An Overview about Medicinal Chemistry and Pharmaceutical Applications of 2, 4-Imidazolidinone and its Derivatives

 

Bhadreshkumar R. Sudani1* and Vikas A. Desai2

1Government Engineering College, Valsad, Near Sanskar Kendra, Tithal Road, Valsad-396001

2 B.K.M. Science College, Near Sanskar Kendra, Tithal Road, Valsad-396001

*Corresponding Author E-mail: brsudani@yahoo.com

 

ABSTRACT:

2,4-imidazolidinedione is a heterocyclic compound commonly well known as Hydantoin. Starting from its first synthesis it is found interesting among the medicinal and pharmaceutical chemists. In this review article we have briefly described different methods of synthesis with the help of some name reactions like Buchere-Bergs reaction and Diels-Alder reaction. It is found that this molecule is synthesized with three substitutions where different organic reactive groups imports different pharmacological properties in the molecules of hydantoin derivatives. The broad pharmacological activities of 2,4-imidazolidinedione is also discussed in this work for more than 16 dieses. This review article will be very good useful for scholars and scientists to explore more possibilities with other derivatives using the methods given in this review paper.

 

KEY WORDS: Hydantoin, Allantoin , Imidazolidinedione, Heterocyclic, phenyl urea.

 

1. INTRODUCTION:

The heterocyclic compound hydantoin is actually glycolylurea with the molecular formula C3H4N2O2, colorless solid (mp.220 oC) which arises from the reaction between urea and glycolic acid there for it is also known as glycolylurea. It is also an oxidized derivative of well known heterocyclic compound immidazolidine. There are so many methods available in literature for the synthesis of hydantoin with different derivatives. The aim of the present work is to carry out systematic study on the activities and pharmacological properties of these derivatives for further directive study for the new derivative synthesis.

 

Fig.-1: View of imidazolidine-2,4-dione(Hydantoin)

 

Historical Time Line:

History of hydantoin indicates that it was first isolated in 1861 by famous scientist Adolf von Baeyer during his study of uric acid. He was a former Munich professor of organic chemistry, and the winner of the Nobel Prize in 1905 too. He synthesized it by removing urea from Allantoin as below[1]. As he found that the 2,4-imidazolidinedione (Hydantoin) is a product of the hydrogenolysis of allantoin.(Scheme-1)

 

Scheme-1: Disbstituted hydantoin synthesis[1]

 

In 1873 Friedrich Urech derived 5-methylhydantoin derivative by reaction between amino acids and potassium cyanate followed by cyclization of the intermediate hydantoic acid (ureido acid) with hydrochloric acid. and later it became known as Urech hydantoin synthesis [2]. After this Buchere[3] and Bergs[4] also prepared hydantoin from cynohydrine and ammonium carbonate which is known as modern hydantoin derivative synthesis rout. (Scheme-2)

 

Scheme-2: Disbstituted hydantoin synthesis[3,4]

 

Here we should not forget the reference of Encyclopædia Britannica (1911), which shows that hydantoin can also be prepared either by heating allantoin and HI or heating bromacetyl urea with alcoholic ammonia.

 

Recent Synthesis Routs:

From the literature survey we found that there are so many methods were developed by different chemists and researchers for hydantoin synthesis in 20th century. But the maximum number of hydantoin derivatives were synthesized and analyzed at end of the 20th century and at the beginning of 21th century. Several routs of these syntheses are described as follows.

 

(a)     S. Paul, M. Gupta, R. Gupta, and A. Loupy (2002) synthesized 1,5-disubstituted hydantoin / thiohydantoins in good yield by a microwave-promoted solvent-free condensation of arylglyoxals and phenylurea/thiourea using polyphosphoric ester (PPE) as a reaction mediator.(Scheme-3) The workup is simple and involves treatment with chilled water.[5]

 

(b)     D. Zhang and co workers (2006) obtained enantiomerically pure hydantoin derivatives from optically pure α-amino amides and triphosgene. A mechanism for the racemization observed with 1,1'-carbonyldiimidazole (CDI) for this type of reaction is proposed[6].(Scheme-4)

 

 

(c)     In 2006 H. M. Hügel, C. J. Rix, and K. Fleck suggested that copper acetate promoted N-arylation of imides with boronic acids can be employed as a major method for the synthesis of N3-aryl hydantoin.[7] (Scheme-5)

 

