INTRODUCTION:

Thiohydantoins are sulfur analogs of hydantoins with one or both carbonyl groups replaced by thiocarbonyl groups.¹ Due to the presence of the nucleophilic carbon atom at position 5 of the thiohydantoin ring, various substituents can be introduced at this position.Among the known thiohydantoins, 2-thiohydantoins are the most notably known due to their wide applications as anticarcinogenic,² antimutagenic,³antithyroidal,⁴ antiviral (e.g., against herpes simplex virus, HSV),⁵human immunodeficiency virus (HIV),⁶ tuberculosis,⁷ antimicrobial, (antifungal and antibacterial),⁸ anti-ulcer and anti-inflammatory agents.⁹Gauthier et al. have reported new series of (±) 3, 5-diaryl-2-thioimidazolidin-4-ones) and evaluation for inhibitors of type-2 cyclooxygenase.¹⁰ Park et al. have reported the synthesis of a novel series of 1, 5- diarylhydantoins which is the hybrid type compound by structural modification of celecoxib and rofecoxib.¹¹

Literature survey revealed that 2-amino 4-substitued thiazoles12 and their various derivatives such as 2-(2, 4-disubstituted-thiazole-5-yl)-3-aryl-3Hquinazoline- 4-ones,¹³ 3-[4'(p-chlorophenyl) thiazol-2'-yl]-2-[(substitutedazetidinone/thiazolidinone)-aminomethy]-6-bromoquinazolin-4-ones,¹⁴4-oxothiazolidine and its 5-arylidenes,¹⁵(Z)-4-((2,4-dioxothiazolidin-5-ylidene) methyl)-N-(4-substituted phenylthiazol-2-yl) benzene sulfonamides and 2-substituted-N-(4-Substituted-phenylthiazol-2yl) acetamides,¹⁶thiazolyl-N-Ph piperazines,¹⁷ 2-(4-arylthiazol-2-yl-amino)-n-aryl acetamides¹⁸ have displayed considerable anti-inflammatory activity. When methane sulphonamido moiety was incorporated in the heteocycles the modified products are found to have appreciable anti-inflammatory activity with COX-2 selectivity.¹⁹ Considering the pharmacological importance of thiohydantoins, sulphonamides and 2-4-disubstituted thiazoles, here it was thought to bring thiohydantoinyl, and 2-methyl sulphonylaminothiazolyl methyl moieties together in one molecular frame work to obtain the new lead molecules with intensified anti-inflammatory activity.

MATERIAL AND METHODS:

Chemicals and reagents:

Reactions were monitored by thin layer chromatography. TLC was performed with Merckprecoated TLC plates, silica gel 60F254 with thickness of 0.25mm and spots were visualized by irradiation with ultraviolet light (254 nm). Melting points were determined by open capillary method and are uncorrected. IR spectra were recorded on Bruker alpha ATR spectrophotometer. 1H NMR was carried out on Bruker apparatus at DRX-300 MHz, using TMS as internal reference and DMSO-d6 as medium. Chemical shifts (δ values) are expressed in parts per million (ppm). Mass spectra have been scanned on DART-MS (ESI+) and on JMS 100LC, AccuTOF spectrometers. Elemental analysis was performed on Perkin–Elmer 2400 CHNS Elemental analyzer at SAIF CDRI Lucknow, India.

Synthesis:

Synthesis of 2-amino-4-(isothiocynatomethyl) thiazole (2):

A mixture of 2-amino-4(chloromethyl) thiazole hydrochloride (1) (22 mmol), potassium thiocynate (26 mmol), and potassium iodide (12 mmol) in methanol (40 mL) was heated at reflux for 2 h. The solvent was concentrated under reduced pressure, and to the resulting residue 10 % aqueous NH₃ (80 mL)was added. Then the mass was extracted with DCM (2×60 mL).The organic layer was dried using anhydrous K₂CO₃. The solvent was removed from the dried organic solution and the crude product obtained was crystallized from benzene, yield: 76% (2). m.p:105-106^oC (Lit.105-106^oC).²⁰

