
AR-AROMATIC/HETEROCYCLIC SUBSTITUTIONS
Characterization of Synthesized Compounds:
General:
After synthesizing the different compounds, they were lyophilized and their % yields were calculated. The Melting points of all Compounds were determined by the capillary method using Melting Point Apparatus (Lab-Hosp, Mumbai). Triplicate observations were recorded for melting range determination.
NMR Analysis:
1H NMR and C13 NMR spectra of all synthesized were recorded on Bruker (400 MHz) spectrometer. The samples were dissolved and measured in DMSO. Chemical shifts are reported as δ (ppm) relative to Tetramethylsilane [TMS] as a standard. Various shifts in the peaks were interpreted for different groups present in conjugated system.
ESI MASS Spectoroscopy:
The electrospray mass spectra were recorded on a MICROMASS QUATTRO II triple mass spectrometer. The samples (dissolved in suitable solvents such as methanol/acetonitrile/DMSO) were introduced into ESI source through a syringe pump at the rate of 5μl/min. The ESI capillary was set at 3.5 KV and the cone voltage was 40 V. The spectra were collected in 6S scans and print outs are averaged spectra of 6-8 scans. Spectra recorded at high mass units are computerized decovoluted.
Elemental Analysis:
The elemental analysis of Carbon, Hydrogen and other elements were performed by CHNS/O Elemental Analyzer (Perkin Elmer PE 2400). This analyzer was used for knowing concentration of C, H, N, S and O in newly synthesized compounds.
Cytotoxic Assay:
Cytotoxicity was evaluated by the 3-(4,5-dimethyl-2-thiazolyl)- 2,5-diphenyl-2H-tetrazolium bromide (MTT) assay which measures the cellular metabolic viability24. The cells were cultured in 96-well plates and, 12 h after incubation, they were treated with different concentrations of test compounds.
Another group of cells was treated with the same concentrations of Doxorubicin as a standard drug. Compounds were previously dissolved in DMSO and the final concentrations were adjusted, through an 8-fold serial dilution, in DMEM in such manner that the final DMSO concentration was lower than 0.5%. After 48 h-treatment the cells were incubated with MTT (0.5 mg ml-1), and formazan crystals were solubilised in DMSO Absorbance was measured in a microplate reader at 570 nm.
Tests using DMSO (0.5% in DMEM) as negative control were carried out in parallel. IC50 values were calculated as the concentration of compound that induced 50% of cytotoxicity. Data were presented as average ± standard deviation. All experiments were carried out in quadruplicates and repeated in at least three independent experiments with full agreement between the results. The statistical significance was assessed using Student’s t-test (p <0.05).
RESULTS AND DISCUSSION:
The prepared compounds were characterized for Melting point, different spectral analysis, and elemental analysis and In- Vitro Cell line studies.
General:
The melting point of different compounds with their molecular weight, Molecular formula and % yield was given in Table 2.
NMR, ESI Mass Spectroscopy and elemental analysis:
The data for 1 H NMR, 13 C NMR, ESI mass and elemental analysis were represented for different compounds as follows.
