Synthesis and Biological Assessment of New 1,2,4-Triazole Derivatives

Abstract

Naphtho[2,1-b]furan-2-carbohydrazide (2) prepared from reaction between ethyl naphtho[2,1-b]furan-2-carboxylate (1) and hydrazine hydrate, then compound (2) on reaction with CS2/KOH gives 5- (naphtho[2,1-b] furan-2-yl)-1,3,4-oxadiazole-2(3H)-thione (3), Which on mannich reaction followed by reaction with benzoic hydrazine gives different N-(1-((dialkylamino)methyl)-3-(naphtho[2,1-b]furan-2-yl)-5- thioxo-1H-1,2,4-triazol-4(5H)-yl)benzamide (4a-e). With the help of analytical and spectral data, the structure of these compounds were detected. Antibacterial and antifungal activities of the synthesized compounds were studied.

Keywords

Triazole, Methylation, N-butylation, Suzuki-Miyaura coupling, Solvent, Spectroscopy

Introduction

Literature survey reveals that various 1,2,4-triazole derivatives display significant biological activities such as bactericidal, [1] diuretic, [2] fungicidal, [3] herbicidal, [4] insecticidal and acaricidal, [5] plant growth regulator, [6] anticancer, [7] 5-lipoxygenase inhibitors [8] and anti-HIV, [9] antileshmanial, [10] antitumor [11] activities. Platinum(II) complexes comprising 1,2,4-triazoles as ligands show antitumor activity similar to cis-platin. [12] Furthermore, ruthenium(III) complexes of 1,2,4-triazoles are promising as potential drugs in anticancer treatment as alternative to the approved platinum-based anticancer drugs. [13] 1,2,4-Triazoles such as rizatriptan as agents for acute treatment of migraine headaches are commercially available drugs; [14] however, they are also still a topic of intensive research [15]. Keeping in mind the pharmacological applications of this class of compounds and with a view to further assess the pharmacological profile of this class of compounds, the present section incorporates synthesis of thirty novel analogues of 1,2,4-triazole derivatives.

Experimental

Materials and Methods

Melting points were determined in open capillary tubes and are uncorrected. Formation of the compounds was routinely checked by TLC on silica gel-G plates of 0.5 mm thickness and spotsvisualization was made with UV light (254 and 365 nm) or with an iodine vapor. IR spectra were recorded on Shimadzu FT-IR-8400 instrument using KBr pellet method. Mass spectra were recorded on Shimadzu GCMS-QP-2010 model using Direct Injection Probe technique. ¹H NMR and ¹³C NMR were determined in DMSO-d₆ solution on a Bruker Ac 400 MHz spectrometer. Elemental analyses of the all the synthesized compounds were carried out on Elemental Vario EL III Carlo Erba 1108 model and the results are in agreement with the structures assigned.

General Procedure

In first step, 4-bromobenzothioamide (Int-1) was prepared from 4-bromobenzonitrile by stirring with sodium hydrogensulphide and magnesium chloride in DMF, which followed by methylation afforded the S-methyl benzothioamide derivative (Int-2). The condensation of S-methyl benzothioamide derivative (Int-2) and 2,2,2-trifluoroacetohydrazide at 150°C in DMF afforded 3-(4-bromophenyl)-5-(trifluoromethyl)-1H-1,2,4-triazole (Int-3) in good yield, which was subjected to N-butylation at 100°C in DMF presence of K₂CO₃ base to afford 3-(4-bromophenyl)-1-butyl-5-(trifluoromethyl)-1H-1,2,4-triazole (Int-4). In the final step, (Int-4) was subjected to Suzuki-Miyaura reaction with various aryl boronic acids in the presence of palladium catalyst, TBAB, K₂CO₃ and DMF:water as a solvent at 120°C to afford the final products 3-([1,1'-biphenyl]4-yl)-1-butyl-5-(trifluoro methyl)-1H-1,2,4-triazole (P116-P125) in moderate to high yield. The structures of all newly substituted-triazole derivatives were identified by Mass, IR, ¹H NMR, ¹³C spectroscopy.

1-butyl-3-(4'-ethyl[1,1'-biphenyl]-4-yl)-5-(trifluoromethyl)-1H-1,2,4-triazole (P 117)

Yield=85%, m.p. 137-139 ˚C; IR (KBr) cm^-1: 3088, 2960, 2877, 1438, 1340, 1166, 1123, 893 ¹H NMR (400 MHz, CDCl₃) δ ppm: 0.66-1.01(t, 6H), 1.25-1.44 (m, 4H), 1.88-1.95 (m, 2H), 4.14-4.22 (t, 2H), 7.54-7.56 (d, 4H, Ar-H), 7.95-7.97 (d, 2H, Ar–H); ¹³C NMR (CDCl₃) δ:14.55, 15.71, 19.78, 28.95, 33.59, 50.12, 122.13, 125.33, 128.12, 132.12, 138.46, 142.14, 142.82, 143.20, 143.44, 161.37; MS (m/z): 373, Anal. Calcd. for C₂₁H₂₂F₃N₃: C, 67.55; H, 5.94; F, 15.26; N, 11.25%; Found: C, 67.05; H, 5.71; F, 14.97; N, 11.02%.

