YE Jiao XIE Xuan-Qing LI Kang-Ming LIU Yong-Chao SUN Li HU Ai-Xi

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Synthesis, Crystal Structure and Antitumor Activity of 4-(-butyl)-5-(1-1,2,4-triazol-1-yl)--(2-hydroxy-3,5-diiodinebenzyl)-thiazol-2-amine①

YE Jiao②XIE Xuan-Qing LI Kang-Ming LIU Yong-Chao SUN Li HU Ai-Xi②

(410082)

The title compound, 4-(-butyl)-5-(1-1,2,4-triazol-1-yl)--(2-hydroxy-3,5-diio- dinebenzyl)thiazol-2-amine, was synthesized via the reduction of 4-(-butyl)-5-(1-1,2,4- triazol-1-yl)--benzylidene-thiazol-2-amine with NaBH4, and its crystal structure was determined by single-crystal X-ray diffraction. The compound crystallizes in monoclinic system, space group21/with= 7.91944(19),= 10.5250(3),= 24.4985(6) ?,= 4,= 2041.66(9) ?3,M= 599.22,D= 1.949 Mg/m3,= 1.120,= 3.203 mm-1,(000) = 1152, the final= 0.0283 and= 0.0592 for 3490 observed reflections (> 2()). X-ray analysis displays that the crystal water takes part in three intermolecular hydrogen bonds of O(2)–H(2A)···O(1), O(2)–H(2B)···N(1) and N(5)–H(5)···O(2), and an octatomic ringis formed via intramolecular hydrogen bond of O(1)–H(1A)···N(4). Furthermore, the I···I contacts are involved in stabilizing the overall three-dimensional network structure. The preliminary biological test shows the title compound has good antitumor activity with the IC50value of 26 μM against thecell line.

4-(-butyl)-5-(1-1,2,4-triazol-1-yl)--(2-hydroxy-3,5-diiodinebenzyl)-thiazol-2-amine, synthesis, crystal structure, antitumor activity;

1 INTRODUCTION

Thiazole derivatives are often used as the inter- mediate in medicines and pesticides due to their broad range of biological activities[1-5]. Meanwhile, Schiff-base, which comes from the condensation reaction of primary amine and carbonyl com- pound[6], has also beenstudied in depth because of its varied potential biological activities[7], such as antimicrobial[8, 9], anti-inflammatory[10], antihyper- tensive[11], antiviral[12]and anticancer[13-15]. Recently, we have synthesized a thiazole Schiff-base,4-(- butyl)-5-(1-1,2,4-triazol-1-yl)--(2-hydroxy-3,5-diiodinebenzylidene)-thiazol-2-amine (1), which shows good antitumor activities and broad-spectrum fungicidal activities[15]. However, to the best of our knowledge, Schiff-base is unstable and easy to hy- drolyze in solution. Hereon, a thiazole benzylamine, 4-(-butyl)-5-(1-1,2,4-triazol-1-yl)--(2-hydro-xy-3,5-diiodinebenzyl)-thiazol-2-amine (2), was synthesized from the reduction of thiazole Schiff- base to find a new scaffold with better antitumor activity. Scheme 1 depicts the synthetic route of compound 2.

Scheme 1. Synthetic route of compound 2

2 EXPERIMENTAL

2. 1 Generals

All solvents were of reagent grade. All chemicals were of analytical reagent grade and used directly without further puri?cation. Melting point was measured on an X-4 electrothermal digital melting point apparatus and uncorrected.1H NMR spectra were recorded on a Bruker advanced instrument with TMS as the internal standard at 400 MHz (chemical shifts () in ppm). Crystal structure deter- mination was executed on a Bruker AXS SMART 1000 CCD diffractometer. Thecell line was offered by Xiangya Medical College.

2. 2 Synthesis of the title compound 2

Compound 1 was synthesized according to literature[15]. NaBH4(2 mmol) was added to a solution of 1 (2 mmol) in EtOH (20 mL) in batches, and the mixture was stirred at room temperature for 15 min till the reaction was completed (monitored by TLC). Then the solution was acidified to pH 6～7 with HCl (aq) and poured into water (100 mL). Finally, the precipitate was separated and washed with water to afford the white solid 2. Yield: 89%, m.p.: 178～180 ℃.1H NMR (CDCl3, 400 MHz),: 1.19 (s, 9H, 3 × CH3), 4.48 (s, 2H, NCH2), 6.19 (s, 1H, NH), 7.43 (d,= 1.6 Hz, 1H, C6H2), 7.98 (d,= 1.6 Hz, 1H, C6H2), 8.07 (s, 1H, C2N3H2), 8.21 (s, 1H, C2N3H2), 10.93 (s, 1H, OH).