Synthesis of 2-methylsuphonyl amino-4-(isothiocynatomethyl) thiazole (3):

To a stirred solution of 2-amino-4-(isothiocynatomethyl) thiazole (2) (15 mmol) in DCM (20 ml) triethyl amine (16.5 mmol) was added and the reaction mixture was cooled to 0-5⁰C.Thenmethylsulphonyl chloride (16.5 mmol) was added in portions. After complete addition of the methylsulphonyl chloride the reaction mixture was further stirred at rt. for 24 h. The Progress of the reaction was monitored by TLC.The reaction mixture was then poured on water to remove un-reacted methylsulphonyl chloride and triethyl amine hydrochloride .Organic layer was separated, dried on sodium sulphate and concentrated to give crude solid which on crystallization with ethanol:DMF yielded the compound (3) with 81% yield. m.p:185-187°C.

2-methylsuphonyl amino-4-(isothiocynatomethyl) thiazole (3):

IR (cm -1): 3310 (N-H stretch), 3020 (C-H stretch, aromatic), 2960 (C-H stretch, aliphatic symme.), 2811 (C-H stretch, ansym.), 2163 (N=C=S stretch), 1620 (C=N), 1558 (C=C), 1280 (S=O assym.) and 1132 (S=O symm.).¹H NMR (DMSO-d6, 300 MHz) δ (ppm): 2.92 (s, 2H, CH₂), 4.21 (s, 3H, -SO₂CH₃), 6.85 (s,1H,thiazolyl), 12.61(s, 1H, exchangable with D₂O).MS (ESI+ mode): m/z (% intensity): 250 (M,+),Elemental Analysis: M.F-C₆H₇N₃O₂S₃: Found % (Calculated %): C, 28.82 (28.90); H, 2.80 (2.83); N, 16.82 (16.85); S, 38.50 (38.58).

Synthesis of 5-arylidene-1-[(2(methylsuphonyl amino) thiazol-4-yl) methyl]-2-thioxoimidazolidin-4-one (5a-f).

A mixture of 2-methyl suphonyl amino-4-isothiocyanato methyl thiazole (10 mmol), glycine (10 mmol) and aryl aldehydes (10 mmol) was heated in a acetic acid (5 mL) at 90^oC. The progress of the reaction was monitored by thin layer chromatography. After heating the reaction mass for 4 h, it was allowed to cool to r.t. and poured in ice cold water. Thus obtained solid mass was filtered, washed with water and dried. The crude product was crystallized using DMF-ethanol.Similarly other compounds of the series were prepared and their characteristic physical data is recorded.

5-Benzylidene-1- ((2 (methylsuphonyl amino) thiazol-4-yl) methyl)-2-thioxoimidazolidin-4-one (4a) IR (cm^-1): 3361 (N-H strech), 3219 (N-H stretch), 3115 (Ar-H), 2950 (C-H aliphatic stretch), 2859 (C-H stretch aliphatic), 1744 (C=S), 1690 (C=O),1698 (C=N), 1646 (C=C), 1520 (N-H bend), 1424 (S=O) and 1122 (S=O).¹H NMR (DMSO-d₆, 300MHz) δ (ppm) :2.12 (s, 2H,-CH₂), 1.23 (s, 2H, -CH₃), 2.90 (s, 3H, -SO₂CH₃CH₃) 6.36-7.59 (m, 6H, Ar-H and olefinic H), 12.12 (s, NH-SO₂CH₃) and 10.19 (s,-NH, exchangeable with D₂O).DART-MS (Scanning mode ESI⁺): m/z: 395 (M).Elemental Analysis : M.F- C₁₅H₁₄N₄O₃S₃:Found% ( Calculated %) : C, 45.65 (45.67); H, 3.52 (3.58); N, 14.17 (14.20); S, 24.32 (24.38).

