alexa Synthesis of Some Aroylhydrazones and 2,5-Disubstituted-1,3,4- Oxadiazoles as DNA Photocleaving Agents | OMICS International
ISSN: 2161-0444
Medicinal Chemistry

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Synthesis of Some Aroylhydrazones and 2,5-Disubstituted-1,3,4- Oxadiazoles as DNA Photocleaving Agents

Vinod Kumar1*, Mohit Kumar1, Vikas Beniwal2, Girish Kumar Gupta3, Sunil Kumar4 and Ramesh Kataria5

1Department of Chemistry, Maharishi Markandeshwar University, Mullana, Ambala, Haryana, India

2Department of Biotechnology, Maharishi Markandeshwar University, Mullana, Ambala, Haryana, India

3Department of Pharmaceutical Chemistry, Maharishi Markandeshwar College of Pharmacy, Maharishi Markandeshwar University, Mullana, Ambala, Haryana, India

4Department of Chemistry, Government Girls PG College, Hisar, Haryana, India

5Department of Chemistry, Panjab University, Chandigarh, India

*Corresponding Author:
Vinod Kumar
Department of Chemistry, Maharishi Markandeshwar University
Mullana, Ambala-133 207, Haryana, India.
Tel: +918059444494
E-mail: [email protected]

Received Date: June 13, 2016; Accepted Date: July 04, 2016; Published Date: July 08, 2016

Citation: Kumar V, Kumar M, Beniwal V, Gupta GK, Kumar S, et al. (2016) Synthesis of Some Aroylhydrazones and 2,5-Disubstituted-1,3,4-Oxadiazoles as DNA Photocleaving Agents. Med chem (Los Angeles) 6:474-485. doi:10.4172/2161- 0444.1000386

Copyright: © 2016 Kumar V, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Abstract

Some 2,5-disubstituted-1,3,4-oxadiazole derivatives have been synthesized conveniently via oxidative cyclization of various synthesized aroylhydrazones by (diacetoxyiodo)benzene in dichloromethane under mild reaction conditions. In addition, the effect of electron-withdrawing/releasing groups on the formation of oxadiazole nucleus has also been studied. Compounds were obtained in good yields and their structures have been established on the basis of their FT-IR, 1H, 13C NMR and mass spectral data. Herein, a total of 42 compounds (hydrazones as well as oxadiazoles) were synthesized and investigated for their DNA photocleavage potential using plasmid DNA. It has been observed that aroylhydrazones showed good DNA photocleavage activity in comparison to their corresponding oxadiazoles.

Keywords

Oxadiazole; Pyrazole; Aroylhydrazone; (Diacetoxyiodo)benzene; DNA photocleavage

Introduction

Azoles are well known for their huge contribution in the pharmaceutical sector and among them pyrazole is still being considered as one of the leading pharmacophores in the development of bioactive compounds [1-10]. Pyrazole derivatives exhibited a broad spectrum of useful properties such as antitumor [11], antitubercular [12], antioxidant [13], anti-inflammatory [14,15], antibacterial [16], anti-obesity [17] and antidepressant [18] activities. Similarly, 1,3,4-oxadiazoles have been reported to exhibit various biological [19,20] and pharmacological activities [21-25]. These compounds, in particular, have been found to exhibit biological potential such as anticancer activity [26-28] specifically in the presence of some potent heterocyclic nuclei. In the past decade much attention has been paid towards the evaluation of the DNA photo cleavage potential of a variety of oxadiazole derivatives [29-31]. DNA is a primary site where most of the drugs interact and lead to inhibition or death of cancerous cells [32]. Therefore, compounds having binding or interacting ability with the DNA structure could be used as probes for DNA structure, as potential chemotherapeutic and diagnostic agents [33]. In view of the above facts, it was decided to synthesize some novel 2,5-disubstituted-1,3,4-oxadiazoles under mild reaction conditions and evaluate their DNA photo cleavage activity.

Experimental

Melting points of all the synthesized compounds were determined in an open capillary using digital melting point apparatus and are uncorrected. IR spectra were recorded as KBr discs on a Perkin-Elmer Spectrophotometer in the 4,000-450 cm-1 range. Both 1H and 13C NMR spectra of the compounds were recorded on a Bruker Advance NMR Spectrophotometer at 400 MHz and 100 MHz, respectively. Chemical shifts were measured relative to internal reference standard, tetramethylsilane (TMS) (δ=0) in CDCl3 or DMSO-d6, and were reported on δ scale (ppm). Coupling constants (J) were given in Hz. Mass spectra were recorded on Waters, Q-Tof micromass, ESI source, Mass Spectrometer. Carbon, nitrogen, hydrogen contents were analyzed using LECO 9320 analyzer. Aroylhydrazines 1 [34], 4-formylpyrazoles 2 [35] utilized in present investigation were synthesized according to the literature methods.