(d)        Hae-Sun Park and co researchers(2007) invented that Methyl α-anilinophenylacetate in ethanol with KNCO and HCl at low temperature and low pressure during one pot synthesis gives 1,5-diphenylhydantoin derivatives[8]. (Scheme-6)

 

 

Scheme-3: 1,5-disubstituted hydantoin synthesis[5]

 

Scheme-4: Optically active hydantoin synthesis[6]

Scheme-5: N3-aryl hydantoin synthesis[7]

Scheme-6: 1,5-diphenylhydantoin synthesis[8]

 

(e)     B. Zhao, H. Du and Y. Shi(2008) found that an intermolecular α-amination process of esters using Copper(I)chloride as catalyst and di-tert-butyldiaziridinone as nitrogen source gives derivatives of hydantoin effectively under mild reaction conditions.[9] (Scheme-7)

Scheme-7: di-tert-butyldiaziridinone synthesis[9]

 

(f)      F. Olimpieri, A. Volonterio and M. Zanda (2008) studied the reaction of carbodiimides with α-Br(Cl)-aryl acetic acids and concluded that it produces N,N′-substituted 5-arylhydantoins under very mild conditions and high yields. When the carbodiimides are generated in situ by Staudinger reaction, the process becomes a one-pot, three-component sequential synthesis of libraries of differently substituted 5-arylhydantoins[10]. (Scheme-8)

 

Scheme-8: 5-arylhydantoin synthesis[10]

 

(g)     V. M. Patel and K. R. Desai(2005) prepared fluorine containing 1,5-disbstituted hydantoin and thiohydantoin derivatives with the assistance of microwaves by solvent free reactions between arylglyoxals and phenylurea /thiourea using acidic alumina medium as solid support[11]. (Scheme-9)

 

Scheme-9:1,5-disbstituted hydantoin and thiohydantoin synthesis [11]

 

(h)     Volodymyr O. Knizhnikov and co-workers(2013) investigated diastereospecific formation of hydantoins from ketopinic and 4-camphorcarboxylic acids under Bucherer-Bergs reaction conditions. The easiness of this transformation provides a straightforward synthetic pathway to enantiopure conformationally rigid amino acids derivatives, as well as functionalized hydantoin, starting from inexpensive and easily available natural camphor.[12](Scheme-10)

 

Scheme-10: diastereospecific hydantoin synthesis [12]

 

(i)      Qun-li  Zahang  and et. al. (2013) prepared a series of new hydantoin compounds with 3-bromo phenylacetic acid and 3,4-dimethylbromobenzene as starting material, 7-bromo-2-tetralone and 2-bromo-5,6,8,9-tetrahydro-7-benzocyclo-heptenone as intermediate and Ullmann reaction, Suzuki reaction and Bucherer-Berg’s reaction as key steps[13].(Scheme-11)

(j)       

Scheme-11: Hydantoin derivative synthesis[13]

 

(k)     P. P. Mistry and V. A. Desai (2012) studied on the synthesis of 3,5‐disubstituted imidazolidine-2,4-dione via Mannich reaction between various secondary amines and hydantoin derivatives. They prepared 5-alkyl, 5-aryl hydantoin derivatives from aryl ketone and KCN with ammonium carbonate by Bucherer-Bergs reaction mechanism and than merged them with secondary amines to get some bioactive hydantoin derivatives[14].

 

Scheme-12: 3,5‐disubstituted imidazolidine-2,4-dione synthesis[14]

 

(l)      Recently in 2014 Hamdi Rmedi and Ahmed Bakouti described two new methods for the synthesis of a new series of hydantoin using the same reagents. Amog these two the best one is an addition of N-aryloxy (alkoxy) sulfonyl isocyanates to an equimolar mixture of bromoamides and triethylamine dissolved in anhydrous acetone. This reaction is violent and provides the urea salts in situ which are transformed into the corresponding substituted hydantoin[15].

 

Scheme-13: 3,5‐disubstituted imidazolidine-2,4-dione synthesis[15]

 

Medicinal Importance of Hydantoin and its derivatives:

Hydantoin or its derivatives are found in several important medicines. In the beginning phenytoin (P) (Dilantin) (Fig.-2) was traditionally used as an antiepileptic drug molecule. Phenytoin is also used to prevent seizures following neurosurgery. Phenytoin is believed to protect against seizures by causing voltage-dependent block of voltage-gated sodium channels [16-18]. Water soluble Fosphenytoin (F) (Fig.-3) was also approved in the United States for the short term (five days or fewer) treatment of epilepsy.  