2. 3 X-ray structure determination

The title compound 2 was dissolved in EtOH and kept for self-volatilization. The colorless crystals suitable for X-ray structure determination were ob- tained after about 12 days with dimensions of 0.41mm × 0.29mm × 0.18mm. Crystal X-ray intensity data were measured on a Bruker AXS SMART 1000 CCD diffractometer equipped with a graphite-monochromatic Mo(= 0.71073 ?) radiation at 150 K. Out of the total 10238 reflec- tions collected in the range of 2.69<<26.00°, 4007 were independent (int= 0.0292) and 3490 were considered to be observed (> 2()) and used in the succeeding refinement. Corrections for incident and empirical adsorption adjustment were applied with SADABS[16], and the structure was solved with SHELXS-97 program[17]and expanded by dif- ference Fourier techniques. All non-hydrogen atoms were refined anisotropically and all H atoms were located at the theoretical positions. The structure was refined by full-matrix least-squares techniques on2with SHELXL-97[18]. The final= 0.0283 and= 0.0592 (= 1/[2(F2) + (0.0259)2], where= (F2+ 2F2)/3).= 1.120, (Δ/)max= 0.001, (?)max= 0.569 and (?)min= –0.916 e×??3.

2. 4 Bioassay of the antitumor activities

Compound 2 was further tested in terms of anti- tumor activity using the typical MTT assay accor- ding to the literature[19].

3 RESULTS AND DISCUSSION

The1H NMR for the product is in good agreement with the structure of the title compound. The com- pound crystallizes in monoclinic system, space group21/with= 7.91944(19),= 10.5250(3),= 24.4985(6) ?,= 4,= 2041.66(9) ?3,M= 599.22,D= 1.949 Mg/m3,= 1.12,= 3.203 mm-1,(000) = 1152, the final= 0.0283 and= 0.0592 for 3490 observed reflections (> 2()). The perspective view of the title compound with atomic numbering scheme is given in Fig. 1. It can be seen from Fig. 1 that each of the title molecule contains one crystal water molecule. The selected bond lengths and bond angles are listed in Table 1.

Table 1. Selected Bond Lengths (?) and Bond Angles (°)

Fig. 1 . X-ray crystal structure of the title compound with atom labels

According to the previous study[15], the thiazole ring, C=N and phenyl ring of thiazole Schiff-base 1 are approximately coplanar because of the con- jugated structure; while in compound 2, the con- jugated bond of C=N is broken, electron density of nitrogen-atoms goes up, and the C–N bond length increases. As shown in Table 1, the bond length of C(10)–N(5) is 1.452 ?, slightly shorter than the typical C–N single bond[20], but still within the scope of single bond. Meanwhile, the benzyl ring deviates from the plane of thiazole with the C(10) becoming3hybridized. The torsion angle of C(11)–C(10)–N(5)–C(9) in compound 2 is 67.4(4)o, which makes the corresponding dihedral angle of the thiazole and benzene rings change from 9.09oin compound 1 to 69.36° in 2. In addition, the thiazole ring is almost perpendicular to the triazole group with a dihedral angle of 79.65°.

There are four kinds of hydrogen bonds in the crystal (Table 2). The water molecule takes part in three intermolecular hydrogen bonds with three adjacent molecules (Fig. 2). The O atom of wateracts as two hydrogen-bond donors to the N atom of triazole ring and the O atom of hydroxyl group,and a hydrogen-bond receptor to the N atom of benzylamine group, forming three hydrogen bonds of O(2)–H(2B)···N(1), O(2)–H(2A)···O(1) and N(5)–H(5)···O(2), which contribute to the forma tion of a two-dimensional framework in the crystal structure. At the same time, an octatomic ringof N(4)–C(9)–N(5)–C(10)–C(11)–C(12)–O(1)–H(1A) is formed via intramolecular hydrogen bond of O(1)–H(1A)···N(4). Furthermore, as shown in Fig. 3, some very clear I···I contacts are involved in stabilizing the overall three-dimensional network structure by forming zig-zag chains, and the bond length of I···I is 3.7047(3) ?.

Table 2. Hydrogen Bond Lengths (?) and Bond Angles (°)

Symmetry codes: (#1),–1,; (#2)–1,,

Fig. 2 . Two-dimensional structure of the title compound with hydrogen bonds

Fig. 3 . Zig-zag chains of the title compound with I···I contacts

Compound 2 was tested for antitumor activity against cervix cancercell line. The IC50value of compound 2 is 26 μM, which is close to that of Cisplatin (IC5020 μM) and better than that of compound 1 (IC5074 μM). The result indicates that the thiazole benzylamine2 is a better scaffold than the thiazole Schiff-base in antitumor activity and seems to be a suitable candidate for further researches.

(1) Faith, M.; Mathew, N.; Krupa, N.; Carmen, D. K.; Peter, J. S.; Valerie, M.; Digby, W.; Kelly, C. Synthesis and biological evaluation of 2-aminothiazole derivatives as antimycobacterial and antiplasmodial agents.2014, 24, 560–564.