Synthesis of Aroylhydrazones (3a-u)

General procedure

A solution of 4-formylpyrazole or substituted benzaldehyde (0.01 mol) and sulfuric acid (one drop) in dichloromethane (DCM) was added to an ethanolic solution of aroylhydrazine (1, 0.01 mol) under stirring. Then reaction mass was refluxed for 40-45 min till completion of the reaction. The reaction was monitored by thin layer chromatography, excess of solvent was distilled out, and then the reaction mass was cooled to room temperature. The obtained product was filtered, washed with alcohol and recrystallised from ethanol. The melting points were noted before submitting the samples for analysis.

N-Benzoyl-N'-(1',3'-diphenyl-4'-pyrazolylmethylidene) hydrazine (3a)

Yield 89 %; m.p.: (Obs.) 180-181 °C, m.p.: (Lit.) 180-182 °C; TLC Rf = 0.37 [ethylacetate: hexane (3:7)]; 1H-NMR (400 MHz, DMSO-d6): δ = 11.76 (s, 1H, H-N, D2O exchangeable), 8.96 (s, 1H, H-5'), 8.61 (s, 1H, H-6'), 7.92-8.00 (m, 4H, H-2, H-6 & H-2'', H-6''), 7.74 (d, 2H, J = 7.1 Hz, H-2''', H-6'''), 7.35-7.60 (m, 9H, H-3, H-4, H-5, H-Ph'' & H-Ph''') ppm; 13C-NMR (100 MHz, CDCl3+DMSO-d6): δ = 162.9 (C, C-7), 151.8 (C, C-3'), 141.0 (CH, C-6'), 139.0 (C, C-1''), 133.3 (C, C-1), 132.0 (CH, C-4), 131.5 (C, C-1'''), 129.4 (CH, C-3''', C-5'''), 128.6 (CH, C-2, C-6), 128.4 (CH, C-3'', C-5''), 128.3 (CH, C-4'''), 128.2 (CH, C-2''', C-6'''), 127.6 (CH, C-3, C-5), 127.5 (CH, C-5'), 126.8 (CH, C-4''), 118.7 (CH, C-2'', C-6''), 116.9 (C, C-4') ppm; FT-IR (KBr): 3427 (N-H str.), 1668 (C=O str.) cm-1; MS (ESI): m/z = 367.2 (M+1)+; Anal. Calcd. for C23H18N4O: C, 75.37; H, 4.91; N, 15.29. Found: C, 75.34; H, 4.89; N, 15.27.

N-Benzoyl-N'-(4'-nitrobenzylidene)hydrazine (3b)

Yield 86.8 %; m.p.: 238-239 °C; TLC Rf = 0.39 [ethylacetate: hexane (3:7)]; 1H-NMR (400 MHz, DMSO-d6): δ = 11.78 (s, 1H, H-N, D2O exchangeable), 8.61 (s, 1H, H-7'), 8.34-8.48 (m, 4H, H-Ph'), 7.25- 7.78 (m, 5H, H-Ph) ppm; 13C-NMR (100 MHz, DMSO-d6): δ = 163.0 (C, C-7), 148.0 (C, C-4'), 141.5 (C, C-1'), 140.8 (CH, C-7'), 132.8 (C, C-1), 132.4 (CH, C-4), 128.5 (CH, C-2, C-6), 127.7 (CH, C-2', C-6'), 127.4 (CH, C-3, C-5), 124.1 (CH, C-3', C-5') ppm; FT-IR (KBr): 3430 (N-H str.), 1668 (C=O str.), 1540 (NO2 asymmetric str.), 1351 (NO2 symmetric str.) cm-1; MS (ESI): m/z = 270.3 (M+1)+; Anal. Calcd. for C14H11N3O3: C, 62.38; H, 4.08; N, 15.59. Found: C, 62.36; H, 4.08; N, 15.58.

