Design of Novel Thiohydantoin Derivatives and Exploration their Physico-Chemical Parameters

Introduction

2-Thiohydantoin is an important class of compounds within chemistry. It is a sulphur derivative of hydantoin which is obtained by replacing the oxygen atom of carbonyl group by sulphur. Thiohydantoin is a intermediate to synthesis of many drugs^1-12 .In solid state thiohydantoin shows π-π stacking,hydrogen bonding which is important in pharmaceutical industries^13-16

One of the most important things that drew the attention of researchers to synthesized thiohydantoin due to wide range of application like anti-inflammatory, anti-ulcer¹⁷, antifungal, antibacterial¹⁸, HIV¹⁹, hypolipidemic²⁰, antimutagenic²¹, against HSV²², anticarcinogenic²³,on tuberculosis²⁴  and pesticide²⁵ ,derivatives of thiohydantoin are also used as a fungicide²⁶ ,N-phenyl derivative of 2-Thiohydantion shows antiparasitic activity against Trypanosoma brucei species²⁷.

 K.H. Chikhalia et al²⁸ reported a series of thiohydantoin derivatives having ethyl linked 3,4-dimethoxyphenylethyl thiourea derivatives with styryl bridge  possessing antibacterial properties as well as anti HIV activity. Abubshait S.A.²⁹ synthesized some 2-thiohydantoin drivatives and reported anticancer and antimicrobial properties against gram positive and gram negative bacteria. Kolhe S.V.³⁰ prepared 2-thiohydantoin derivatives by mixing aurones derivative with suitable thiourea by refluxing with KOH and ethaonol as a solvent and reported antimicrobial properties using microbes such as Escherichia coli, Staphylococcus aureus, Klebsilla, Pseudomons. Saied E.M. et al³¹ synthesized 1, 3-disubstituted 2-thiohydantoin analogues and reported anti-inflammatory activity. Gotmare P.A.et al³² synthesized 2-Thiohydantoin analogous and reported physicochemical properties.

Literature survey reveals that, substituted 2-thiohydantoin were found to be very instrumental in controlling the diseases in the field of medicine, agriculture. The present study has been undertaken to synthesis some new 2-thiohydantoin analogues and test them for their physico-chemical properties.

Materials and Methods

All chemical s and reagents used in this research were commercially sourced and of analytical grade. The purity of resultant compound was check by using TLC. The IR spectra were recorded in KBr by using FT-(IR Perkin Elmer – Spectrum RX-FTIR). Mass spectra were recorded on mass spectrometer while ¹HNMR were recorded on FT NMR Spectrometer (Bruker Avance Neo 500 MHz).

General Procedure for synthesis of 2-Thiohydantoin

Aurone  (0.01 M) and N-substituted thiourea (0.01 M) were taking in round bottom flask along with 10% KOH and Ethanol as a solvent. A reaction mixture was reflux for 3 h. After this period, the mixture was poured in to ice cold water and filter it by using suction pump. The final product recrystallized with Ethanol.

Scheme 1 Click here to View Scheme

Table 1

Sr. no.	Compounds	R1	R2	R3
1.	1a	C4H3O	C6H5	C6H5
2.	1b	C6H4Cl	C6H5	H

 

Preparation of 5-(hydroxyl(4-methoxyphenyl)methyl)-5-(2-hydroxyphenyl)-1,3-diphenyl-2-thioxoimidazolidin-4-one(1a)

2-(4-methoxybenzylidene)benzofuran-3(2H)-one (0.01M) reflux with N,N-diphenyl thiourea (0.01M) in presence of 10% KOH and appropriate ethanol solvent up to 3 hours. After completion of reaction, cooled the mixture and poured in to ice cold water. The solid product obtained which was filter and washed with dilute HCl and water. The product was crystallized by using ethanol.  

