Stereoselective synthesis, X-ray analysis, computational studies and biological evaluation of new thiazole derivatives as potential anticancer agents
© The Author(s) 2018
Received: 3 February 2018
Accepted: 26 April 2018
Published: 11 May 2018
The synthesis of new thiazole derivatives is very important because of their diverse biological activities. Also , many drugs containing thiazole ring in their skeletons are available in the market such as Abafungin, Acotiamide, Alagebrium, Amiphenazole, Brecanavir, Carumonam, Cefepime, and Cefmatilen.
Ethyl cyanoacetate reacted with phenylisothiocyanate, chloroacetone, in two different basic mediums to afford the thiazole derivative 6, which reacted with dimethylformamide- dimethyl acetal in the presence of DMF to afford the unexpected thiazole derivative 11. The structures of the thiazoles 6 and 11 were optimized using B3LYP/6-31G(d,p) method. The experimentally and theoretically geometric parameters agreed very well. Also, the natural charges at the different atomic sites were predicted. HOMO and LUMO demands were discussed. The anticancer activity of the prepared compounds was evaluated and showed moderate activity.
Currently marketed anticancer medications have increasing problems of various toxic side effects and development of resistance to their action. So, there is an urgent clinical need for the synthesis of novel anticancer agents that are potentially more effective and have higher safety profile. The synthesis of different thiazole derivatives has attracted great attention due to their diverse biological activities that include anticonvulsant [1, 2], antimicrobial [3, 4], anti-inflammatory [5, 6], anticancer , antidiabetic , anti-HIV , anti-Alzheimer , antihypertensive , and antioxidant activities . The reaction between active methylene compounds with phenylisothiocyanate and α-haloketones in DMF in the presence of potassium hydroxide is the simple and convenient method for the synthesis of many thiazole derivatives [13–15]. In continuation of our interest in the synthesis of new biologically active heterocyclic rings [16–22] and motivated by these information, it was thought worthwhile to synthesize some novel thiazole derivatives and to test their antitumor activity in order to discover new potentially biologically active drugs of synthetic origin.
Results and discussion
The thiazole derivative 6 was previously obtained by the reaction of ethyl cyanoacetate with phenylisothiocyanate and propargyl bromide in DMF-NaH . The presence of many functional groups attached to this bioactive thiazole ring motivated us to prepare it again to use it as a precursor for some new heterocycles bearing the bioactive thiazole ring. In this research, we used, instead of propargyl bromide, other reagents, such as chloroacetone, and we studied the configuration of the isolated products.
In many reports dimethylformamide were used as a formylating agent for indole , thiophene , and substituted benzene . Based on these information, we suggested that the reaction was started via formylation of thiazole derivative 6 by DMF to afford the formyl derivative 7, which involved a reversible opening of the thiazole ring to give intermediate 8. The subsequent cyclization of 8 afforded 9, which underwent dehydration to give the methyl ketone 10. Reaction of intermediate 10 with dimethylformamide-dimethylacetal (DMF-DMA) afforded the unexpected thiazole derivative 11 (Scheme 2).
For more details see (Additional file 1: Tables S1–S6) (these files are available in the ESI section).
Charge population analysis
Frontier molecular orbitals
Viability values and IC50 of thiophenes 6 and 11 against HCT-116 Cell Line
Sample concentration (μg/mL) viability %
All the melting points were measured on a Gallen Kamp apparatus in open glass capillaries and are uncorrected. The IR Spectra were recorded using Nicolet 6700 FT-IR spectrophotometer. 1H- and 13C-NMR spectra were recorded on a JEOL ECP 400 NMR spectrometer operating at 400 MHz in deuterated chloroform (CDCl3) as solvent and TMS as an internal standard; chemical shifts δ are expressed in ppm units. Mass spectra were recorded on a Shimadzu GCMS-QP 1000 EX mass spectrometer (Tokyo, Japan) at 70 eV. Elemental analysis was carried out on a 2400 CHN Elemental Analyzer. The single-crystal X-ray diffraction measurements were accomplished on a Bruker SMART APEX II CCD diffractometer. The biological evaluations of the products were carried out in the Medical Mycology Laboratory of the Regional Center for Mycology and Biotechnology of Al-Azhar University, Cairo, Egypt.