5-(4-Bromo) benzylidenyl-1- ((2 (methylsuphonyl amino) thiazol-4-yl) methyl)-2-thioxoimidazolidin-4-one (4b) IR (cm^-1): 3374 (N-H stretch), 3226 (N-H stretch), 3122 (Ar-H), 2957 (C-H aliphatic stretch), 2866 (C-H stretch aliphatic), 1736 (C=S), 1697 (C=O),1706 (C=N), 1651 (C=C), 1526 (N-H bend), 1428 (S=O) and 1127 (S=O).¹H NMR (DMSO-d₆, 300MHz) δ (ppm) :2.17 (s, 2H,-CH₂), 1.29 (s, 2H, -CH₃), 2.93 (s, 3H, -SO₂CH₃CH₃),7.62 (2H, d, ), 7.76 (2H, d), 7.97 (1H, s, =CH–), 12.18 (s, NH-SO₂CH₃) and 10.24 (s,-NH, exchangeable with D₂O).DART-MS (Scanning mode ESI⁺): m/z : 473.93 (M+1), 474.93 (M+2).Elemental Analysis : M.F-C₁₅H₁₃BrN₄O₃S₃:Found% ( Calculated %) :C, 38.02(38.06); H, 2.71(2.77); Br, 16.81(16.88); N, 11.85(11.84); O, 10.11(10.14); S, 20.29(20.32).

5-(3-Methoxy) bezylidenyl-1- ((2 (methylsuphonyl amino) thiazol-4-yl) methyl)-2-thioxoimidazolidin-4-one (4c) IR (cm^-1): 3367 (N-H strech), 3233 (N-H stretch), 3127 (Ar-H), 2963 (C-H aliphatic stretch), 2872 (C-H stretch aliphatic), 1701 (C=S), 1642 (C=O), 1658 (C=N), 1634 (C=C), 1534 (N-H bend), 1434 (S=O) and 1133 (S=O).¹H NMR (DMSO-d₆, 300MHz) δ (ppm) :2.22 (s, 2H,-CH₂), 1.32 (s, 2H, -CH₃), 2.97 (s, 3H, -SO₂CH₃), 7.40-7.47 (m, 2H, Ar-H), 7.55 (d, 1H, ArH), 7.57 (d, 1H, Ar-H), 7.94 (s, 1H, -CH=), 12.26 (s, NH-SO₂CH₃) and 10.30 (s,-NH, exchangeable with D₂O).DART-MS (Scanning mode ESI⁺): m/z : 425.04 (M,).Elemental Analysis : M.F- C₁₆H₁₆N₄O₄S₃:Found% ( Calculated %) :C, 45.27; H, 3.80; N, 13.20; O, 15.08; S, 22.66

5-(4-methoxy) bezylidenyl-1- ((2 (methylsuphonyl amino) thiazol-4-yl) methyl)-2-thioxoimidazolidin-4-one (4d) IR (cm^-1): 3368 (N-H strech), 3239 (N-H stretch), 3115 (Ar-H), 2980 (C-H aliphatic stretch), 2871 (C-H stretch aliphatic), 1703 (C=S), 1648 (C=O), 1698 (C=N), 1646 (C=C), 1539 (N-H bend), 1434 (S=O) and 1141 (S=O).¹H NMR (DMSO-d₆, 300MHz) δ (ppm) :2.12 (s, 2H,-CH₂), 1.23 (s, 2H, -CH₃), 2.90 (s, 3H, -SO₂CH₃CH₃) 7.11 (d, 2H, Ar-H), 7.41(d, 2H,Ar-H), 7.94 (s, 1H, -CH=),12.12 (s, NH-SO₂CH₃) and 10.34 (s,-NH, exchangeable with D₂O).DART-MS (Scanning mode ESI⁺): m/z: 425.04 (M,).Elemental Analysis : M.F- C₁₆H1₆N4O₄S₃:Found% ( Calculated %) : C, 45.22 (45.27); H, 3.78 (3.80); N, 13.19 (13.20); O, 15.06 (15.08); S, 22.63 (22.66).