Mol. Formula C₂₉H₂₄O₄N₂S: Yellowish Crystalline solid. m.p 258 ^oC yield 70%, Elemental analysis (%):C,70.14; H,4.87; N,5.64; S,6.46; O,12.89; IR (KBr cm-1) 3617.5 (O-H), 3016 (=CH), 1614 (C=N), 1438 (Ar C=C),ESI-MS[M+H]+ Calculated for C₂₉H₂₄O₄N₂S: m/z  496.15, 497.15,498.15   ; ¹H-NMR (500 MHz, DMSO) δ3.76 (s, 3H), 5.68 (s,1H), 6.86-7.38 (m, J =8.4,1.1 Hz, 11H), 7.43 7.70 (m, 6H),

Preparation of 5-((4-chlorophenyl)(hydroxy)methyl)-5-(2-hydroxyphenyl)-3-phenyl-2-thioxoimidazolidin-4-one (1b)

2-(4-chlorobenzylidene)benzofuran-3(2H)-one(0.01M) reflux with N-phenyl thiourea (0.01M) in presence of 10% KOH and appropriate ethanol solvent up to 3 hours. After completion of reaction, cooled the mixture and poured in to ice cold water. The solid product obtained which was filter and washed with dilute HCl and water. The product was crystallized by using ethanol.  

Mol. Formula C₂₂H₁₇O₃N₂SCl : faint yellowish Crystalline solid, m.p 228^oC, yield 74%, Elemental analysis (%):C,62.19; H,4.03; N,6.59; O,11.30; S,7.55;Cl,8.34. IR (KBr cm-1) 3616.5 (O-H), 3268.1 (N-H), 1682(Amide C=O), 1436 (Ar C=C), 755.2 (C-Cl); ESI-MS[M+H]+ Calculated for C₂₂H₁₇O₃N₂SCl: m/z  424.06, 426.06, 425.07, 427.07. ¹H-NMR (500 MHz, DMSO) δ5.58 (s, 1H), 7.04 (m, J = 8.0,7.8 Hz, 1H), 7.48 (m, J = 8.3,1.6,0.5 Hz, 8H), 8.02(m, J = 8.0,1.4 Hz, 1H).

Physicochemical Properties of Thiohydantoin Derivatives

Physico-chemical properties are essential indicators used in hazard, exposure and risk assessments, hence in this experiments the physico-chemical parameters were studied in different solvents, and different concentrations, with temperature 20 °C.

Density and Viscosity

Viscosity and density are affected by temperature. Which implies, for any given fluid, when the temperature is raised, the particle in it start to move apart, bringing down fluid density thereby the value of viscosity also falls down or fluid becomes less viscous. The density and viscosity were taken in different solvent like DMSO and DMF with different concentration and temperature at 20 degree. The density was measured by using pycnometer and viscosity by Ostwald viscometer using fallowing formula.

Acoustic parameters

 Ultrasonic velocity was useful to determine the strength of material as well as particle interaction in solution hence most of the scientist are attracted toward these parameters. Here ultrasonic parameters was measured using a single-crystal Interferometer (Mittal Enterprises) operating at 1MHz with an accuracy of ±1.0m/s.

The acoustic parameters were determine using fallowing formulae

Adiabatic compressibility (𝛽)

Intermolecular free path length (𝐿_𝑓)

Where 𝐾 is the temperature dependent Jacobson’s constant

Acoustic impedance (𝑍) is given as follows

Relative association (RA)

Ultrasonic attenuation (𝛼/𝑓²)

Relaxation time (𝜏)

Results and Discussion

The physico-chemical properties of thiohydantoin derivatives were given below

Compound 1a

Table 2: Solvent: DMF  Temp. 20 °C

Conc. (M) Mol/dm3	Density(ρ) Kg/m-3	Viscosity(ƞ) ×103 NSm-2	Ultasonic velocity(v) m/s	Refractive Index
0.000	970.76	0.94577	1415.0	1.4305
0.001	972.46	1.19646	1434.4	1.422
0.002	972.94	1.24280	1558.8	1.424
0.003	973.88	1.30469	1603.2	1.425
0.004	974.68	1.40073	1632.0	1.426
0.005	976.20	1.50860	1694.8	1.426

Table 3: Ultrasonic parameters in DMF

Conc. (M) Mol/dm3	Adiabetic compressibility (β) × 10-10	Intermolecular Free path (Lf) × 10-11	Acoustic impedances (Z) ×106	Relative  Association (RA)	Ultrasonic Attenuation  (∝/ f2 ) x 10-14	Relaxation Time (t) ×10-13
0.000	5.14488	4.622658	1.373625	1.000000	2.7124	6.4869
0.001	4.99790	4.556149	1.394896	0.988202	3.28825	7.9731
0.002	4.22993	4.191512	1.516618	0.909788	2.66007	7.0094
0.003	3.99502	4.073461	1.561324	0.885446	2.56637	6.9498
0.004	3.85210	3.999935	1.590677	0.870535	2.60784	7.1944
0.005	3.56635	3.848718	1.654463	0.839585	2.50397	7.1737