N-Benzoyl-N'-(4'-bromobenzylidene)hydrazine (3c)

Yield 87.5 %; m.p.: 201-202 °C; TLC Rf = 0.51 [ethylacetate: hexane (3:7)]; 1H-NMR (400 MHz, DMSO-d6): δ = 11.80 (s, 1H, H-N, D2O exchangeable), 8.48 (s, 1H, H-7'), 7.89 (d, 2H, J = 7.4 Hz, H-2, H-6), 7.31-7.75 (m, 7H, H-Ph' & H-3, H-4, H-5) ppm; 13C-NMR (100 MHz, DMSO-d6): δ = 162.9 (C, C-7), 141.2 (CH, C-7'), 133.6 (CH, C-3', C-5'), 133.1 (C, C-1), 132.2 (CH, C-4), 130.1 (C, C-1'), 128.4 (CH, C-2, C-6), 127.8 (CH, C-3, C-5), 127.4 (CH, C-2', C-6'), 123.1 (C, C-4') ppm; FTIR (KBr): 3433 (N-H str.), 1665 (C=O str.) cm-1; MS (ESI): m/z = 303.4 (M+1)+, 305.5 (M+2)+ in the ratio showing typical bromine isotope profile (1:1); Anal. Calcd. for C14H11BrN2O: C, 55.55; H, 3.64; N, 9.26. Found: C, 55.54; H, 3.62; N, 9.23.

N-Benzoyl-N'-(4'-methoxybenzylidene)hydrazine (3d)

Yield 87.9 %; m.p.: 189-190 °C; TLC Rf = 0.35 [ethylacetate: hexane (3:7)]; 1H-NMR (400 MHz, DMSO-d6): δ = 11.94 (s, 1H, H-N, D2O exchangeable), 8.42 (s, 1H, H-7'), 7.32-7.92 (m, 7H, H-2', H-6' & H-Ph), 6.99 (d, 2H, J = 8.6 Hz, H-3', H-5'), 3.79 (s, 3H, 4'-OCH3) ppm; 13C-NMR (100 MHz, DMSO-d6): δ =161.4 (C, C-7), 160.0 (C, C-4'), 140.8 (CH, C-7'), 132.9 (C, C-1), 132.0 (CH, C-4), 129.1 (CH, C-2', C-6'), 128.1 (CH, C-2, C-6), 127.8 (CH, C-3, C-5), 122.4 (C, C-1'), 114.1 (CH, C-3', C-5'), 55.1 (OCH3) ppm; FT-IR (KBr): 3421 (N-H str.), 1666 (C=O str.) cm-1; MS (ESI): m/z = 255.2 (M+1)+; Anal. Calcd. for C15H14N2O2: C, 70.81; H, 5.51; N, 11.01. Found: C, 70.78; H, 5.50; N, 11.00.

N-Benzoyl-N'-(4'-methylbenzylidene)hydrazine (3e)

Yield 88.7 %; m.p.: 195-196 °C; TLC Rf = 0.49 [ethylacetate: hexane (3:7)]; 1H-NMR (400 MHz, DMSO-d6): δ = 11.97 (s, 1H, H-N, D2O exchangeable), 8.44 (s, 1H, H-7'), 7.40-7.93 (m, 7H, H-2', H-6' & H-Ph), 7.23 (d, 2H, J = 8.4 Hz, H-3', H-5'), 2.34 (s, 3H, 4'-CH3) ppm; 13C-NMR (100 MHz, DMSO-d6): δ = 161.0 (C, C-7), 140.7 (CH, C-7'), 140.1 (C, C-4'), 132.2 (C, C-1), 131.9 (CH, C-4), 129.4 (CH, C-2', C-6'), 129.2 (CH, C-3', C-5'), 128.6 (CH, C-2, C-6), 128.5 (C, C-1'), 127.5 (CH, C-3, C-5), 21.1 (CH3) ppm; FT-IR (KBr): 3425 (N-H str.), 1665 (C=O str.) cm-1; MS (ESI): m/z = 239.2 (M+1)+; Anal. Calcd. for C15H14N2O: C, 75.57; H, 5.88; N, 11.75. Found: C, 75.54; H, 5.87; N, 11.72.

N-Benzoyl-N'-(thien-2'-yl-methylidene)hydrazine (3f)

Yield 86.5 %; m.p.: 149-150 °C; TLC Rf = 0.36 [ethylacetate: hexane (3:7)]; 1H-NMR (400 MHz, DMSO-d6): δ = 11.82 (s, 1H, H-N, D2O exchangeable), 8.69 (s, 1H, H-6'), 7.91 (d, 2H, J = 7.3 Hz, H-2, H-6), 7.11-7.61 (m, 6H, H-3, H-4, H-5 & H-3', H-4', H-5') ppm; 13C-NMR (100 MHz, DMSO-d6): δ = 163.1 (C, C-7), 142.9 (CH, C-6'), 139.1 (CH, C-5'), 133.3 (C, C-1), 131.6 (CH, C-4), 130.6 (C, C-2'), 128.6 (CH, C-4'), 128.3 (CH, C-2, C-6), 127.6 (CH, C-3'), 127.5 (CH, C-3, C-5) ppm; FT-IR (KBr): 3421 (N-H str.), 1665 (C=O str.) cm-1; MS (ESI): m/z = 231.1 (M+1)+; Anal. Calcd. for C12H10N2OS: C, 62.58; H, 4.34; N, 12.17. Found: C, 62.57; H, 4.33; N, 12.15.