- (Tsc-1) 1-(adamantan-1-yl)-3-[(E)-(1H-indol-3-ylmethylidene) amino] thiourea 1H NMR (DMSO- d6 , 400MHz): δ66-1.74(t, 6H, Adamantane-H), 2.13(s, 3H, Adamantane-H), 2.35 (s, 6H, Adamantane-H), 8.05(s, 1H, CH=N), 8.13(s,1H, NH),11.32 (s,1H, CS-NH), 9.84 (s,1H,NH-Indole),7.18 (s,1H,CH,Indole), 7.41(s,2H, Ar-CH), 7.47 (s,2H,Ar-CH) 13C NMR: δ 147.19 (C=N), 177.52(C=S), 28.5, 36.4, 39.8, 43.2 (Adamantane-C), 111.5 (Indole-C), 102.5, 119.3, 120.8, 124.7, 127.5, 135.5 (Ar-C). ESI-MS m/z: 353 (M+ +1) Anal. Calcd for C20H24N4S: C, 68.14; H, 6.86; N, 15.89. S, 9.08 Found: C, 68.12; H, 6.56; N, 15.34; S, 9.24
- (Tsc-2)1-(adamantan-1-yl)-3-[(E)-(1H-1,3-benzoimidazol-2 yl methylidene) amino] thiourea 1H NMR (DMSO- d6 , 400MHz): δ66 (s, 6H, Adamantane-H), 2.08-2.21 (m, 9H, Adamantane-H), 8.02 (s, 1H, CH=N), 8.23(s,1H, NH),11.30 (s,1H, CS-NH), 9.84 (s,1H,NH-Indole),7.8 (s,1H,Imidazole), 7.5-7.98 (m,8H, Ar-CH). 13C NMR: δ 148.21 (C=N), 176.82 (C=S), 29.53, 37.41, 38.51, 40.53 (Adamantane-C), 121.12, 122.43, 123.90, 126.85, 130.56 (Ar-C). ESI-MS m/z: 355 (M+ +2). Anal. Calcd for C19H23N5S: C, 64.56; H, 6.56; N, 19.81. S, 9.07 Found: C, 65.12; H, 6.48; N, 18.34; S, 9.04
- (Tsc-3) 3-(adamantan - 1-yl) – 1 - [(E)-{[3-(naphthalen-2-yl) phenyl] methylidene} amino] thiourea: 1H NMR (DMSO- d6, 400MHz): δ62-1.84 (m, 6H, Adamantane-H), 1.91 -2.06 (m, 9H, Adamantane-H), 8.04 (s, 1H, CH=N), 8.34 (s, 1H, NH), 11.53 (s, 1H, CS-NH), 6.98-8.63 (m, 11H, Ar-CH). 13C NMR: δ 150.63 (C=N), 178.65 (C=S), 27.42, 33.62, 34.91, 38.02 (Adamantane-C), 126.26, 128.13, 130.31, 131.34, 134.35, 135.32 (Ar-C). ESI-MS m/z: 440 (M+ +1) Anal. Calcd for C28H29N3S: C, 76.42; H, 6.66; N, 9.55. S, 7.30 Found: C, 76.35; H, 6.74; N, 8.68. S, 8.98.
- (Tsc-4)1-(adamantan-1-yl) – 3 - [(E) - ({5-[3-(hydroxynitroso) phenyl] furan - 2 yl} methylidene) amino] thiourea: 1H NMR (DMSO- d6 , 400MHz): δ68-1.86 (m, 6H, Adamantane-H), 2.06-2.23 (m, 9H, Adamantane-H), 8.23 (s, 1H, CH=N), 7.93 (s,1H, NH),11.63 (s,1H, CS-NH), 6.68 (s,1H, Furan-CH),7.04-7.15(m,4H, Ar-CH) 13C NMR: δ 146.53 (C=N), 174.32 (C=S), 28.58, 37.36, 38.54, 32.33 (Adamantane-C), 126.26, 128.13, 130.31, 131.14, 134.25, 135.82, 144.34 (Ar-C). ESI-MS m/z: 426 (M+ +2) Anal. Calcd for C22H24N4O3S: C, 62.34; H, 5.60; N, 13.10. S, 7.55 Found: C, 63.15; H, 6.04; N, 12.46. S, 7.72