 

 

Fig.-2: Phenytoin                                      Fig.-3: Fosphenytoin

 

The invention of biological activities of hydantoin and their analogous has made wonderful progress from its discovery and accelerated from the last two decades. More over it hydantoin derivatives have been therapeutically applied in numbers of diseases either alone or combinational therapy.(Fig.-4).

 

Fig.-4: Medicinal Uses of Hydantoin.

 

 

CONCLUSION:

From the above literature survey it is concluded that hydantoin and its derivatives with different organic and organometallic compound are very much important to medicinal chemists and pharmaceutical industries too. Recent usefulness shows that most of the hydantoin containing moieties are found biological active compounds. Yet there is a vast possibility to explore the better useful route of synthesis with good combination of other bioactive compounds too.

 

REFFERENCES:

1.        (a) Baeyer A. and Liebig J., Ann. Chem., 1861,119, 126. 

(b) Baeyer A. and Liebig J., Ann. Chem.,1864, 130, 129.

2.        Urech F. and Liebig J., Ann. Chem., 1873, 165, 99.

3.        (a) Bucherer H. T. and Brandt W., J. Prakt. Chem., 1934,140,129.

(b)Bucherer H. T. and Steiner W., J. Prakt. Chem., 1934, 140,291 (1934).

(c) Bucherer H. T. and Lieb V.  A., J. Prakt. Chem., 1934, 141, 5.

4.        Bergs, Ger. pat. 566,094 (1929) [C. A., 27, 1001 (1933)].

5.        Paul S., Gupta M., Gupta R., Loupy A., Synthesis, 2002, 1, 75-78.

6.        Zhang D., Xing X., Cuny G. D., J. Org. Chem., 2006, 71, 1750-1753.

7.        Hügel H. M., Rix C. J., Fleck K., Synlett., 2006, 2290-2292.

8.        Park H-S., Choi H-J., Shin H-S., Lee S. K., and Park M-S., Bull. Korean Chem. Soc., 2007, 28(5), 751-757.

9.        B. Zhao, H. Du and Y. Shi, J. Am. Chem. Soc. 2008, 130, 7220-7221.

10.     F. Olimpieri, A. Volonterio and M. Zanda, Synlett., 2008, 3016-3020.

11.     V. M. Patel and K. R. Desai, Ind. J. Chem., 2005, 44B, 1084-1087.

12.     Volodymyr O. Knizhnikova, Zoia V. Voitenkoa, and Marian V. Gorichko, French-Ukrainian, J. of Chem., 2013, 1(1), 23-26.

13.     Zhang Qun-li, Song Li-Jun and Wang En-si, Chem. Res. Chi. Uni., 2013, 29(1), 76-81.

14.     P. P. Mistry and V. A. Desai, Der Chemica Sinica., 2012, 3(5), 1198-1203.

15.     H. Rmedi and A. Baklouti, Tettr. Lett., 2014, 25(26), 3585-3587.

16.     M. A. Rogawski, W. Loscher, Nat. Rev. Neurosci., 2004, 5(7), 553-564.

17.     J. Bosch, T. Roca, J. Domenech, and M. Suriol, Bioorg. Med. Chem. Lett., 1999, 9(13), 1859-1862.

18.     T. Anger, D. J. Madge, M.  Mulla, and D. Riddall, J. Med. Chem., 2001, 44, 115-137.

19.     R. Sarges, J. Bordner, B. W. Dominy, M. J. Peterson, and E. B. Whipple, J. Med. Chem., 1985, 28(11), 1716-1720.

20.     J. P. Rizzi, R. C. Schn, N.  J. Hutson, K.  G. Kraus, and P. R. Kelbaugh, J. Med. Chem.,  1989, 32(6), 1208-1213.

21.     R. Sarges and P. J. Oates, Prog. Drug Res., 1993, 40, 99-161. 

22.     N. Murakami, M. Ohta, K. Kato, K. Nakayama, M. Mizota, I. Miwa, and J. Okuda, Drug Res., 1997, 47,1222-1225.

23.     M. Oka, Y.  Matsumoto,  S. Sugiyama, N. Tsuruta, and M. Matsushima, J. Med. Chem., 2000, 43, 2479-2483.

24.     L. Somshk, L. Kovfics, M. Tbth, E. Osz, L. Szilfigyi, Gyorgydehk, Z. Dinya, T. Docsa, B. Tbth, and P. Gergely,  J. Med. Chem., 2001, 44, 2843-2848.