Synthesis of (Z)-ethyl 2-cyano-2-(4-methyl-3-phenylthiazol-2(3H)-ylidene)acetate (6)
To a stirred solution of ethyl cyanoacetate (1.13 g, 1.07 mL, 10 mmol), in dimethylformamide (10 mL) was added potassium carbonate (1.38 g, 10 mmol). Stirring was continued at room temperature for 30 min, then phenylisothiocyanate (1.35 g, 1.2 mL, 10 mmol) was added dropwise to this mixture and stirring was continued for another 1 h. To this reaction mixture, chloroacetone (0.92 g, 0.8 mL, 10 mmol) was added and the mixture was stirred for additional 3 h at room temperature. Finally, the content was poured on cold water (50 mL). The crude solid product was filtered off and recrystallized from DMF, yield 85%, mp. 215 °C [lit mp . 190 °C]; IR (KBr)vmax1680 (CO), 2214 (C≡N), 2988 (aliphatic, CH), 3281(aromatic, CH) cm−1; 1H NMR (400 MHz, CDCl3): δ 1.19 (t, 3H. CH3, J = 7.2 Hz), 1.84 (s, 3H, CH3), 4.15 (q, 2H, CH2, J = 7.2 Hz), 6.39 (s, 1H. 5-H), 7.20–7.55 (m, 5H, Ar–H); 13C NMR (100 MHz, CDCl3): δ 14.46, 29.59, 60.48, 66.36, 105.62, 115.22, 128.72, 129.88, 131.07, 136.26, 138.45, 167.94, 168.05. Anal. calcd. for C15H14N2O2S: C, 62.92; H, 4.93; N, 9.78 Found: C, 62.89; H, 4.88; N, 9.79.
A mixture of ethyl cyanoacetate (1.13 g, 1.07 mL, 10 mmol) in sodium ethoxide (0.23 g Sodium in 10 ml of absolute ethanol) was stirred for 10 min. To this mixture, phenyl isothiocyanate (1.35 g, 10 mmol) was added dropwise and the mixture was stirred for another 1 h. Chloroacetone (0.92 g, 0.8 mL, 10 mmol) was added to the reaction mixture and stirring was continued for 3 h. Finally, it was poured on cold water and the solid precipitate that formed was filtered and recrystallized from DMF to afford the same product which obtained from method A, yield 65%.
Synthesis of (Z)-ethyl 2-cyano-2-(5-((E)-3-(dimethylamino)acryloyl)-3-phenyl thiazol-2(3H)-ylidene)acetate (11)
A mixture of thiazole 6 (2.86 g, 10 mmol) and DMF-DMA (1.19 g, 1.33 mL, 10 mmol) in DMF (3 mL) was heated on a water bath for 1 h, then left to cool to room temperature. The precipitated solid filtered off, washed with EtOH and recrystallized from DMF to afford the thiazole derivative 11 in 82% yield, m.p. 260 °C; IR (KBr) vmax 1669 (C=O), 2189 (C≡N), 2928 (aliphatic, CH), 3056 (aromatic, CH) cm−1; 1H NMR (400 MHz, CDCl3): δ 1.26 (t, 3H. CH3, J = 7.3 Hz), 2.88 (s, 3H, CH3), 3.16 (s, 3H, CH3), 4.21 (q, 2H, CH2, J = 7.3 Hz), 5.28 (d, 1H, CH, J = 12.5 Hz), 7.43–7.56 (m, 7H, Ar–H); MS m/z (%) 369 (M+, 23.78), 299 (0.98), 271(1.36), 98 (100), 77 (10.05), 70 (7.8). calcd. for C19H19N3O3S: C, 61.77; H, 5.18; N, 11.37. Found: 61.82; H, 5.21; N, 11.28.
The thiazoles of 6 and 11 were obtained as single crystals by slow evaporation from DMF solution of the pure compound at room temperature. Data were collected on a BrukerAPEX-II D8 Venture area diffractometer, equipped with graphite monochromatic Mo Kα radiation, λ = 0.71073 Å at 100 (2) K. Cell refinement and data reduction were carried out by Bruker SAINT. SHELXT [30, 31] was used to solve structure. The final refinement was carried out by full-matrix least-squares techniques with anisotropic thermal data for nonhydrogen atoms on F. CCDC 1504892 and 1505279 contain the supplementary crystallographic data for this compound can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
The X-ray structure coordinates of the studied thiazoles were used for geometry optimization followed by frequency calculations. For this task, we used Gaussian 03 software  and B3LYP/6‒31G(d,p) method. All obtained frequencies are positive, and no imaginary modes were detected. GaussView4.1  and Chemcraft  programs have been used to extract the calculation results and to visualize the optimized structures.
Stereoselective synthesis of (Z)-ethyl 2-cyano-2-(4-methyl-3-phenylthiazol-2(3H)-ylidene) acetate (6) and its unexpected reaction with DMF-DMA gave (Z)-ethyl 2-cyano-2-(5-((E)-3-(dimethylamino)acryloyl)-3-phenylthiazol-2(3H)-ylidene)acetate (11). Optimized molecular structures at the B3LYP/6-31G(d,p) level are presented. Thiazole 11 has more electropositive S-atom than Thiazole 6. The HOMO–LUMO energy gap is lower in the former compared to the latter. The cytotoxic activity of the synthesized thiazoles was evaluated and the results revealed that thiazole derivative 11 had more activity than thiazole derivative 6.