N-Benzoyl-N'-(furl-2'-yl-methylidene)hydrazine (3g)

Yield 87 %; m.p.: 139-140 °C; TLC Rf = 0.32 [ethylacetate: hexane (3:7)]; 1H-NMR (400 MHz, DMSO-d6): δ = 11.85 (s, 1H, H-N, D2O exchangeable), 8.72 (s, 1H, H-6'), 7.89 (d, 2H, J = 7.4 Hz, H-2, H-6), 7.09-7.58 (m, 6H, H-3, H-4, H-5 & H-3', H-4', H-5') ppm; 13C-NMR (100 MHz, DMSO-d6): δ = 162.5 (C, C-7), 144.1 (CH, C-6'), 139.3 (C, C-2'), 138.8 (CH, C-5'), 132.6 (C, C-1), 131.8 (CH, C-4), 127.9 (CH, C-2, C-6), 126.8 (CH, C-3, C-5), 113.9 (CH, C-4'), 112.3 (CH, C-3') ppm; FT-IR (KBr): 3422 (N-H str.), 1663 (C=O str.) cm-1; MS (ESI): m/z = 215.3 (M+1)+; Anal. Calcd. for C12H10N2O2: C, 67.19; H, 4.67; N, 13.06. Found: C, 67.18; H, 4.65; N, 13.05.

N'-(1',3'-Diphenyl-4'-pyrazolylmethylidene)-N-(4- methylbenzoyl)hydrazine (3h)

Yield 88 %; m.p.: 192-193 °C; TLC Rf = 0.30 [ethylacetate: hexane (3:7)]; 1H-NMR (400 MHz, DMSO-d6): δ = 11.70 (s, 1H, H-N, D2O exchangeable), 8.92 (s, 1H, H-5'), 8.62 (s, 1H, H-6'), 7.99 (d, 2H, J = 8.2 Hz, H-2'', H-6''), 7.85 (d, 2H, J = 8.0 Hz, H-2, H-6), 7.74 (d, 2H, J = 7.1 Hz, H-2''', H-6'''), 7.28-7.54 (m, 8H, H-3, H-5, H-Ph'' & H-Ph'''), 2.38 (s, 3H, 4-CH3) ppm; 13C-NMR (100 MHz, DMSO-d6): δ = 162.8 (C, C-7), 151.8 (C, C-3'), 141.4 (CH, C-6'), 140.7 (C, C-4), 139.0 (C, C-1''), 132.1 (C, C-1'''), 130.5 (C, C-1), 129.3 (CH, C-3''', C-5'''), 128.7 (CH, C-2, C-6), 128.4 (CH, C-3'', C-5''), 128.3 (CH, C-4'''), 128.2 (CH, C-2''', C-6'''), 127.4 (CH, C-3, C-5), 126.6 (CH, C-5'), 126.4 (CH, C-4''), 118.6 (CH, C-2'', C-6''), 116.9 (C, C-4'), 21.2 (CH3) ppm; FT-IR (KBr): 3415 (N-H str.), 1664 (C=O str.) cm-1; MS (ESI): m/z = 381.2 (M+1)+; Anal. Calcd. for C24H20N4O: C, 75.75; H, 5.26; N, 14.73. Found: C, 75.74; H, 5.23; N, 14.71.

4-Methyl-N'-(4'-nitrobenzylidene)-N-benzoylhydrazine (3i)

Yield 85.9 %; m.p.: 189-190 °C; TLC Rf = 0.33 [ethylacetate: hexane (3:7)]; 1H-NMR (400 MHz, DMSO-d6): δ = 12.05 (s, 1H, H-N, D2O exchangeable), 8.56 (s, 1H, H-7'), 8.27 (d, 2H, J = 8.6 Hz, H-3', H-5'), 7.85-8.00 (m, 4H, H-2, H-6 & H-2', H-6'), 7.32 (d, 2H, J = 7.8 Hz, H-3, H-5), 2.41 (s, 3H, 4-CH3) ppm; 13C-NMR (100 MHz, DMSO-d6): δ = 163.3 (C, C-7), 147.7 (C, C-4'), 144.8 (C, C-4), 142.0 (C, C-1'), 140.7 (CH, C-7'), 130.1 (C, C-1), 128.8 (CH, C-2, C-6), 127.8 (CH, C-3, C-5), 127.7 (CH, C-2', C-6'), 123.8 (CH, C-3', C-5'), 21.1 (CH3) ppm; FT-IR (KBr): 3433 (N-H str.), 1667 (C=O str.), 1543 (NO2 asymmetric str.), 1349 (NO2 symmetric str.) cm-1; MS (ESI): m/z = 284.3 (M+1)+; Anal. Calcd. for C15H13N3O3: C, 63.54; H, 4.59; N, 14.82. Found: C, 63.51; H, 4.58; N, 14.82.