25.     U. H. Ramadhan, J. of Basrah Res.(Sciences), 2012,38(4A), 26-44.

26.     H. Byrtus, J. Obniska, Anna Czopek  and Krzysztof Kamiński, Archiv der Phrmazie, 2011, 344(4), 231-241.

27.     S.-K. Kwon and M.-S. Park, J. Med. Chem., 1991, 34, 1845-1849.

28.     H. U. Stilz, B. Jablonka, M. Just, J. Knolle, E. F. Paulus, and G. Zoller, J. Med. Chem., 1996,  39(11), 2118-2122.

29.     P. Barraclough, M. L. Bolofo, H. Giles, J. Gillam, C. J. Harris, M. G. Kelly, P. Leff, A. McNeill, A. D. Robertson, R. J. Stepney, and B. J. R. Whittle, Bioorg. Med. Chem., 1996, 4(1), 81-90.

30.     G. Zoller, W. Konig, J. Knolle, M. Just and B. Jablonka, US5397796 A, (1995)

31.     M. A. Khanfar, K. A. El Sayed, Euro. J. Med. Chem., 2010, 45(11), 5397-5405.    

32.     R. Severinsen,  J. F. Lau, K. Bondensgaard,  B. S. Hansen, M. Begtrup,  and M. Ankersen, Bioorg. Med. Chem., Lett., 2004, 14,317.

33.     H. Elokdah, T. S. Sulkowski, M. Abou-Gharbia, J. A. Butera, S.-Y. Chai, G. R. McFarlane, M.-L. McKean, J. L. Babiak, S.  J. Adelman, and E. M. Quinet, J. Med. Chem., 2004,  47, 681.

34.     G. Singh, P.H. Driever, J.W. Sander and L. Sander, Brain, 2005,128, 7-17.

35.     N. Opacic, et. al., J. Med. Chem., 2005, 48, 475-482.

36.     T. Marcelli, F. Olimpieri and A. Volonterio, Org. Biomol. Chem., 2011, 9, 5156-5161.

37.     D. Kim, and et. al., Bioorg. Med. Chem. Lett., 2001, 11, 3099.

38.     Y. Verlinden, A. Cuconati, E. Wimmer, and B. Rombaut, Antiviral Res., 2000, 48, 61.

39.     M. Collin, C. Thiemermann, Eur. J. Pharmacol., 2003, 29, 257-258.

40.     M. Mudit, F. A. Behery,  V. B. Wali, P. W. Sylvester, K. A.  El Sayed, Nat. Prod. Commu., 2010, 5(10), 1623-1626.

41.     P. Marinova and et. al., Comp. Rendus de l’Academie bulgare des Sciences., 2014, 67(4), 513-518.

42.     A. H. Abadi, J. Lehmann, G. A. Piazza, Md. Abdel-Halim, and Md. S. M. Ali, Int. J. Med. Chem., 2011,11, 1-9.

43.     H. A. Mohamed and et. al., J. Med. Chem., 2011, 54(2), 495-509.

44.     York Jr. B. M. US4438272 (1984)

45.     A. Ahmedova, P. Marinova, K. Paradowska, M. Marinov, I. Wawer, M. Mitewa, Polyhedron, 2010, 29, 1639-1645.

46.     Yuyu Sun and Gang Sun, J. Appl.Poly. Sci., 2001, 80(13), 2460-2467.

47.     Vinod B., Selvakumar D. and Chacko B. K., Int. J. Pharm. Bio. Sci., 2013, 4(1), 759-767.

48.     Menendez J. C. and et. al., Eur. J. Med.Chem., 1992, 21, 61-66.

49.     Spengler G. and et. al., Antican. Res., 2010, 30, 4867-4872.

50.     Trisovic N. and et. al., Monat. Fur chemie Chemical, 2011, 142(12), 1227-1234.

51.     Dylag T. and et. al., Eur. J. Med. Chem., 2004, 39, 1013-1027.

52.     Savjani J. K. and Gajjar A. K., Pak. J. Bio. Sci., 2011, 14(24), 1076-1089.

 

 

 

 

Received on 31.03.2015          Accepted on 22.04.2015        

© Asian Pharma Press All Right Reserved

Asian J. Pharm. Tech.  2015; Vol. 5: Issue 3, July- Sept. Pg 153-157

DOI: 10.5958/2231-5713.2015.00022.7