- (Tsc-5)1-(adamantan-1-yl)-3-[ (E) - {[2- (3-nitrophenyl)imidazo[1,2-a] pyridin-3-yl] methylidene} amino] thiourea: 1H NMR (DMSO- d6, 400MHz): δ84-1.99 (m, 6H, Adamantane-H), 2.13-2.27 (m, 9H, Adamantane-H), 8.34 (s, 1H, CH=N), 7.52 (s, 1H, NH), 11.82 (s, 1H, CS-NH), 6.90-8.30 (m, 8H, Ar-CH) 13C NMR: δ 148.21 (C=N), 178.22 (C=S), 29.24, 36.42, 40.52, 42.34 (Adamantane-C), 112.35, 122.29, 126.64, 128.43, 141.28, 145.32, 148.28 (Ar-C). ESI-MS m/z: 475 (M+ +1) Anal. Calcd for C25H26N6O2S: C, 63.24; H, 5.32; N, 17.62. S, 6.73 Found: C, 62.35; H, 6.18; N, 16.32. S, 6.72
- (Tsc-6) 3 - (adamantan-1-yl) - 1 -[(E)-[(2,4,5 trimethoxyphenyl) methylidene ]amino] thiourea: 1H NMR (DMSO- d6 , 400MHz): δ68-1.88 (m, 6H, Adamantane-H), 1.98-2.10 (m, 9H, Adamantane-H), 8.18 (s, 1H, CH=N), 7.53 (s,1H, NH),11.38 (s,1H, CS-NH), 6.98 (s,2H, Ar-CH), 3.62 (s,3H,OCH3), 3.72 (s,6H,OCH3) 13C NMR: δ 146.09 (C=N), 178.60 (C=S), 27.61, 34.23, 35.24, 38, 98 (Adamantane-C), 98.47, 110.39, 112.46, 120.21, 122.26 (Ar-C), 55.32, 54.43, 56.18 (Methoxy-C) ESI-MS m/z: 404 (M+ +1) Anal. Calcd for C21H29N3O3S: C, 62.51; H, 7.24; N, 10.41. S, 7.95 Found: C, 62.48; H, 6.39; N, 9.38. S, 7.98
- (Tsc-7) 3 - [(E)-{[(4S)-4- (acetylsulfanyl)-2-formylpyrazolidin-1-yl] methylidene} amino]-1-(adamantan-1-yl) thiourea: 1H NMR (DMSO- d6 , 400MHz): δ78 (s, 6H, Adamantane-H), 2.08 (s, 9H, Adamantane-H), 8.29 (s, 1H, CH=N), 7.50 (s,1H, NH),10.82 (s,1H, CS-NH), 4.26-4.52 (m,4H, pyrazolidine-CH), 3.08 (s,3H,OCH3), 8.82 (s,1H,CHO) 13C NMR: δ 143.60 (C=N), 179.50 (C=S), 28.60, 33.24, 35.24, 39, 98 (Adamantane-C), 60.82, 62.36, 57.43 (Pyrazolidine-C), 45.34 (Alkyl-C), 168.41 (N-C=0), 184.32(S-C=O) ESI-MS m/z: 410 (M+ +1) Anal. Calcd for C18H27N5O2S2: C, 52.79; H, 6.64; N, 17.10. S, 15.66 Found: C, 52.68; H, 6.75; N, 17.48. S, 14.64.
- (Tsc-8) 3-(adamantan-1-yl)-1-[(E)-{[3,4-bis(benzyloxy)phenyl]methylidene}amino]thiourea: 1H NMR (DMSO- d6 , 400MHz): δ62-2.13 (m, 15H, Adamantane-H), 8.42 (s, 1H, CH=N), 7.52 (s,1H, NH),11.32 (s,1H, CS-NH), 4.23-4.26 (m,4H,O-CH2),7.23-7.48 (m,6H, Ar-CH), 7.54-7.62 (m,7H, Ar-CH) 13C NMR: δ 144.25 (C=N), 175.69 (C=S), 28.63, 32.98, 36.18, 42.29 (Adamantane-C), 62.32 (CH2), 111.82, 120.97,1 27.65, 128.86, 132.43, 136.57, 143.64, 146.32, 148.53 (Ar-CH) ESI-MS m/z: 527 (M+ +2) Anal. Calcd for C32H35N3O2S: C, 73.10; H, 6.72; N, 7.96. S, 6.16 Found: C, 75.10; H, 6.85; N, 6.98. S, 6.58.