YNM, NAK and SSA designed research; MMA, HAG, SMS and WF performed research, analyzed the data, wrote the paper. All authors read and approved the final manuscript.
The authors extend their sincere appreciation to the Deanship of Scientific Research at the King Saud University for its funding this Prolific Research group (PRG-007).
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
- Satoh A, Nagatomi Y, Hirata Y, Ito S, Suzuki G, Kimura T, Maehara S, Hikichi H, Satow A, Hata M, Ohta H, Kawamoto H (2009) Discovery and in vitro and in vivo profiles of 4-fluoro-N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-N- methylbenzamide as novel class of an orally active metabotropic glutamate receptor 1 (mGluR1) antagonist. Bioorg Med Chem Lett 19:5464–5468View ArticleGoogle Scholar
- Siddiqui N, Ahsan W (2011) Synthesis, anticonvulsant and toxicity screening of thiazolyl–thiadiazole derivatives. Med Chem Res 20:261–268View ArticleGoogle Scholar
- Dawane BS, Konda SG, Mandawad GG, Shaikh BM (2010) Poly(ethylene glycol) (PEG-400) as an alternative reaction solvent for the synthesis of some new 1-(4-(4′-chlorophenyl)-2-thiazolyl)-3-aryl-5-(2-butyl-4-chloro-1H-imidazol-5yl)-2-pyrazolines and their in vitro antimicrobial evaluation. Eur J Med Chem 45:387–392View ArticleGoogle Scholar
- Adibpour N, Khalaj A, Rajabalian S (2010) Synthesis and antibacterial activity of isothiazolyloxazolidinones and analogous 3(2H)-isothiazolones. Eur J Med Chem 45:19–24View ArticleGoogle Scholar
- Sondhi SM, Singh N, Lahoti AM, Bajaj K, Kumar A, Lozach O, Meijer L (2005) Synthesis of acridinyl-thiazolino derivatives and their evaluation for anti-inflammatory, analgesic and kinase inhibition activities. Bioorg Med Chem 13:4291–4299View ArticleGoogle Scholar
- Singh N, Bhati SK, Kumar A (2008) Thiazolyl/oxazolylformazanylindoles as potent anti-inflammatory agents. Eur J Med Chem 43:2597–2609View ArticleGoogle Scholar
- Luzina EL, Popov AV (2009) Synthesis and anticancer activity of N-bis(trifluoromethyl)alkyl-N’-thiazolyl and N-bis(trifluoromethyl)alkyl-N’-benzo- thiazolylureas. Eur J Med Chem 44:4944–4953View ArticleGoogle Scholar
- Iino T, Hashimoto N, Sasaki K, Ohyama S, Yoshimoto R, Hosaka H, Hasegawa T, Chiba M, Nagata Y, Nishimura JET (2009) Structure activity relationships of 3,5-disubstituted benzamides as glucokinase activators with potent in vivo efficacy. Bioorg Med Chem 17:3800–3809View ArticleGoogle Scholar
- Rawal RK, Tripathi R, Katti SB, Pannecouque C, Clercq ED (2008) Design and synthesis of 2-(2,6-dibromophenyl)-3-heteroaryl-1,3-thiazolidin-4-ones as anti-HIV agents. Eur J Med Chem 43:2800–2806View ArticleGoogle Scholar
- Shiradkar MR, Akula KC, Dasari V, Baru V, Chiningiri B, Gandhi S, Kaur R (2007) Clubbed thiazoles by MAOS: a novel approach to cyclin-dependent kinase 5/p25 inhibitors as a potential treatment for Alzheimer’s disease. Bioorg Med Chem 15:2601–2610View ArticleGoogle Scholar
- Turan-Zitouni G, Chevallet P, Kiliç FS, Erol K (2000) Synthesis of some thiazolyl-pyrazoline derivatives and preliminary investigation of their hypotensive activity. Eur J Med Chem 35:635–641View ArticleGoogle Scholar
- Shih MH, Ke FY (2004) Syntheses and evaluation of antioxidant activity of sydnonyl substituted thiazolidinone and thiazoline derivatives. Bioorg Med Chem 12:4633–4643View ArticleGoogle Scholar
- Kheder NA, Riyadh SM, Asiry AM (2013) Azoles and bis-azoles: synthesis and biological evaluation as antimicrobial and anti-cancer Agents. Chem Pharm Bull 61:504–510View ArticleGoogle Scholar
- Dawood KM, Abdel-Gawad H, Rageb EA, Ellithey M, Mohamed HA (2006) Synthesis, anticonvulsant, and anti-inflammatory evaluation of some new benzotriazole and benzofuran-based heterocycles. Bioorg Med Chem 14:3672–3680View ArticleGoogle Scholar