5-(3-Choro) bezylidenyl-1- ((2 (methylsuphonyl amino) thiazol-4-yl) methyl)-2-thioxoimidazolidin-4-one (4e) IR (cm^-1): 3370 (N-H strech), 3245(N-H stretch), 3142 (Ar-H), 2979 (C-H aliphatic stretch), 2875 (C-H stretch aliphatic), 1743 (C=S), 1703 (C=O),1726 (C=N), 1672 (C=C), 1546 (N-H bend), 1451 (S=O) and 1149 (S=O).¹H NMR (DMSO-d₆, 300MHz) δ (ppm) :2.12 (s, 2H,-CH₂), 1.23 (s, 2H, -CH₃), 2.90 (s, 3H, -SO₂CH₃), 7.77 (s 1H, C=H); 7.34 (s 1H), 7.18 (d 1H); 7.30-7.36(m, 2H ), 7.26 (d 1H),12.38 (s, NH-SO₂CH₃) and 10.39 (s,-NH, exchangeable with D₂O).DART-MS (Scanning mode ESI⁺): m/z : 428.99 (M+ 1),429.98 (M+ 2).Elemental Analysis : M.F- C₁₅H₁₃ClN₄O₃S₃:Found% ( Calculated %) :C, 42.02 (42.00); H, 3.02 (3.05); Cl, 8.26 (8.27); N, 13.02 (13.06); O, 11.17 (11.19); S, 22.40 (22.43).

5-(4-Choro) bezylidenyl-1- ((2 (methylsuphonyl amino) thiazol-4-yl) methyl)-2-thioxoimidazolidin-4-one (4f) IR (cm^-1): 3372 (N-H strech), 3248 (N-H stretch), 3146 (Ar-H), 2982 (C-H aliphatic stretch), 2879 (C-H stretch aliphatic), 1743 (C=S), 1703 (C=O),1698 (C=N), 1677 (C=C), 1551 (N-H bend), 1455 (S=O) and 1153 (S=O).¹H NMR (DMSO-d₆, 300MHz) δ (ppm) :2.12 (s, 2H,-CH₂), 1.23 (s, 2H, -CH₃), 2.90 (s, 3H, -SO₂CH₃),7.92 (d, 2H,Ar-H), 8.36 (d, 2H, Ar-H), 8.32 (s, 1H, -CH=),12.42 (s, NH-SO₂CH₃) and 10.43 (s,-NH, exchangeable with D₂O).DART-MS (Scanning mode ESI⁺): m/z:428.99 (M+1), 429.98 (M+2).Elemental Analysis : M.F-C₁₅H₁₃ClN₄O₃S₃:Found% ( Calculated %) :C, 42.01 (42.00); H, 3.04 (3.05); Cl, 8.25 (8.27); N, 13.04 (13.06); O, 11.16 (11.19); S, 22.41 (22.43).

5-(4-Methyl) bezylidenyl-1- ((2 (methylsuphonyl amino) thiazol-4-yl) methyl)-2-thioxoimidazolidin-4-one (4g) IR (cm^-1): 3356 (N-H strech), 3215 (N-H stretch), 3110 (Ar-H), 2946 (C-H aliphatic stretch), 2853 (C-H stretch aliphatic), 1744 (C=S), 1690 (C=O),1698 (C=N), 1646 (C=C), 1514 (N-H bend), 1419 (S=O) and 1126 (S=O).¹H NMR (DMSO-d₆, 300MHz) δ (ppm) :2.12 (s, 2H,-CH₂), 1.23 (s, 2H, -CH₃), 2.90 (s, 3H, -SO₂CH₃),7.25(d, 2H, Ar-H), 7.36 (d,2H, Ar-H), 7.95 (s, 1H, -CH=),12.10 (s, NH-SO₂CH₃) and 10.17 (s,-NH, exchangeable with D₂O).DART-MS (Scanning mode ESI⁺): m/z: 409.04 (M,).Elemental Analysis: M.F-C₁₆H₁₆N₄O₃S₃:Found% (Calculated %):C, 47.02 (47.04); H, 3.93 (3.95); N, 13.69 (13.71); O, 11.73 (11.75); S, 23.51 (23.55).

