Synthesis and anti-Helicobacter pylori activity of (4-nitro-1-imidazolylmethyl)-1,2,4-triazoles, 1,3,4-thiadiazoles, and 1,3,4-oxadiazoles

Turk J Chem 35 (2011) , 307 – 316. c TÜBİTAK  doi:10.3906/kim-1004-522 Synthesis and anti-Helicobacter pylori activity of (4-nitro-1-imidazolylmethyl)-1,2,4-triazoles, 1,3,4-thiadiazoles, and 1,3,4-oxadiazoles Asal FALLAH TAFTI1 , Tahmineh AKBARZADEH1 , Parastoo SANIEE2 , Farideh SIAVOSHI2, Abbas SHAFIEE1 , Alireza FOROUMADI1,∗ 1 Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, 2 Tehran University of Medical Sciences, Tehran, 14176, IRAN Microbiology Department, Faculty of Sciences, University of Tehran, Tehran-IRAN e-mail: Received 07.04.2010 A series of [(4-nitro-1 H -imidazol-1-yl)methyl]-1,2,4-triazoles and 1,3,4-thiadiazoles were prepared and evaluated for their activity against sensitive and resistant H. pylori strains. Study of the structure-activity relationship of these series of compounds indicated that the type of nitroimidazole moiety and the pendent group on the heteroaryl analog dramatically impact the anti-H. pylori activity. In triazole series, compound 5d, containing a 4-methyl phenyl group on the triazole ring, was the most potent compound tested against both metronidazole-sensitive and -resistant strains at a concentration of 8 μ g. Key Words: 4-Nitroimidazole, 1,2,4-triazoles, 1,3,4-thiadiazoles, 1,3,4-oxadiazoles, anti-H. pylori activity Introduction It is well known that Helicobacter pylori, an s-shaped spiral microaerophilic gram-negative bacterium first isolated in human gastric mucosa in 1982, 1−3 is considered the major causative agent of several gastric pathologies, such as chronic active gastritis, peptic ulcer disease, and gastric cancer. 4−6 Hence, the World Health Organization (WHO) has classified H. pylori as a Class 1 carcinogen in humans; the eradication of H. pylori can significantly reduce the risk of ulcer relapse and may help prevent corresponding ∗ Corresponding author 307 Synthesis and anti-Helicobacter pylori activity of..., A. FALLAH TAFTI, et al., gastric disorders. 7 Since oral administration of metronidazole, PPI, clarithromycin, and amoxicillin was put to use, infection can be cured in up to 80%-90% of cases. However, eradication is not always successful and a few problems have been observed in the use of these drugs, such as the emergence of drug resistance, especially against metronidazole, clarithromycin, and amoxicillin, 8 and low compliance 9 related to the occurrence of a number of harmful side effects. 10−11 Nitroimidazole compounds, especially metronidazole, have been frequently used in treatment regimens for H. pylori infection; moreover, the antimicrobial properties of 1,2,4-triazole, 1,3,4oxadiazole, and 1,3,4-thiadiazole derivatives are well documented. Their attachment with other heterocycles often ameliorates the bioresponses, depending on the type of substituent and the position of attachment. 12−16 In continuation of our research on nitroheterocyclic compounds as anti-H. pylori agents, 17−20 we decided to synthesize a new series of (4-nitroimidazol-1-ylmethyl)-1,2,4-triazoles (4a-e and 5a-l), 1,3,4-thiadiazoles (6ah), and 1,3,4-oxadiazoles (7a-d) and evaluate their activity against clinical isolates of H. pylori strains. Experimental Melting points were determined on a Kofler hot-stage microscope and were corrected. The 1 H-NMR spectra were obtained using Bruker FT-80 or Varian Unity Plus 400 instruments with tetramethylsilane as the internal standard. The solvents used were CDCl 3 and DMSO-d6. IR spectra were recorded on a Nicolet Magna FTIR 550 spectrometer (KBr disks). Mass spectra were taken using a Finnigan TSQ-70 at 70 eV. Elemental analyses were carried out on a CHN-O-rapid elemental analyzer (Heraeus GmbH, Hanau, Germany) for C, H, and N, and the results were within ±0.4% of the theoretical values. Liarre Starsonic ultrasonic cleaner (Italy) was used as an ultrasonic device with a generator variable frequency of 28-34 KHz and 100 W of power line heating. 