- Farag AM, Dawood KM, Elmenoufy HA (2004) A convenient route to pyridones, pyrazolo[2,3-a]pyrimidines and pyrazolo[5,1-c]triazines incorporating antipyrine moiety. Heteroat Chem 15:508–514View ArticleGoogle Scholar
- Gomha SM, Kheder NA, Abdelaziz MR, Mabkhot YN, Alhajoj AM (2017) A facile synthesis and anticancer activity of some novel thiazoles carrying 1,3,4-thiadiazole moiety. Chem Cent J 11:25View ArticleGoogle Scholar
- Mabkhot YN, Alatibi F, El-Sayed NN, Al-Showiman S, Kheder NA, Wadood A, Rauf A, Bawazeer S, Hadda T (2016) Antimicrobial activity of some novel armed thiophene derivatives and petra/osiris/molinspiration (POM) analyses. Molecules 21:222View ArticleGoogle Scholar
- Mabkhot YN, Kheder NA, Barakat A, Choudhary MI, Yousuf S, Frey W (2016) Synthesis, antimicrobial, anti-cancer and molecular docking of two novel hitherto unreported thiophenes. RSC Adv. 6:63724–63729View ArticleGoogle Scholar
- Gomha SM, Kheder NA, Abdelhamid AO, Mabkhot YN (2016) One pot single step synthesis and biological evaluation of some novel Bis(1,3,4-thiadiazole) derivatives as potential cytotoxic agents. Molecules 21:1532View ArticleGoogle Scholar
- Mabkhot YN, Alatibi F, El-Sayed NNE, Kheder NA, Al-Showiman SS (2016) Synthesis and structure-activity relationship of some new thiophene-based heterocycles as potential antimicrobial agents. Molecules 21:1036View ArticleGoogle Scholar
- Farag AM, Kheder NA, Mabkhot YN (2009) Synthesis and antimicrobial evaluation of new pyrazole, thiophene, thiazole and 1,3,4-thiadiazole derivatives incorporating pyrimidine ring. Heterocycles 78:1787–1798View ArticleGoogle Scholar
- Kheder NA, Mabkhot YN, Farag AM (2008) Synthesis and antimicrobial evaluation of some new pyrimidine derivatives. Heterocycles 75:887–897View ArticleGoogle Scholar
- Ram VJ, Haque N, Singh SK, Nath M, Shoeb A (1994) Polarized ketene dithioacetals-part ii: synthesis of S, S- and S, N-cyclic ketene dithioacetals and their transformation to azoles and 1,3-dithiole-2-thiones. Phosphorus Sulfur Silicon Relat Elem 88:155–161View ArticleGoogle Scholar
- The crystallographic data for thiazole 6 (CCDC 1504892) and thiazole 11 (CCDC 1505279) can be obtained free of charge from the Cambridge Crystallographic Data Center via www.ccdc.cam.ac.uk/data_request/cif
- Tyson FT, Shaw JT (1952) A new approach to 3-indolecarboxaldehyde. J Am Chem Soc 74:2273–2274View ArticleGoogle Scholar
- Emerson WS, Patrick TM Jr (1952) U.S. Patent 2,581,009, C.A, 46, 9610, 1 Jan 1952Google Scholar
- Campaigne E, Archer WL (1953) The use of dimethylformamide as a formylation reagent. J Am Chem Soc 75:989–991View ArticleGoogle Scholar
- Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63View ArticleGoogle Scholar
- Elaasser MM, Abdel-Aziz MM, El-Kassas RA (2011) Antioxidant, antimicrobial, antiviral and antitumor activities of pyranone derivative obtained from Aspergillus candidus. J Microbiol Biotech Res 1:5–17Google Scholar
- Sheldrick GM (2008) A short history of SHELX. Acta Crystallogr A 64:112–122View ArticleGoogle Scholar
- Sheldrick GM (1997) SHELXTL-PC (Version 5.1). Siemens Analytical Instruments, Inc., Madison, WI, USAGoogle Scholar
- Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Montgomery JA Jr, Vreven T, Kudin KN, Burant JC et al (2004) Gaussian–03, Revision C.01. Gaussian Inc, Wallingford, CT, USAGoogle Scholar
- Dennington RDII, Keith TA, Millam J (2007) Gauss View, Version 4.1. Semichem Inc, Shawnee Mission, KS, USAGoogle Scholar
- Zhurko GA, Zhurko DA (2005) Chemcraft. Lite Version Build 08. Available online: http://www.chemcraftprog.com/. Accessed 1 Apr 2005