1-butyl-3-(4'-ethoxy[1,1'-biphenyl]-4-yl)-5-(trifluoromethyl)-1H-1,2,4-triazole (P118)

Yield=79%, m.p. 139-141˚C; IR (KBr) cm^-1: 3036, 2962, 2875, 1599, 1510, 1431, 1338, 1259, 1166, 1128, 839, 510; ¹H NMR (400 MHz, CDCl₃) δ ppm: 0.95-0.99 (t, 3H), 1.26-1.29 (t, 3H), 1.33-1.42 (m, 2H), 1.89-1.91 (m, 2H), 2.67-2.73 (q, 2H), 4.18- 4.22 (t, 2H), 7.29-7.31 (d, 2H, Ar-H), 7.60-7.62 (d, 2H), 7.72-7.74 (d, 2H), 7.89-7.91 (d, 2H, Ar–H); ¹³C NMR (CDCl₃) δ:13.8, 14.8, 19.9, 30.8, 44.6, 64.7, 113.2, 114.9, 128.0, 128.4, 128.5, 129.6, 136.5, 156.4, 160.0, 164.0; MS (m/z): 375, Anal. Calcd. for C₂₁H₂₂F₃N₃O: C, 64.77; H, 5.69; F, 14.64; N, 10.79; O, 4.11%; Found: C, 64.11; H, 5.60; F, 14.22; N, 10.42; O, 4.03%

3-(4'-bromo[1,1'-biphenyl]-4-yl)-1-butyl-5-(trifluoromethyl)-1H-1,2,4-triazole (P122)

Yield=91%, m.p. 135-137˚C; IR (KBr) cm^-1: 2960, 2870, 1602,1600, 1462, 1307, 1168, 1217, 889, 589 ¹H NMR (400 MHz, CDCl₃) δ ppm: 0.96-1.00(t, 3H), 1.20-1.36 (m, 2H), 1.94-2.05 (m, 2H), 4.20-4.23 (t, 2H), 7.2-7.24 (d, 2H, Ar-H), 7.62-7.64 (d, 2H, Ar–H), 7.86-7.88 (d, 2H, Ar-H), 8.00-8.20 (d, 2H, Ar-H); ¹³C NMR (CDCl₃) δ: 13.8, 19.9, 30.9, 44.7, 122.0, 126.02, 128.40, 129.01, 132.25, 137.50, 142.08, 142.97, 143.20, 162.05, 163.0 MS (m/z): 424, Anal. Calcd. for C₁₉H₁₇BrF₃N₃: C, 53.79; H, 4.04; Br, 18.83; F, 13.43; N, 9.90%; Found: C, 52.78; H, 3.97; Br, 18.62; F, 13.05; N, 9.53%

Results and Discussion

All the synthesized compounds (P116-P125) were tested for their antibacterial and antifungal activity (MIC) in vitro by broth dilution method [16-18] with two Gram-positive bacteria Staphylococcus aureus MTCC-96, Streptococcus pyogenes-MTCC-443, two Gram-negative bacteria Escherichia coli MTCC-442, Pseudomonas aeruginosa-MTCC-441 and three fungal strains Candida albicans MTCC-227, Aspergillus Niger MTCC-282, Aspergillus clavatus MTCC-1323 taking ampicillin, chloramphenicol, ciprofloxacin, norfloxacin, nystatin, and greseofulvin as standard drugs. The standard strains were procured from the Microbial Type Culture Collection (MTCC) and Gene Bank, Institute of Microbial Technology, Chandigarh, India. The results obtained from antimicrobial susceptibility testing are depicted in Tables 1 and 2.

Code	R	R1	M.F.	M.W.	M.P.	Yield	Rf
P116	4-Br		C19H18F3N3	345	131-133	89	0.58
P117	4-Br		C21H22F3N3	373	137-139	85	0.63
P118	4-Br		C20H20F3N3O	375	139-141	79	0.61
P119	4-Br		C22H24F3N3	389	157-159	77	0.64
P120	4-Br		C19H17F4N3	363	129-131	83	0.55
P121	4-Br		C19H17ClF3N3	380	151-152	78	0.57
P122	4-Br		C19H17BrF3N3	424	135-137	91	0.58
P123	4-Br		C19H17F4N3	363	131-133	81	0.59
P124	4-Br		C17H16F3N3S	351	145-147	86	0.66
P125	4-Br		C24H22F3N3O	346	176-178	77	0.59

Table 1: Physical parameters TLC Solvent system Rf: Ethyl acetate:Hexane–4:6.

Table 2: Antibacterial and antifungal activity of synthesized compounds.

The minimal inhibitory concentration (MIC) values for all the newly synthesized compounds, defined as the lowest concentration of the compound preventing the visible growth, were determined by using microdilution broth method according to NCCLS standards [16].

Conclusion

In the present article, we report the synthesis, spectral studies, antibacterial and antifungal activities of a novel series of 1,2,4 triazole scaffold. The preliminary in vitro biological activities revealed that compounds P117, P123 and P124 exhibited moderate antibacterial activities.

Acknowledgements

We are thankful to UGC to provide Rajiv Gandhi National Fellowship for research. The authors are also gratified to Department of chemistry, Saurashtra University-Rajkot to provide research facilities.

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