- (Tsc-9)3-(adamantan-1-yl)-1-[(E)-{[3-(3-hydroxyphenyl) phenyl]methylidene}amino] thiourea 1H NMR (DMSO- d6, 400MHz): δ72 (s, 6H, Adamantane-H), 2.16 (s, 9H, Adamantane-H), 8.34 (s, 1H, CH=N), 7.35 (s, 1H, NH), 11.33 (s, 1H, CS-NH), 7.40-7.58 (m, 8H, Ar-CH), 4.78 (s, 1H, OH) 13C NMR: δ 141.25 (C=N), 177.62 (C=S), 26.23, 31.82, 34.24, 40.30 (Adamantane-C), 126.35, 128.23, 130.37, 132.43, 148.74, 151.94 (Ar-CH) ESI-MS m/z: 405 (M+), Anal. Calcd for C24H27N3OS: C, 71.05; H, 6.71; N, 10.32. S, 7.92. Found: C, 70.14; H, 6.92; N, 10.58. S, 6.98.
- (Tsc-10) 3 - (adamantan-1-yl) – 1 - [(E)-({4-[(4fluorophenyl) methoxy] phenyl} methylidene) amino] thiourea: 1H NMR (DMSO- d6, 400MHz): δ76 (s, 6H, Adamantane-H), 2.08 (s, 9H, Adamantane-H), 9.32 (s, 1H, CH=N), 7.46 (s, 1H, NH), 11.72 (s, 1H, CS-NH), 6.23 (d, 2H, CH2), 7.58-7.70 (m, 8H, Ar-CH). 13C NMR: δ 136.82 (C=N), 178.54 (C=S), 27.44, 32.58, 34.34, 39.45 (Adamantane-C), 64.42(O-CH2), 114.58, 115.76, 124.28, 131.52, 133.49, 136.57, 138.49, 162.54 (Ar-CH) ESI-MS m/z: 438 (M+ +1) Anal. Calcd for C25H28 FN3OS: C, 68.64; H, 6.44; N, 9.62. S, 7.34. Found: C, 70.37; H, 6.52; N, 10.13. S, 7.18
- Tsc-11) 3-(adamantan-1-yl)-1-[(E)-[(2-amino-6-bromo - 4 - oxo- 4H -chromen-3-yl) methylidene] amino] thiourea 1H NMR (DMSO- d6, 400MHz): δ58-2.13 (m, 15H, Adamantane-H), 9.28 (s, 1H, CH=N), 7.28 (s, 1H, NH), 11.80 (s, 1H, CS-NH), 8.94 (s, 2H, NH2), 7.64-7.82 (m, 3H, Ar-CH). 13C NMR: δ 134.92 (C=N), 177.98 (C=S), 24.68, 26.58, 29.82, 36.48 (Adamantane-C), 64.42(O-CH2), 98.55, 117.28, 124.35, 126.13, 152.53, 154.65 (Chromyl-CH) ESI-MS m/z: 477 (M+ +2) Anal. Calcd for C21H23 BrN4O2S: C, 53.06; H, 4.86; N, 11.72. S, 6.76. Found: C, 55.06; H, 4.96; N, 11.76. S, 6.89.
- Tsc-12) 1-(adamantan – 1 - yl) -3-[(E)-{8-oxatricyclo [7.4.0.0 {2, 7}] trideca-1(13), 2, 4, 6, 9, 11-hexaen-4-ylmethylidene} amino] thiourea 1H NMR (DMSO- d6, 400MHz): δ68 (s, 6H, Adamantane-H), 2.14 (s, 9H, Adamantane-H), 9.32 (s, 1H, CH=N), 7.38 (s, 1H, NH), 11.52 (s, 1H, CS-NH), 8.94 (s, 2H, NH2), 7.42-7.80 (m, 7H, Ar-CH). 13C NMR: δ 140.23 (C=N), 177.54 (C=S), 29.32, 32.45, 40.36, 41.42 (Adamantane-C), 98.75, 110.87, 121.57, 123.45, 132.61, 134.87, 136.93, 140.22, 143.28 (Aryl & Furan CH) ESI-MS m/z: 404 (M+ +1) Anal. Calcd for C24H25 N3OS: C, 71.44; H, 6.28; N, 10.42. S, 7.92. Found: C, 70.89; H, 7.34; N, 10.58. S, 7.95.