 

Table 4: Solvent: DMSO Temp. 20 °C

Conc. (M) Mol/dm3	Density(ρ) Kg/m-3	Viscosity(ƞ) ×103 NSm-2	Ultasonic velocity(v) m/s	Refractive Index
0.000	1126.28	2.2026	1553.0	1.4740
0.001	1129.04	2.4404	1566.2	1.4742
0.002	1129.86	2.6248	1594.6	1.4744
0.003	1130.12	2.8067	1604.0	1.4748
0.004	1130.98	3.2115	1734.2	1.4751
0.005	1131.06	3.3924	1788.2	1.4752

Table 5: Ultrasonic parameters in DMSO

Conc. (M) Mol/dm3	Adiabetic compressibility (β) × 10-10	Intermolecular Free path (Lf) ×10-11	Acoustic impedances (Z) ×106	Relative  Association (RA)	Ultrasonic Attenuation (∝/ f2 ) × 10-14	Relaxation Time (t ) ×10-13
0.000	3.68138	3.910414	1.749110	1	4.11835	10.8115
0.001	3.61074	3.872715	1.768302	0.994001	4.43771	11.7489
0.002	3.48074	3.802360	1.801674	0.977024	4.51924	12.1817
0.003	3.43897	3.779470	1.812872	0.971591	4.74645	12.8695
0.004	2.94000	3.494549	1.961345	0.899266	4.29442	12.5891
0.005	2.76492	3.388900	2.022560	0.872172	4.13954	12.5063

Figure 1 Click here to View Figure

Compound 2a

Table 6: Solvent: DMF  Temp. 20 ^oC

Conc. (M) Mol/dm3	Density(ρ) Kg/m-3	Viscosity(ƞ) ×103 NSm-2	Ultasonic velocity(v) m/s	Refractive Index
0.000	970.76	0.94577	1415	1.4305
0.001	971.68	1.15997	1438.72	1.4306
0.002	971.91	1.22426	1452.81	1.4308
0.003	972.18	1.30241	1464.86	1.4309
0.004	972.82	1.42826	1506.91	1.4311
0.005	973.52	1.51763	1585.68	1.4312

 

Table 7: Ultrasonic parameters in DMF

Conc. (M) Mol/dm3	Adiabetic compressibility (β) × 10-10	Intermolecular Free path (Lf) ×10-11	Acoustic impedances (Z) ×106	Relative  Association (RA)	Ultrasonic Attenuation  (∝)/f2 × 10-14	Relaxation Time (t ) ×10-13
0.000	5.14488	4.622658	1.373625	1.000000	2.71240	6.4878
0.001	4.97192	4.544431	1.397975	0.984445	3.16187	7.6897
0.002	4.87479	4.499826	1.412000	0.975128	3.24019	7.9574
0.003	4.79359	4.462190	1.424107	0.967375	3.16000	8.3243
0.004	4.52681	4.336246	1.465952	0.941000	3.38424	8.6206
0.005	4.08530	4.119357	1.543691	0.894898	3.08406	8.2666

Table 8: Solvent: DMSO  Temp. 20 ^oC

Conc. (M) Mol/dm3	Density(ρ) Kg/m-3	Viscosity(ƞ) ×103 NSm-2	Ultasonic velocity(v) m/s	Refractive Index
0.000	1126.28	2.2026	1553.0	1.4740
0.001	1127.26	2.5128	1609.0	1.4742
0.002	1127.98	2.5247	1612.22	1.4746
0.003	1128.48	2.5382	1614.20	1.4747
0.004	1128.82	2.6141	1618.70	1.4748
0.005	1129.72	2.8663	1622.0	1.4750