N'-(4'-Bromobenzylidene)-N-(4-methylbenzoyl)hydrazine (3j)

Yield 89 %; m.p.: 231-232 °C; TLC Rf = 0.39 [ethylacetate: hexane (3:7)]; 1H-NMR (400 MHz, DMSO-d6): δ = 11.79 (s, 1H, H-N, D2O exchangeable), 8.41 (s, 1H, H-7'), 7.55-7.83 (m, 6H, H-2, H-6 & H-Ph'), 7.27 (d, 2H, J = 7.8 Hz, H-3, H-5), 2.38 (s, 3H, 4-CH3) ppm; 13C-NMR (100 MHz, DMSO-d6): δ = 163.2 (C, C-7), 146.2 (C, C-4), 141.5 (CH, C-7'), 133.5 (CH, C-3', C-5'), 131.5 (CH, C-2, C-6), 130.3 (C, C-1'), 129.9 (C, C-1), 128.7 (CH, C-3, C-5), 127.6 (CH, C-2', C-6'), 123.2 (C, C-4'), 21.1 (CH3) ppm; FT-IR (KBr): 3436 (N-H str.), 1665 (C=O str.) cm-1; MS (ESI): m/z = 317.2 (M+1)+, 319.2 (M+2)+ in the ratio showing typical bromine isotope profile (1:1); Anal. Calcd. for C15H13BrN2O: C, 56.92; H, 4.11; N, 8.85. Found: C, 56.90; H, 4.09; N, 8.84.

N'-(4'-Methoxybenzylidene)-N-(4-methylbenzoyl)hydrazine (3k)

Yield 89.1 %; m.p.: 199-200 °C; TLC Rf = 0.31 [ethylacetate: hexane (3:7)]; 1H-NMR (400 MHz, DMSO-d6): δ = 12.01 (s, 1H, H-N, D2O exchangeable), 8.41 (s, 1H, H-7'), 7.66-7.72 (m, 4H, H-2', H-6' & H-2, H-6), 7.27 (d, 2H, J = 7.6 Hz, H-3, H-5), 6.99 (d, 2H, J = 8.6 Hz, H-3', H-5'), 3.82 (s, 3H, 4'-OCH3), 2.36 (s, 3H, 4-CH3) ppm; 13C-NMR (100 MHz, DMSO-d6): δ = 161.3 (C, C-7), 159.8 (C, C-4'), 145.9 (C, C-4), 141.0 (CH, C-7'), 130.8 (C, C-1), 130.1 (CH, C-2, C-6), 128.9 (CH, C-2', C-6'), 128.6 (CH, C-3, 5), 122.4 (C, C-1'), 114.1 (CH, C-3', C-5'), 55.1 (OCH3), 21.1 (CH3) ppm; FT-IR (KBr): 3425 (N-H str.), 1664 (C=O str.) cm-1; MS (ESI): m/z = 269.1 (M+1)+; Anal. Calcd. for C16H16N2O2: C, 71.61; H, 5.97; N, 10.44. Found: C, 71.60; H, 5.94; N, 10.41.

N'-(4'-Methylbenzylidene)-N-(4-methylbenzoyl)hydrazine (13l)

Yield 86 %; m.p.: 209-210 °C; TLC Rf = 0.42 [ethylacetate: hexane (3:7)]; 1H-NMR (400 MHz, DMSO-d6): δ = 11.85 (s, 1H, H-N, D2O exchangeable), 8.41 (s, 1H, H-7'), 7.64-7.70 (m, 4H, H-2', H-6' & H-2, H-6), 7.33 (d, 2H, J = 7.7 Hz, H-3, H-5), 7.26 (d, 2H, J = 8.2 Hz, H-3', H-5'), 2.30 (s, 6H, 4,4'-CH3) ppm; 13C-NMR (100 MHz, DMSO-d6): δ = 161.2 (C, C-7), 143.1 (C, C-4), 140.2 (CH, C-7'), 140.1 (C, C-4'), 131.0 (C, C-1), 129.3 (CH, C-2', C-6'), 129.1 (CH, C-3', C-5'), 128.8 (CH, C-2, C-6), 128.1 (C, C-1'), 127.6 (CH, C-3, C-5), 21.1 (CH3) ppm; FT-IR (KBr): 3429 (N-H str.), 1667 (C=O str.) cm-1; MS (ESI): m/z = 253.2 (M+1)+; Anal. Calcd. for C16H16N2O: C, 76.13; H, 6.34; N, 11.10. Found: C, 76.12; H, 6.33; N, 11.08.