- (Tsc-13) 1-(adamantan-1-yl)-3-[(E)-{[5-(dimethylamino) furan-2-yl] methylidene} amino] thiourea 1H NMR (DMSO- d6, 400MHz): δ63-2.02 (m, 15H, Adamantane-H), 8.92 (s, 1H, CH=N), 7.29 (s, 1H, NH), 11.32 (s, 1H, CS-NH), 6.82 (s, 1H, Furan-H), 7.23 (s, 1H, Furan-H), 2.54 (m, 6H, CH3). 13C NMR: δ 138.56 (C=N), 178.24 (C=S), 30.23, 32.45, 34.36, 35.42 (Adamantane-C), 105.07, 111.31, 141.82, 145.68 (Furan CH), 38.4 (N-CH3) ESI-MS m/z: 347 (M+ +1) Anal. Calcd for C18H26 N4OS: C, 62.49; H, 7.56; N, 16.17. S, 9.25. Found: C, 61.87; H, 6.96; N, 16.87. S, 8.75.
- (Tsc-14) 3 - (adamantan-1-yl) – 1 - [(E)-{[3-cyano-4-(dimethylamino)-2-fluorophenyl] methylidene} amino] thiourea 1H NMR (DMSO- d6, 400MHz): δ63-1.82 (m, 6H, Adamantane-H),1.95- 2.34 (m, 9H, Adamantane-H), 9.02 (s, 1H, CH=N), 7.28 (s, 1H, NH), 11.45 (s, 1H, CS-NH), 3.52- 4.02 (m, 6H, CH3), 7.92 (s, 2H, Ar-CH). 13C NMR: δ 148.54 (C=N), 174.25 (C=S), 28.32, 31.46, 32.32, 34.42 (Adamantane-C), 40.80 (N-CH3) 98.75, 115.87(CN)89.43,96.28,110.26,113.48 (Aryl CH ) ESI-MS m/z: 400 (M+ +1) Anal. Calcd for C21H26 FN5S: C, 63.04; H, 6.56; N, 17.52. S, 8.03. Found: C, 63.18; H, 7.06; N, 17.98. S, 9.83.
- (Tsc-15) 3 - (adamantan-1-yl) - 1-[(E)-[(2-chloro-6-methylquinolin-3-yl) methylidene] amino] thiourea 1H NMR (DMSO- d6, 400MHz): δ56-1.78 (m, 6H, Adamantane-H),1.94- 2.32 (m, 9H, Adamantane-H), 8.43 (s, 1H, CH=N), 7.42 (s, 1H, NH), 11.23 (s, 1H, CS-NH), 2.42 (s, 3H, CH3), 8.52-9.62 (m, 4H, Ar-CH). 13C NMR: δ 146.43 (C=N), 172.38 (C=S), 30.23, 36.59, 40.24, 41.32 (Adamantane-C), 20.48 (CH3) 118.23, 122.12, 124.28, 126.31, 128.18, 132.57, 142.76, 151.63 (Aryl CH) ESI-MS m/z: 412 (M+) Anal. Calcd for C22H25 ClN4S: C, 63.94; H, 6.12; N, 13.72. S, 7.76. Found: C, 64.18; H, 7.01; N, 13.12. S, 7.08
- (Tsc-16) 3-(adamantan-1-yl)-1-[(E)-[(2-chloro-6-methylquinolin-3-yl) methylidene] amino] thiourea 1H NMR (DMSO- d6, 400MHz): δ71-2.01 (m, 6H, Adamantane-H), 2.12- 2.41 (m, 9H, Adamantane-H), 9.10 (s, 1H, CH=N), 7.49 (s, 1H, NH), 11.26 (s, 1H, CS-NH), 7.52-8.83 (m, 6H, Ar-CH). 13C NMR: δ 148.25 (C=N), 176.88 (C=S), 30.34, 32.36, 34.42, 41.08 (Adamantane-C), 119.56, 120.87, 121.52, 128.72, 130.65, 131.72, 144.81 (Aryl CH) ESI-MS m/z: 366 (M+ +2) Anal. Calcd for C21H24 N4S: C, 69.25; H, 6.64; N, 15.37. S, 8.86. Found: C, 67.97; H, 6.85; N, 14.65. S, 8.64