In vitro anti-inflammatory activity by HRBC membrane stabilization method:

Fresh whole human blood was collected and it was mixed with equal volumes of sterilized Alsever’s solution (Dextrose 2%, Sodium citrate 0.8%, Citric acid 0.05%, Sodium chloride 0.42%, and Distilled water 100mL). This blood solution was centrifuged at 3000 rpm for 10 min and was washed three times with equal volume of normal saline. The volume of the blood is measured and reconstituted as 10% v/v suspension with normal saline. The reaction mixture consists of 1.0mL of test sample of different concentrations in normal saline and 0.5mL of 10% HRBC suspension, 1mL of 0.2M phosphate buffer, 1ml hypo saline were incubated at 37°C for 30 min and centrifuged at 3,000 rpm for 30 minutes. The hemoglobin content of the supernatant solution was estimated spectrophotometrically at 560nm wavelength. Each experiment was performed in triplicate. Dichlofenac sodium was used as standard and distilled water as control in this study.²¹Where the blood control represents 100% lysis or zero percent stability, the percentage of HRBC hemolysis calculated by formula,

% Hemolysis = (O.D of Test Sample / O.D of Control) × 100.

The concentration of a compound, where 50% of its maximal effect is observed (EC50) using graph pad prism was measured.²²

RESULTS AND DISCUSSION:

Chemistry:

The synthetic sequence is outlined in Scheme 1.Synthesis of the target molecules was carried using starting material 2-amino-4-chloromethyl thiazole hydrochloride (1) which was freshly synthesized by cyclocondensing 1, 3-dichloroacetone and thiourea by following Hantzsch method. 2-Amino-4-(chloromethyl)thiazole hydrochloride (1) was then condensed in methanol with ammonium thiocynate in the presence of potassium iodide in methanol and obtained 2-amino-4-(isothiocynatomethyl)-thiazole(2).The 2-amino derivative (2) when mesylated with methyl sulphonyl chloride in DCM using triethylamine as catalyst at 0^oC gave desired 2-methylsuphonamido-4-(isothiocynatomethyl) thiazole(3).An environmental begin and ecosustainable one-pot synthetic protocol has been used to synthesise 5-arylidene-1- [(2 (methylsuphonyl amino) thiazol-4-yl) methyl]-2-thioxoimidazolidin-4-ones (5a-f) by carrying the one pot condensation of 2-methyl suphonyl amino-4-isothiocynato methyl thiazole (3) glycine and aryl aldehydes (4a-f) in acetic acid at 90^oC.In this one pot route the first step would be the cyclocondensation of 2-methyl suphonyl amino-4-isothiocynato methyl thiazole (3) and glycine giving 2-thiohydantoin insitu, an intermediate. This intermediate on subsequent Knovenagel condensation with aryl aldehydes would have been yielded the titled 5-arylidene-1- [(2 (methylsuphonyl amino) thiazol-4-yl) methyl]-2-thioxoimidazolidin-4-ones.The structures of intermediate and all new 5-arylidene-1- [(2 (methylsuphonyl amino) thiazol-4-yl) methyl]-2-thioxoimidazolidin-4-ones (5a-f) have been elucidated by elemental analyses, I.R., ¹H NMR, and Mass spectroscopic measurements. IR spectra of intermediate(3)diagnostic peak such as 2163 (N=C=S stretch), 1620 (C=N), 1558 (C=C), 1280 (S=O assym.) and 1132 (S=O symm.) are observed.¹H NMR spectra of intermediate (3) display peak at 2.92 (s, 2H, CH₂), 4.21 (s, 3H, -SO₂CH₃), 6.85 (s,1H,thiazolyl), 12.61(s, 1H, exchangable with D₂O, -NHSO₂CH₃) and MS (ESI⁺mode): 250 (M, +) which suppotes the stucture 2-methylsuphonyl amino-4-(isothiocynatomethyl) thiazole . In the IR spectra of compounds (5a-f) along with other diagnostic peak secondary amine N-H bending vibrations are observed (3356-3374cm^-1) and (3215-3245 cm^-1) is recorded. ¹H NMR spectra all final compounds display all significant and distinctive broad D₂O exchangeable secondary amino peaks in (10.17-10.43) and (12.12-12.42) range. The spectral data prove disubstituted thiohydantoin structures of final compounds. Mass spectra of titled compounds are in good agreement with molecular weight calculated and structures proposed for (5a-f).