N-Methylbenzoyl-N'-(thien-2'-yl-methylidene)hydrazine (3m)

Yield 85.9 %; m.p.: 165-166 °C; TLC Rf = 0.30 [ethylacetate: hexane (3:7)]; 1H-NMR (400 MHz, DMSO-d6): δ = 11.99 (s, 1H, H-N, D2O exchangeable), 8.70 (s, 1H, H-6'), 7.68 (d, 2H, J = 7.6 Hz, H-2, H-6), 7.12-7.55 (m, 5H, H-3', H-4', H-5' & H-3, H-5), 2.36 (s, 3H, 4-CH3) ppm; 13C-NMR (100 MHz, DMSO-d6): δ = 162.9 (C, C-7), 143.0 (CH, C-6'), 140.5 (C, C-4), 138.2 (C, C-2'), 137.9 (CH, C-5'), 131.5 (C, C-1), 129.0 (CH, C-4'), 128.8 (CH, C-2, C-6), 127.8 (CH, C-3'), 127.4 (CH, C-3, C-5), 21.1 (CH3) ppm; FT-IR (KBr): 3424 (N-H str.), 1666 (C=O str.) cm-1; MS (ESI): m/z = 245.1 (M+1)+; Anal. Calcd. for C13H12N2OS: C, 63.91; H, 4.92; N, 11.47. Found: C, 63.89; H, 4.90; N, 11.46.

N'-(Fur-2'-yl-methylidene)-N-(4-methylbenzoyl)hydrazine (3n)

Yield 86.2 %; m.p.: 157-158 °C; TLC Rf = 0.29 [ethylacetate: hexane (3:7)]; 1H-NMR (400 MHz, DMSO-d6): δ = 12.01 (s, 1H, H-N, D2O exchangeable), 8.68 (s, 1H, H-6'), 7.66 (d, 2H, J = 7.7 Hz, H-2, H-6), 7.02-7.45 (m, 5H, H-3', H-4', H-5' & H-3, H-5), 2.34 (s, 3H, 4-CH3) ppm; 13C-NMR (100 MHz, DMSO-d6): δ = 162.2 (C, C-7), 143.8 (CH, C-6'), 141.1 (C, C-4), 139.1 (C, C-2'), 138.6 (CH, C-5'), 130.7 (C, C-1), 128.3 (CH, C-2, C-6), 126.9 (CH, C-3, C-5), 114.0 (CH, C-4'), 111.6 (CH, C-3'), 21.1 (CH3) ppm; FT-IR (KBr): 3420 (N-H str.), 1663 (C=O str.) cm-1; MS (ESI): m/z = 229.1 (M+1)+; Anal. Calcd. for C13H12N2O2: C, 68.39; H, 5.26; N, 12.27. Found: C, 68.38; H, 5.24; N, 12.25.

N'-(1',3'-Diphenyl-4'-pyrazolylmethylidene)-N-(4- nitrobenzoyl)hydrazine (3o)

Yield 87.6 %; m.p.: 232-233 °C; TLC Rf = 0.33 [ethylacetate: hexane (3:7)]; 1H-NMR (400 MHz, DMSO-d6): δ = 11.98 (s, 1H, H-N, D2O exchangeable), 8.98 (s, 1H, H-5'), 8.61 (s, 1H, H-6'), 8.16-8.36 (m, 4H, H-2, H-6 & H-3, H-5), 8.02 (d, 2H, J = 8.0 Hz, H-2'', H-6''), 7.75 (d, 2H, J = 7.2 Hz, H-2''', H-6'''), 7.35-7.56 (m, 6H, H-Ph'' & H-Ph''') ppm; 13C-NMR (100 MHz, DMSO-d6): δ = 160.9 (C, C-7), 152.0 (C, C-3'), 149.1 (C, C-4), 142.2 (CH, C-6'), 139.1 (C, C-1''), 139.0 (C, C-1), 132.0 (C, C-1'''), 129.4 (CH, C-3''', C-5'''), 129.0 (CH, C-3'', C-5''), 128.6 (CH, C-2, C-6), 128.5 (CH, C-4'''), 128.4 (CH, C-2''', C-6'''), 127.0 (CH, C-5'), 126.8 (CH, C-4''), 123.4 (CH, C-3, C-5), 118.7 (CH, C-2'', C-6''), 116.6 (C, C-4') ppm; FT-IR (KBr): 3434 (N-H str.), 1670 (C=O str.) cm-1; MS (ESI): m/z = 412.1 (M+1)+; Anal. Calcd. for C23H17N5O3: C, 67.14; H, 4.13; N, 17.03. Found: C, 67.10; H, 4.12; N, 17.01.