- (Tsc-17) 1 - (adamantan-1-yl) – 3 - [(E)-[(1-methyl-1H-imidazol – 2 - yl) methylidene] amino] thiourea 1H NMR (DMSO- d6, 400MHz): δ72-2.03 (m, 15H, Adamantane-H), 8.83 (s, 1H, CH=N), 7.64 (s, 1H, NH), 11.53 (s, 1H, CS-NH), 3.48(s, 3H, CH3) 6.84-7.16 (m, 2H, Ar-CH). 13C NMR: δ 143.36 (C=N), 174.25 (C=S), 30.07, 32.48, 34.36, 40.14 (Adamantane-C), 32.32(CH3) 120.43, 130.26, 132.47 (Imidazole CH) ESI-MS m/z: 318 (M+ +1) Anal. Calcd for C16H23 N5S: C, 60.53; H, 7.37; N, 22.05. S, 10.13. Found C, 60.38; H, 7.58; N, 22.87. S, 9.98
- (Tsc-18) 3 - (adamantan -1-yl) – 1 - [(E)-{[(2R,4R)- 2 – bromopiperidin - 4 - yl] methylidene} amino] thiourea 1H NMR (DMSO- d6, 400MHz): δ71 (s, 6H, Adamantane-H), 2.21 (s, 9H, Adamantane-H), 8.26 (s, 1H, CH=N), 7.42 (s, 1H, NH), 11.53 (s, 1H, CS-NH), 1.93(s, 1H, NH- Piperidine) 1.42-1.86 (m, 8H, Piperidine). 13C NMR: δ 144.35 (C=N), 175.23 (C=S), 28.46, 29.54, 30.88, 34.69 (Adamantane-C), 21.56, 23.56, 24.58, 26.76, 27.89 (Aryl CH) ESI-MS m/z: 400 (M+ +1) Anal. Calcd for C17H27 Br N4S: C, 51.13; H, 6.83; N, 14.06. S, 8.04. Found: C, 51.26; H, 6.97; N, 15.86. S, 8.57
- (Tsc-19) 1-(adamantan-1-yl) – 3 - [(E)-[(4-bromothiophen-2-yl) methylidene] amino] thiourea 1H NMR (DMSO- d6, 400MHz): δ69-1.78 (m, 6H, Adamantane-H), 1.86- 2.02 (m, 9H, Adamantane-H), 8.43 (s, 1H, CH=N), 7.68 (s, 1H, NH), 11.62 (s, 1H, CS-NH), 6.88 (s, 2H, Thiophene). 13C NMR: δ 146.43 (C=N), 174.64 (C=S), 30.53, 32.34, 34.58, 41.08 (Adamantane-C), 113.43, 122.53, 124.63, 128.53 (Thiophene CH) ESI-MS m/z: 399 (M+ +1) Anal. Calcd for C16H20 Br N3S2: C, 48.24; H, 5.06; N, 10.57. S, 16.17. Found: C, 48.78; H, 5.76; N, 10.43; S, 15.23
- (Tsc-20) 1-(adamantan-1-yl)-3-[(E)-[(3,5-dimethyl - 1,2-oxazol – 4 - yl) methylidene] amino] thiourea: 1H NMR (DMSO- d6, 400MHz): δ63-1.84 (m, 6H, Adamantane-H), 1.92 (s, 9H, Adamantane-H), 8.23 (s, 1H, CH=N), 7.32 (s, 1H, NH), 11.38 (s, 1H, CS-NH), 2.08 (s, 6H, CH3) . 13C NMR: δ 146.25 (C=N), 172.98 (C=S), 29.43, 30.68, 31.42, 34.32 (Adamantane-C), 156.36 (CH3), 100.46, 130.61, 146.34 (Oxazole C) ESI-MS m/z: 333 (M+ +1) Anal. Calcd for C17H24 N4 OS: C, 64.41; H, 7.28; N, 16.83; S, 9.64. Found: C, 63.48; H, 7.43; N, 15.88; S, 9.43.
