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Asian Journal of Chemistry; Vol Asian Journal of Chemistry; Vol. 26, No. 10 (2014), 2921-2926 ASIAN JOURNAL OF CHEMISTRY http://dx.doi.org/10.14233/ajchem.2014.16038 Synthesis, Antibacterial Evaluation and Molecular Docking Study of Nitazoxanide Analogues * X.W. LIU, H. ZHANG, Y.J. YANG, J.Y. LI , B. LI, X.Z. ZHOU and J.Y. ZHANG Key Laboratory of New Animal Drug Project, Gansu Province; Key Laboratory of Veterinary Pharmaceutical Development, Ministry of Agriculture; Lanzhou Institute of Husbandry and Pharmaceutical Sciences of CAAS, Lanzhou 730050, P. R. China *Corresponding author: Tel/Fax: +86 931 2115290; E-mail: [email protected]; [email protected] Received: 11 July 2013; Accepted: 21 August 2013; Published online: 10 May 2014; AJC-15149 A series of nitazoxanide analogues were synthesized and characterized by means of 1H NMR, 13C NMR and HR-MS. The antibacterial activities of synthesized compounds against Clostridium difficile were evaluated and 1d was the most promising compound. The preliminary results showed that compounds containing nitro-substituted thiazole ring displayed notable activities. Compounds that thiazole moiety replaced by a pyrimidine ring exhibited moderate activities. Molecular docking study of nitazoxanide and 1d with pyruvate ferredoxin oxidoreductase suggested that the nitro group interacts with thiamine pyrophosphate and surrounding amino acids, which were almost same compared with pyruvate. The results revealed that nitazoxanide may be a competitive inhibitor of pyruvate and nitro-group is necessary for thiazolide's activities against anaerobic organisms containing pyruvate ferredoxin oxidoreductase enzyme. Keywords: Nitazoxanide analogues, Synthesis, Antibacterial activity, Molecular docking. INTRODUCTION N OAc O N NO2 Parasitic and bacterial infections are the major cause of N NO2 H3C morbidity and mortality in the world especially in developing N S countries. Diseases caused by intestinal parasites affect billions H of people every year and there have been few drug innovations OH for treating these infections in the past three decades. Fortu- Nitazoxanide (1 ) Metronidazole (2 ) nately, nitazoxanide (Fig. 1) belongs to nitrothiazole analogue was developed as a promising compound to treat these diseases. Nitazoxanide, 2-acetyloloxy-N-(5-nitro-2-thiazolyl)benzamide was first synthesized by Rossignol and Cavier1 and has shown activities against Taenia saginata and Hymenolepis nana2. Further studies reported that nitazoxanide exhibited an unusually broad spectrum of activities against various parasites Nitrofurantioin (3 ) Benznidazole (4 ) in human being and animals3-5. In 1996, nitazoxanide has been Fig. 1. Nitro heterocyclic drugs marketed in Latin America and then approved by the US food and drug administration as an agent treating infections caused reveal that nitazoxanide inhibits pyruvate ferredoxin oxido- by parasites6,7. Nitazoxanide also showed broad anti-microbial reductase, a key enzyme of central intermediary metabolism action against anaerobic bacteria (Clostridium difficile, in anaerobic organisms. Nitazoxanide appears to interact with Helicobacter pylori) as well as notable activities against pyruvate ferredoxin oxidoreductase and the nitro group is not influenza virus and hepatitis virus8-11. For highly pathogenic metabolically reduced. The mechanism was supposed that virus rotavirus and mycobacterium tuberculosis, studies have the amide anion (nitazoxanide ions) may directly couple with found that nitazoxanide can kill the virus or cure relative thiamine pyrophosphate, which is a cofactor of pyruvate diseases12,13. ferredoxin oxidoreductase (Fig. 2)15. Recently, a number of In contrast to other nitro-drugs like metronidazole, nitazoxanide derivatives have been synthesized and their nitazoxanide has been shown to be non-mutagenic, which activities were also investigated16-17. The results demonstrated suggested that the two class compounds have fundamental that the nitro group may be essential for the antimicrobial differences with the mode of action14. In fact, recent studies efficacy with a minimum inhibitory concentration of organisms 2922 Liu et al. Asian J. Chem. 18 (MIC90) of 0.06-4 mg/L . Meanwhile, several analogues dis- the reactions was monitored by TLC and column chromato- played more potent antiprotozoal and antivirus activities19-22. graphy purification was carried out using silica gel. Melting But notably, specific replacements of the nitro group shown points were determined by XT-4 melting point apparatus. 