Anti-inflammatory activity:

Anti-inflammatory agents inhibit the cyclooxygenase enzymes which are responsible for the conversion of arachidonic acid to prostaglandins. Because human red blood cell (HRBC) membranes are similar to these lysosomal membrane components, the prevention of hypotonicity induced HRBC membrane lysis was taken as a measure in estimating anti-inflammatory activity.²¹ Anti-inflammatory activity done by Human Red Blood Cell (HRBC), DFS stabilizes the membrane, thereby reducing the hemolysis. Thus with the increase in the component are prevented from leaking, thus as the concentration of DFS increases, the O.D decreases thereby decreasing the effect of the tonicity caused by hypo saline. Thus, HRBC membrane stabilization method²³ was used to estimate anti-inflammatory activity. The result of the in vitro membrane stabilization activity of synthesized thiazolyl thiohydantoins(5a-f) is presented in Table 1, Fig.1 and Fig.2. According to these results all the compounds showed dose dependent inhibition of hemolysis. Compound 5b (EC₅₀ = 6.50 ± 0.06), 5f (EC₅₀ = 3.01 ± 0.10) and 5g (EC₅₀ = 4.47 ± 0.05) displayed very good activity among the series as compared to standard Diclofenac sodium (EC₅₀ = 13.24 ± 0.09). Other compound 5c (EC₅₀ = 14.35 ± 0.11) showed moderate activity and 5a (22.48 ± 0.12), 5d (20.36 ± 0.04) and 5e (22.88 ± 0.15) had exhibited lower anti-inflammatory activity as compared to standard DCS.

Table1. In vitro anti-inflammatory activity of synthesized compounds (5a-f).

Compound	% Hemolysis at different concentrations 1ug/ml 5ug/ml 25ug/ml 50ug/ml				(EC₅₀ ± SD)
5a	59.28	63.80	73.61	80.98	22.48 ± 0.12
5b	64.41	77.91	86.50	93.25	6.50 ± 0.06
5c	53.98	62.57	72.39	76.68	14.35 ± 0.11
5d	63.80	71.77	75.46	80.98	20.36 ± 0.04
5e	57.05	65.64	73.71	81.59	22.88 ± 0.15
5f	74.84	84.04	87.73	93.86	3.01 ± 0.10
5g	73.61	80.36	85.27	91.41	4.47 ± 0.05
DCS	61.34	63.19	65.64	70.55	13.24 ± 0.09

CONCLUSION:

A new series of 5-arylidenyl, N-thiazolylthiohydantoins with methylsulphonylamino pharmacophore has been synthesized by convenient synthesis and characterized by different spectral and elemental analyses. The newly synthesized thiohydantoins(5a-g) exhibited good in vitro anti-inflammatory activity compared with Standard Diclofenac sodium. The compounds 5b, 5f and 5g exhibited most promising anti-inflammatory activity.

ACKNOWLEDGEMENT:

Author is thankful to Dr. R. A. Mane, Professor and Ex. Head, Dept. of Chemistry, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad, for valuable guidance. Author is thankful to CDRI Lucknow for spectral analysis and Haffkine Institute, Mumbai for evaluating biological activity.

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

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Received on 11.08.2017 Modified on 22.09.2017

Asian J. Research Chem. 2017; 10(6):739-744.

DOI: 10.5958/0974-4150.2017.00125.0