Cytotoxic Studies:
The % cell inhibitions of different compounds were estimated by MTT assay. The IC50 values of different batches were represented in table no 3-4. (Tsc- 1 to Tsc-10 in table 3 and Tsc- 11 to Tsc 20 in Table 4). The values were compared with standard drug doxorubicin and R2 values were calculated. It was found that Amongst all the tested compounds Tsc-1, Tsc-2, Tsc-5, Tsc-7, Tsc-11, Tsc-12, Tsc-15, Tsc-16 and Tsc-18 gives highest potential effect on MCF-7 cell lines. Same ways compounds Tsc-3, Tsc-4, Tsc-13, Tsc-17 and Tsc-19 has comparable activity with Std. drug Doxorubicin as IC50 values were almost same. While IC50 values of Tsc-6, Tsc-8, Tsc-9, Tsc-10, Tsc-14 and Tsc-20 has less effective as compare to std. drug.
TABLE 1: HETEROCYCLIC SUBSTITUTION WITH THEIR CODE
TABLE 2: GENERAL PROPERTIES OF SYNTHESIZED COMPOUNDS
TABLE 3: % CELL GROWTH INHIBITION OF TEST COMPOUNDS ON MCF-7 CELL LINE.
Conc.
µM/ml |
Log conc. | % Cell Inhibition | ||||||||||
Tsc-1 | Tsc -2 | Tsc -3 | Tsc -4 | Tsc -5 | Tsc -6 | Tsc -7 | Tsc -8 | Tsc -9 | Tsc -10 | Std. Doxorubicin | ||
0.01 | -2.29 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 5.03 |
0.02 | -1.82 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | -4.06 | 0.00 | 11.25 |
0.05 | -1.34 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | -9.26 | -5.08 | 15.26 |
0.14 | -0.86 | 0.00 | 18.00 | 10.10 | 5.23 | 12.82 | 00.00 | 08.09 | 0.00 | -9.26 | -3.18 | 20.31 |
0.41 | -0.39 | 0.00 | 30.00 | 15.26 | 7.34 | 19.53 | 11.44 | 10.97 | 2.23 | 5.00 | 5.00 | 27.46 |
1.23 | 0.09 | 42.83 | 58.56 | 20.64 | 15.27 | 27.82 | 16.35 | 23.34 | 7.44 | 6.26 | 6.00 | 36.17 |
3.70 | 0.57 | 72.70 | 62.37 | 32.83 | 38.22 | 35.36 | 20.58 | 46.41 | 20.10 | 5.00 | 11.58 | 40.87 |
11.11 | 1.05 | 85.92 | 80.32 | 48.70 | 42.44 | 45.15 | 33.52 | 58.36 | 22.66 | 60.06 | 56.12 | 49.03 |
33.33 | 1.52 | 90.16 | 70.38 | 56.84 | 54.18 | 58.72 | 48.61 | 64.74 | 24.33 | 83.76 | 63.36 | 61.52 |
100.00 | 2.00 | 70.64 | 90.64 | 68.92 | 68.12 | 60.38 | 55.47 | 72.48 | 46.01 | 56.31 | 69.56 | 78.24 |
IC50 (µM/ml) | 1.463 | 1.317 | 3.499 | 3.203 | 1.337 | 4.532 | 2.354 | 5.629 | 5.889 | 6.673 | 3.710 | |
R2 | 0.949 | 0.920 | 0.984 | 0.985 | 0.980 | 0.975 | 0.995 | 0.930 | 0.836 | 0.985 | 0.919 |
TABLE 4: % CELL GROWTH INHIBITION OF TEST COMPOUNDS ON MCF-7 CELL LINE
Conc.