2-(4-Nitro-1H -imidazol-1-yl)acetohydrazide (2a) Hydrazine hydrate (15 mL) was added dropwise to a stirred solution of 1a (12 g, 0.06 mol) in methanol (40 mL) in an ice-water bath. The mixture was stirred at the same temperature for 2 h. The precipitate was filtered and recrystallized from methanol to give 10.4 g (83%) of 2a; mp 122-123 ◦ C. IR (KBr): ν = 3345, 3300, 3124 (NH-NH 2 ), 1660 cm −1 (C=O). 1 H-NMR (CDCl 3 ): δ 8.27 (d, J = 1.2 Hz, H-5 imidazole), 7.77 (d, J = 1.2 Hz, 1H, H-2 imidazole), 4.76 ppm (s, 2H, N-CH 2 ). MS m/z (%): 185 (M + , 78), 154 (44), 139 (75), 127 (100), 114(18), 110 (12). Anal. Calcd. for C 5 H 7 N 5 O 3 ; C, 32.44; H, 3.81; N, 37.83. Found C, 32.49; H, 3.79; N, 37.56. 2-(2-Methyl-4-nitro-1H -imidazol-1-yl)acetohydrazide (2b) This compound was prepared in a similar manner to 2a with 87% yield. Mp 190-192 ◦ C (methanol). IR (KBr): ν = 3343, 3269, 3151 (NH-NH 2 ), 1695 cm −1 (C=O). 1 H-NMR (CDCl 3 ): δ 8.24 (s, 1H, H-5 imidazole), 4.70 (s, 2H, N-CH 2 ), 2.33 ppm (s, 3H, CH3). MS m/z (%): 199 (M + , 90), 168 (85), 152 (37), 141 (100), 124 (18), 81 (9). Anal. Calcd. for C 6 H 9 N 5 O 3 ; C, 36.18; H, 4.55; N, 35.16. Found C, 36.50; H, 4.77; N, 35.07. 308 Synthesis and anti-Helicobacter pylori activity of..., A. FALLAH TAFTI, et al., General procedure for the synthesis of 4-alkyl(aryl)-5-[(4-nitro-1H -imidazol-1-yl) methyl]-4H -1,2,4-triazole-3-thiol (4a-d) To a stirred solution of compound 2 (0.01 mol) in ethanol (20 mL), NaOH (2 N, 5 mL) and alkyl(aryl)isothiocyanate (0.01 mol) were added. The mixture was stirred for 2 h at room temperature and then acidified with an aqueous solution of HCl in an ice bath. The mixture was kept in a refrigerator for 3 h to complete the precipitation. The precipitate was filtered and crystallized from ethanol to give compounds 3a-m, which were pure enough to be used in the next reaction. Compound 3 (0.01 mol) was dissolved in 10 mL of an aqueous solution of sodium bicarbonate (5%) while being heated and stirred. The mixture was refluxed for 2.5 h, cooled to room temperature, and acidified with an aqueous solution of HCl in an ice bath. The precipitate was filtered and crystallized from ethanol to give 4a-d. The chemical and physical properties of compounds 4a-d are given in Table 1. General procedure for the synthesis of 4-alkyl(aryl)-5-[(4-nitro-1H -imidazol-1-yl) methyl]-3-methylthio-1,2,4-triazoles (5b-i) To a mixture of compound 4 (1.6 mmol) in ethanol (1 mL), 0.83 mL of an aqueous solution of sodium hydroxide (10%) was added; it was kept in ultrasonic conditions for 1 min. Methyl iodide (0.15 mL, 2.4 mmol) was added to the solution and the reaction was continued for 20 min. The precipitate was filtered and crystallized from ethanol to give compounds 5b-i. The chemical and physical properties of compounds 5b-i are presented in Table 1. General procedure for the synthesis of 5-alkyl(aryl)amino-2-[(4-nitro-1H -imidazol1-yl)methyl]1,3,4-thiadiazoles (6a-g) A mixture of compound 3 (0.6 mmol) and concentrated H 2 SO 4 (1 mL) was stirr (...truncated)