Table 9: Ultrasonic parameters in DMSO

Conc. (M) Mol/dm3	Adiabetic compressibility (β) × 10-10	Intermolecular Free path (Lf) ×10-11	Acoustic impedances (Z) ×106	Relative  Association (RA)	Ultrasonic Attenuation (∝/f2) × 10-14	Relaxation Time (τ) ×10-13
0.000	3.68138	3.910414	1.749110	1	4.11835	10.8115
0.001	3.426603	3.772675	1.813761	0.966035	4.22099	11.4808
0.002	3.410751	3.763938	1.818551	0.964721	4.21303	11.4817
0.003	3.400881	3.758488	1.821592	0.963965	4.21802	11.5094
0.004	3.380980	3.747475	1.827220	0.961575	4.30687	11.7846
0.005	3.645538	3.738360	1.832405	0.960384	4.39528	12.0510

Figure 2 Click here to View Figure

Physicochemical properties are a key to determinant of pharmacokinetic and pharmacodynamics profile, and essential to increasing the success rate of drug sample candidates within the preclinical development process. The importance of the physicochemical properties for active transport. The density and viscosity are depends on temperature and concentration, here the density and viscosity increases by increasing concentration but solvent changes change the density and viscosity that means density as well as viscosity  affected by solvent.

Ultrasonic velocity in which sound waves travel through liquid sample. Here Ultrasonic velocity increases by increasing concentration due to an increase of cohesive forces which is created due to  strong molecular interactions. The experimental Ultrasonic velocity values are different for the same compound in the two different solvents. This suggests that solvent plays an important role in solutions, molecular interactions exists which differs with different solvents. In this case thiohydantoins shows higher Ultrasonic velocity in DMSO solvent than DMF because in DMSO samples shows strong interaction with solvent DMSO.

If intermolecular free path decreases with increase of concentration, explain that the distance between solute and solvent molecules decrease due to increase in solute-solvent interactions, which causes velocity to increase. It is supported by compressibility and relaxation time. Here relaxation time increases by increasing concentration. Compressibility is a measure of the relative volume change of a sample as a response to a pressure change. Here compressibility decreases by increasing concentration that means concentration increases which increase strong interaction between solute and solvent.

Conclusion

It is concluded that physicochemical properties of a thiohydantoin derivatives depends on its structure, concentration and solvents in which it is dissolved. In this case DMSO and DMF shows different values for same compound due to interactions changes in different solvents thereby affecting properties. Further, position of substitution in a compound also affects physicochemical properties. In DMSO solvent, strong solute solvent interaction appear than DMF.

Acknowledgement

 We are thankful to Principal Dr. S.H. Pande sir and Department of chemistry Shri Shivaji Arts Commerce and Science College Akot for providing lab equipment’s. Also thankful to Shri D. M. Jakate for his cooperation. We are also thankful to CIL and SAIF, Panjab University, Chandigarh for providing spectral data.  

Conflict of Interest

The authors declare no conflict of interest.