µM/ml |
Log conc. | % Cell Inhibition | ||||||||||
Tsc -11 | Tsc -12 | Tsc -13 | Tsc -14 | Tsc -15 | Tsc -16 | Tsc -17 | Tsc -18 | Tsc -19 | Tsc -20 | Std. Doxorubicin | ||
0.01 | -2.29 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 5.03 |
0.02 | -1.82 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 11.25 |
0.05 | -1.34 | -10.10 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | -7.62 | -5.00 | 0.00 | -2.62 | 15.26 |
0.14 | -0.86 | 14.62 | 0.00 | 4.18 | 0.00 | 0.00 | 0.00 | 5.34 | 10.89 | 5.28 | 6.29 | 20.31 |
0.41 | -0.39 | 29.65 | 15.97 | 6.88 | 0.00 | 0.00 | 18.54 | 5.90 | 18.09 | 5.98 | 7.49 | 27.46 |
1.23 | 0.09 | 34.43 | 29.65 | 13.74 | 18.08 | 29.49 | 23.38 | 12.21 | 28.08 | 13.34 | 15.32 | 36.17 |
3.70 | 0.57 | 48.33 | 35.38 | 28.52 | 36.38 | 39.71 | 38.67 | 25.53 | 48.65 | 27.34 | 34.21 | 40.87 |
11.11 | 1.05 | 58.56 | 42.36 | 47.34 | 67.76 | 45.35 | 46.45 | 48.65 | 55.76 | 49.58 | 46.38 | 49.03 |
33.33 | 1.52 | 65.21 | 64.68 | 55.21 | 90.69 | 56.08 | 66.83 | 52.45 | 58.85 | 54.31 | 58.90 | 61.52 |
100.00 | 2.00 | 72.45 | 70.31 | 69.03 | 62.59 | 68.63 | 70.39 | 58.43 | 65.86 | 70.43 | 69.91 | 78.24 |
IC50 (µM/ml) | 1.289 | 2.562 | 3.452 | 4.452 | 2.889 | 2.684 | 3.826 | 1.262 | 3.471 | 4.137 | 3.710 | |
R2 | 0.964 | 0.968 | 0.994 | 0.929 | 0.963 | 0.977 | 0.980 | 0.986 | 0.991 | 0.993 | 0.9197 |
CONCLUSION: In present work, 20 compounds of thiosemicarbazones were synthesized by conjugating Admantyl Group and using aromatic Substitution. The synthesized compounds were characterized on basis of Melting point, 1H- NMR, 13C NMR, ESI- mass and elemental analysis. The results of cytotoxic assay prove that some compounds shows more effective than standard drug. So this fusion of thiosemicarbazones with adamantyl group may be used further for synthesizing new anticancer compounds.
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How to cite this article:
Gokhale N and Jain S: Synthesis and Evaluation of Novel Thiosemicarbazone Derivatives as Anticancer Agents. Int J Pharm Sci Res 2015; 6(4): 1792-04.doi: 10.13040/IJPSR.0975-8232.6(4).1792-04.
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Article Information
58
1792-1804
586
1333
English
Ijpsr
Niharika Gokhale * and Sanjay Jain
Department of Pharmaceutical Sciences, Gyan vihar University, Jaipur Rajasthan, India
niharikasubhedar@gmail.com
28 August, 2014
16 February, 2015
25 March, 2015
10.13040/IJPSR.0975-8232.6(4).1792-04
01 April, 2015