N-(4-Nitrobenzoyl)-N'-(4'-nitrobenzylidene)hydrazine (3p)

Yield 88.5 %; m.p.: 247-248 °C; TLC Rf = 0.36 [ethylacetate: hexane (3:7)]; 1H-NMR (400 MHz, DMSO-d6): δ = 12.10 (s, 1H, H-N, D2O exchangeable), 8.67 (s, 1H, H-7'), 8.05-8.38 (m, 8H, H-Ph & H-Ph') ppm; 13C-NMR (100 MHz, DMSO-d6): δ = 163.4 (C, C-7), 148.3 (C, C-4), 148.1 (C, C-4'), 141.9 (C, C-1'), 140.6 (CH, C-7'), 131.4 (C, C-1), 128.0 (CH, C-2, C-6), 127.9 (CH, C-2', C-6'), 123.7 (CH, C-3', C-5'), 123.6 (CH, C-3, C-5) ppm; FT-IR (KBr): 3436 (N-H str.), 1668 (C=O str.), 1546 (NO2 asymmetric str.), 1354 (NO2 symmetric str.) cm-1; MS (ESI): m/z = 315.1 (M+1)+; Anal. Calcd. for C14H10N4O5: C, 53.49; H, 3.18; N, 17.83. Found: C, 53.47; H, 3.16; N, 17.81.

N'-(4'-Bromobenzylidene)-N-4-nitrobenzoylhydrazine (3q)

Yield 86.5 %; m.p.: 227-228 °C; TLC Rf = 0.48 [ethylacetate: hexane (3:7)]; 1H-NMR (400 MHz, DMSO-d6): δ = 12.14 (s, 1H, H-N, D2O exchangeable), 8.47 (s, 1H, H-7'), 8.17-8.36 (m, 4H, H-2, H-6 & H-3, H-5), 7.51-7.71 (m, 4H, H-Ph') ppm; 13C-NMR (100 MHz, DMSO-d6): δ = 163.4 (C, C-7), 149.1 (C, C-4), 141.0 (CH, C-7'), 133.5 (CH, C-3', C-5'), 131.2 (C, C-1), 130.0 (C, C-1'), 127.7 (CH, C-2, C-6), 127.6 (CH, C-2', C-6'), 124.2 (CH, C-3, C-5), 123.4 (C, C-4') ppm; FT-IR (KBr): 3435 (N-H str.), 1669 (C=O str.) cm-1; MS (ESI): m/z = 348.1 (M+1)+, 350.2 (M+2)+ in the ratio showing typical bromine isotope profile (1:1); Anal. Calcd. for C14H10BrN3O3: C, 48.40; H, 2.88; N, 12.10. Found: C, 48.38; H, 2.86; N, 12.09.

N'-(4'-Methoxybenzylidene)-N-(4-nitrobenzoyl)hydrazine (3r)

Yield 89.2 %; m.p.: 198-199 °C; TLC Rf = 0.33 [ethylacetate: hexane (3:7)]; 1H-NMR (400 MHz, DMSO-d6): δ = 11.96 (s, 1H, H-N, D2O exchangeable), 8.40 (s, 1H, H-7'), 8.14-8.33 (m, 4H, H-2, H-6 & H-3, H-5), 7.68 (d, 2H, J = 8.6 Hz, H-2', H-6'), 6.97 (d, 2H, J = 8.7 Hz, H-3', H-5'), 3.80 (s, 3H, 4'-OCH3) ppm; 13C-NMR (100 MHz, DMSO-d6): δ = 161.5 (C, C-7), 160.3 (C, C-4'), 148.8 (C, C-4), 139.1 (CH, C-7'), 130.6 (C, C-1), 128.8 (CH, C-2', C-6'), 126.5 (CH, C-2, C-6), 123.3 (CH, C-3, C-5), 122.5 (C, C-1'), 114.1 (CH, C-3', C-5'), 55.1 (OCH3) ppm; FT-IR (KBr): 3426 (N-H str.), 1670 (C=O str.) cm-1; MS (ESI): m/z = 300.1 (M+1)+; Anal. Calcd. for C15H13N3O4: C, 60.18; H, 4.35; N, 14.04. Found: C, 60.16; H, 4.33; N, 14.03.