(2) Siddiqui, N.; Kumar, S.; Ahsan, W.; Azad, B. Diverse biological activities of thiazoles: a retrospect.2011, 3, 55–67.

(3) Mickevi?ius, V.; Voskien?, A.; Jonu?kien?, I.; Kolosej, R.; ?iug?dait?, J.; Venskutonis, P. R.; Kazernavi?iūt?, R.; Brazien?, Z.; Jakien?, E. Synthesis and biological activity of 3-[phenyl(1,3-thiazol-2-yl)-amino]propanoic acids and their derivatives.2013, 18, 15000–15018.

(4) Ankit, K. J.; Rajeev, K. S.; Birendra, S. Thiazole: a remarkable antimicrobial and antioxidant agents.2011, 2, 1072–1084.

(5) Zheng, S.; Zhong, Q.; Jiang, Q.; Mottamal, M.; Zhang, Q.; Zhu, N.; Burrow, M. E.; Worthylake, R. A.; Wang, G. Modification and biological evaluation of thiazole derivatives as novel inhibitors of metastatic cancer cell migration and invasion.2013, 4, 191–196.

(6) Bell, S. C.; Conklin, G. L.; Childress, S. J. The separation of ketimine isomers.1963, 85, 2868–2869.

(7) Kajal, A.; Bala, S.; Kamboj, S.; Sharma, N.; Saini, V. Schiff bases: a versatile pharmacophore.2013, 2013, 1–14.

(8) Da Silvaa, C. M.; Da Silvaa, D. L.; Modolob, L. V.; Alvesa, R. B.; De Resendec, M. A.; Martinsc, C. V. B.;De Fátima, ?. Schiff bases: a short review of their antimicrobial activities.2011, 2, 1–8.

(9) Sabry, N. M.; Flefel, E. M.; Al-Omar, M. A.; Amr, A. E. Synthesis and antimicrobial activities of some new synthesized imide and Schiff’s base derivatives.2013, 2013, 1–6.

(10) Vazzana, I.; Terranova, E.; Mattioli, F.; Sparatore, F. Aromatic Schiff bases and 2,3-disubstituted-1,3-thiazolidin-4-one derivatives as antiinflammatory agents.2004, v, 364–374.

(11) Sharma, M. C.; Kohli, D. V.; Sharma, S.; Sharma, A. D. Synthesis and antihypertensive activity of Schiff bases of 4?-(6-chloro-5-nitro-2-[4-(3- substituted-phenyl-acryloylamino)-phenyl]-benzimidazole-1-ylmethyl)-biphenyl-2-carboxylic acids.2010, 1, 120–132.

(12) Kumar, K. S.; Ganguly, S.; Veerasamy, R.; Clercq, E. D. Synthesis, antiviral activity and cytotoxicity evaluation of Schiff bases of some 2-phenyl quinazoline-4(3)H-ones.2010, 45, 5474–5479.

(13) Shukla, S.; Srivastava, R. S.; Shrivastava, S. K.; Sodhi, A.; Kumar, P. Synthesis, characterization, in vitro anticancer activity, and docking of Schiff bases of 4-amino-1,2-naphthoquinone.2013, 22, 1607–1617.

(14) Sunil, D.; Isloor, A. M.; Shetty, P.; Nayak, P. G.; Pai, K. S. R. In vivo anticancer and histopathology studies of Schiff bases on Ehrlich ascitic carcinoma cells.2013, 6, 25–33.

(15) Hu, A. X.; Qin, Z.; Chen, P.; Ye, J. Synthesis and application of 4-tert-butyl-5-(1,2,4-triazol-1-yl)-2-benzylimino thiazole.2011.

(16) Sheldrick, G. M.University of G?ttingen, Germany 2004.

(17) Sheldrick, G. M.University of G?ttingen, Germany 1997.

(18) Sheldrick, G. M.University of G?ttingen, Germany 1997.

(19) Hu, A. X.; Qin, Z.; Ye, J.; Xia, S. Synthesis, crystal structure and antitumor activity of (E)-4-tert-butyl-N-(2,4-dichlorobenzylidene)-5-(1,2,4- triazol-1-yl)-thiazol-2-amine.2010, 29, 1680–1683.

(20) Chen, X. M.; Cai, J. W.Science Press: Beijing 2003, 114–115.

9 October 2014; accepted 13 November 2014 (CCDC 1026465)

① Project supported by the National Undergraduate Training Programs for Innovation and Entrepreneurship of Hunan University and the Natural Science Foundation of Hunan Province (No. 12jj3012)

② Corresponding author. Born in 1971, associate professor, majoring in medicinal chemistry. E-mail: yejiao@hnu.edu.cn

. Born in 1957, professor, majoring in medicinal chemistry. E-mail: axhu@hnu.edu.cn

10.14102/j.cnki.0254-5861.2011-0530