1H significant activities against intracellular parasites while and 13C NMR spectrum was recorded on a Varian 400 NMR invalidity for intestinal parasite Giardia lamblia23. On the other spectrometer at room temperature operating at 400 MHz for 1 13 hand, modifications of the salicylate moiety may reduce the H NMR and 100 MHz for C NMR by using DMSO-d6 as activity even abrogate it24. This indicated that other enzymes solvent. Mass spectra were obtained at Bruker Daltonics beside pyruvate ferredoxin oxidoreductase might also be APEXTM 4.7T ESI/MS. The C. difficile (ATCC 43593) and relevant. culture medium were purchased from China Center of Industrial Culture Collection. A Glucose General procedure of preparation of nitazoxanide analogues: To an ice cool solution of amino-heterocycle in distilled tetrahydrofuran (with 1.1 eq triethylamine) or pyridine was added an equimolar amount of benzoyl chloride with Pyruvate stirring. After the addition was complete, the reaction mixture Fd or FId CoA was allowed to stand at room temperature and stirred overnight. (Reduced) Hydrogenase (H ) or The reaction was judged complete by TLC analysis. The crude PFOR 2 Reductases product that separated on dilution was filtered, washed with (NADPH) CO 2 Fd or FId 10 % NaHCO3 solution, then several times with water. The (Oxidized) pure compound was obtained by gradient column chromato- Acetyl-CoA graphy. While for circumstances which dilution does not give precipitate, then the mixture was extracted by EtOAc and purified by chromatography. Spectral data of novel compounds B were listed as following. N-(5-Chlorothiazol-2-yl)-2,4-difluorobenzamide (2a): Obtained in 56 % yield as white solid; m.p. 155-156 °C; 1H- NMR (400 MHz, DMSO-d6): δ 12.91(s, 1H), 7.85 (td, 1H, J = 8.3, 6.5 Hz), 7.62 (s, 1H), 7.48 (ddd, 1H, J = 10.9, 9.5, 2.4 13 Hz), 7.32-7.22 (m, 1H); C NMR (100 MHz, DMSO-d6): δ 164.2 (dd, JCF = 252, 12.3 Hz), 162.2, 160.2 (dd, JCF = 255, 13.1 Hz),155.7, 135.9, 132.3 (dd, JCF = 10.7, 3.4 Hz), 118.7, 118.4 (dd, JCF = 13.3, 3.5 Hz), 112 (dd, JCF = 21.8, 3.5 Hz), 105 Two 1e– transfer (t, J = 26.1 Hz). HR-MS (ESI): Calcd. for C H N OSClF Acetyl-CoA CF 10 5 2 2 (M + H): 274.9852; Found: 274.9846. Fig. 2. Mechanism of pyruvate ferredoxin oxidoreductase enzymatic N-(5-Chlorothiazol-2-yl)-3,4-difluorobenzamide (2b): reaction Obtained in 51 % yield as white solid; m.p. 196-197 °C; 1H NMR (400 MHz, DMSO-d ): δ 12.99 (s, 1H), 8.18 (ddd, 1H, Owing to the structural specificity and notably efficacy, 6 J = 11.5, 7.7, 2.1 Hz), 8.04-7.94 (m, 1H), 7.71-7.52 (m, 2H); we hypothesized that modifications of the benzene ring and 13C NMR (100 MHz, DMSO-d ): δ 163.3, 156.4, 152.2 (dd, thiazole moiety may result increased bioactivities. In this work, 6 J = 253, 12.6 Hz), 149.2 (dd, J = 247, 13 Hz), 135.8, 128.8, the benzene ring hydrogen and nitro-group were substituted CF CF 126 (dd, J = 7.5, 3.3 Hz), 118.7, 117.8 (t, J = 19.3 Hz). by halides, part of the compounds contained a pyrimidine ring CF CF HR-MS (ESI): Calcd. for C H N OSClF (M + H): 274.9852; instead of thiazole moiety. Actually, all the electron-withdra- 10 5 2 2 Found: 274.9849. wing substituent can lead easily to the formation of nitazo- N-(5-Chlorothiazol-2-yl)-2-(trifluoromethyl)benzamide xanide ions which can act on thiamine pyrophosphate causing (2c): Obtained in 54 % yield as white solid; m.p. 207-208 °C; the inhibition of pyruvate ferredoxin oxidoreductase. The 1H NMR (400 MHz, DMSO-d ): δ 13.10 (s, 1H), 7.89 (d, 1H, antibacterial activities of these compounds are evaluated as a 6 J = 7.5 Hz), 7.85-7.73 (m, 3H), 7.61 (s, 1H); 13C NMR (100 preliminary screening to provide some information about their MHz, DMSO-d ): δ 165.8, 155.6, 135.9, 132.9, 132.6, 131.1, antiparasitic efficiency, which is the final purpose of this 6 129, 126.5 (d, J = 4.6 Hz), 126.2 (q, J = 31.7 Hz), 123.5 (q, project. In addition, a molecular docking study of nitazoxanide CF CF J = 274 Hz ), 118.8. HR-MS (ESI): Calcd. for C H N OSClF with pyruvate ferredoxin oxidoreductase was firstly established CF 11 6 2 3 (M + H): 306.9914; Found: 306.9920 using discovery studio software package. The results of mole- N-(5-Chlorothiazol-2-yl)-4-(trifluoromethyl)benzamide cular docking supported the previous mechanism that Nitro (2d): Obtained in 36 % yield as white solid; m.p. 189-190 °C; group interacts with the 4-amino group of thiamine pyrophos- 1H NMR (400 MHz, DMSO-d ): δ 13.18 (s, 1H), 8.27 (d, 2H, phate and surrounding amino acids. 6 J = 8.1 Hz), 7.94 (d, 2H, J = 8.3 Hz), 7.66 (s, 1H); 13C NMR EXPERIMENTAL (100 MHz, DMSO-d6): δ 164.4, 156.4, 135.9, 135.3, 132.3 (q, JCF = 32.1 Hz), 129.2, 125.6 (d, JCF = 3.7 Hz), 123.7 (q, JCF All chemicals employed in this study were analytical = 273 Hz), 118.8. HR-MS (ESI): Calcd. for C11H6N2OSClF3 reagents and solvents were distilled before use. The course of (M + H): 306.9914; Found: 306.9923 Vol. 26, No. 10 (2014) Synthesis, Antibacterial Evaluation and Molecular Docking Study of Nitazoxanide Analogues 2923 N-(5-Bromothiazol-2-yl)-2,4-difluorobenzamide (3a): N-(5-Chloropyrimidin-2-yl)-3,4-difluorobenzamide Obtained in 68 % yield as white solid; m.p.
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