 References

1. Ono, M.; Hayashi, S.; Matsumura, K.; Kimura, H.; Okamoto, Y.; Ihara, M. ; Takahashi, R.; Mori, H.; Saji, H.  J.ACS Chem. Neurosci, 2011, 2, 269.
   CrossRef
2. Han, J.; Dong, H.; Xu, Z.; Lei, J.; Wang, M.  Int. J. Mol. Sci. 2013, 14, 12484.
   CrossRef
3. Hussain, N.; Joshi, A.; Sharma, C.; Talesara, G.L. Asian J. Chem. 2012, 24, 5917.
4. Raghuvanshi, D.S.; Singh K.N. Phosphorus Sulfur Silicon, Rel. Elem. 2010, 185, 2243.
   CrossRef
5. Yao, C.; Zhang, Y.; Zhang, G.; Chen, W.; Yu, Y; Houghten, R. A. Synth.  Commun. 2010, 40, 717.
6. Carboni, M.; Gomis, J.M.; Loreau, O.; Taran, F. Synthesis. 2008, 40, 417.
   CrossRef
7. Cao, S.; Zhu, L.Z.; Zhao, C.M.; Tang, X.H.; Sun, H.J.; Feng, X.; Qian, X.H., Monatsh. Chem. 2008, 139, 923.
8. Sundaram, G.S.M.; Venkatesh, C.; Ila, H.; Junjappa, H. Synlett. 2007, 2   251.
9. Wang, Z.D.; Sheikh, S.O.;  Zhang, Y. Molecules. 2006, 11, 739.
   CrossRef
10. Reyes, S.; Burgess, K. J. Org. Chem.  2006, 71, 2507.
    CrossRef
11. Porwal, S.; Kumar, R.;Maulik, P.R.; Chauhan, P.M.S. Tetrahedron Lett. 2006, 47, 5863.
    CrossRef
12. Li, J.P.; Ma C.M.; Qu, G.R. Synth. Commun. 2005, 35, 1203.
    CrossRef
13. Bernstein, J. Polymorphism in Molecular Crystals.2002.
14. Lu, J.; Rohani, S. Current Medicinal Chem.  2009, 16, 884–905.
    CrossRef
15. Custelcean, R. Chem. Commun.  2008, 295–307.
    CrossRef
16. Jha, S.; Silversides, J.D.; Boyle, R.W.; Archibald, S.J. CrystEng Comm. 2010, 12, 1730-139.
    CrossRef
17. Curran, A. C. W. U. S. Pat.3. 1976, 984,430.
    CrossRef
18. (a) Lacroix, G.; Bascou, J.-P.; Perez, J. Gadras, A. U. S. Pat.6. 2000,018,052. (b) Lacroix, G.;Bascou, J.-P.; Perez, J. Gadras, A. U. S. Pat.5. 1997,650,519. (c) Marton, J.; Enisz, J.; Hosztafi, S.; Timar, T. J. Agric. Food Chem. 1993, 41, 148.
    CrossRef
19. (a) Chérouvrier, J.-R.; Carreaux, F.; Bazureau, J. P. Molecules. 2004, 9, 867.(b) Khodair, A. I.; El-Subbagh, H. I.; El-Emam, A. A. Boll. Chim. Farm. 1997, 136, 561.
    CrossRef
20. (a) Tompkins, J. E. J. Med. Chem. 1986, 29, 855. (b) Elwood, J. C.; Richert, D. A.; Westerfeld, W.W. Biochem. Pharmacol. 1972, 21, 1127.
    CrossRef
21. (a) Takahashi, A.; Matsuoka, H.; Ozawa, Y.; Uda, Y. J. Agric. Food Chem. 1998, 46, 5037. (b)Froelich, E.; Fruehan, A.; Jackman, M.; Kirchner, F. K.; Alexander, E. J.; Archer, S. J. Am. Chem. Soc. 1954, 76, 3099.
    CrossRef
22. El-Barbary, A. A.; Khodair, A. I.; Pedersen, E. B.; Nielsen, C. J. Med. Chem. 1994,37, 73.
    CrossRef
23. Al-Obaid, A. M.; El-Subbagh, H. I.; Khodair, A. I.; Elmazar, M. M. Anticancer Drugs. 1996, 7,873.
24. Archer, S.; Unser, M. J.; Froelich, E. J. Am. Chem. Soc. 1956, 78, 6182.
    CrossRef
25. Nagpal, K. L. U. S. Pat.4. 1984,473,393.
26. Schroder, L. Eur. Pat. Appl. Ep. 1982, 3, 47.
27. Buchynskyy, A.; Gillespie, J.R.; Herbst, Z.M; Ranade, R.M.; Buckner, F.S.; Gelb M.H. ACS Med Chem. Lett. 2017, 8, 886–891
28. Patel, R. B., Desai, K.R., Chikhalia, K.H.  j. Indian Journal of chem.  2006, 45B,1716-1721.
    CrossRef
29. Abubshait, S.A. j. Indian Journal of chem. 2017, 56B, 641-648.
30. Kolhe, S.V.  j. I J R B A T.  2017, 5, 101-105.
31. Khirallah, S.M.; Ramdan, H.M.; Shawky, A.; Quahl ,S.H.; Baty, R.S.; Alqadri A.; Alsuhaibani, A.M.; Jaremko, M.; Emwas, A.H.; Saied,E.M. j. molecule. 2022, 27,6271.
    CrossRef
32. Gotmare, P. A.; Kolhe, S.V. A Review of the Physicochemical Approach to the Analysis of 2-Thiohydantoin.  j. International Journal of Research in Engineering and Science. 2023, 11(9), 134-143.

---

This work is licensed under a Creative Commons Attribution 4.0 International License.