N'-(4'-Methylbenzylidene)-N-(4-nitrobenzoyl)hydrazine (3s)

Yield 86.7 %; m.p.: 215-216 °C; TLC Rf = 0.45 [ethylacetate: hexane (3:7)]; 1H-NMR (400 MHz, DMSO-d6): δ = 12.05 (s, 1H, H-N, D2O exchangeable), 8.44 (s, 1H, H-7'), 8.16-8.36 (m, 4H, H-2, H-6 & H-3, H-5), 7.65 (d, 2H, J = 8.6 Hz, H-2', H-6'), 7.25 (d, 2H, J = 8.4 Hz, H-3', H-5'), 2.32 (s, 3H, 4'-CH3) ppm; 13C-NMR (100 MHz, DMSO-d6): δ = 161.4 (C, C-7), 149.1 (C, C-4), 140.1 (CH, C-7'), 139.0 (C, C-4'), 130.6 (C, C-1), 129.3 (CH, C-2', C-6'), 129.0 (CH, C-3', C-5'), 128.2 (C, C-1'), 127.2 (CH, C-2, C-6), 123.3 (CH, C-3, C-5), 21.1 (CH3) ppm; FT-IR (KBr): 3428 (N-H str.), 1667 (C=O str.) cm-1; MS (ESI): m/z = 284.2 (M+1)+; Anal. Calcd. for C15H13N3O3: C, 63.56; H, 4.59; N, 14.83. Found: C, 63.55; H, 4.57; N, 14.81.

N-4-Nitrobenzoyl-N'-(thien-2'-yl-methylidene)hydrazine (3t)

Yield 85.7 %; m.p.: 189-190 °C; TLC Rf = 0.30 [ethylacetate: hexane (3:7)]; 1H-NMR (400 MHz, DMSO-d6): δ = 12.04 (s, 1H, H-N, D2O exchangeable), 8.67 (s, 1H, H-6'), 8.12-8.33 (m, 4H, H-2, H-6 & H-3, H-5), 7.09-7.58 (m, 3H, H-2', H-3', H-5') ppm; 13C-NMR (100 MHz, DMSO-d6): δ = 161.2 (C, C-7), 149.1 (C, C-4), 143.9 (CH, C-6'), 138.9 (C, C-2'), 138.7 (CH, C-5'), 130.9 (C, C-1), 129.0 (CH, C-2, C-6), 128.9 (CH, C-4'), 127.5 (CH, C-3'), 123.3 (CH, C-3, C-5) ppm; FT-IR (KBr): 3425 (N-H str.), 1667 (C=O str.) cm-1; MS (ESI): m/z = 276.2 (M+1)+; Anal. Calcd. for C12H9N3O3S: C, 52.32; H, 3.27; N, 15.26. Found: C, 52.31; H, 3.24; N, 15.24.

N'-(Fur-2'-yl-methylidene)-N-(4-nitrobenzoyl)hydrazine (3u)

Yield 84.9 %; m.p.: 168-169 °C; TLC Rf = 0.27 [ethylacetate: hexane (3:7)]; 1H-NMR (400 MHz, DMSO-d6): δ = 12.06 (s, 1H, H-N, D2O exchangeable), 8.38 (s, 1H, H-6'), 8.14-8.36 (m, 4H, H-2, H-6 & H-3, H-5), 6.58-7.74 (m, 3H, H-2', H-3', H-5') ppm; 13C-NMR (100 MHz, DMSO-d6): δ = 161.3 (C, C-7), 149.2 (C, C-4), 144.9 (CH, C-6'), 138.8 (C, C-2'), 138.5 (CH, C-5'), 130.8 (C, C-1), 129.0 (CH, C-2, C-6), 123.3 (CH, C-3, C-5), 113.6 (CH, C-4'), 111.9 (CH, C-3') ppm; FT-IR (KBr):3426 (N-H str.), 1666 (C=O str.) cm-1; MS (ESI): m/z = 260.0 (M+1)+; Anal. Calcd. for C12H9N3O4: C, 55.60; H, 3.47; N, 16.22. Found: C, 55.59; H, 3.45; N, 16.19.

Synthesis of 2,5-disubstituted-1,3,4-oxadiazoles (4)

General procedure

IBD (0.011 mol) was added in a portion-wise manner to the suspension or solution of an appropriate aroylhydrazone (3, 0.01 mol) in dichloromethane while stirring. The reaction mass was further stirred for 0.5-2.15 h and the reaction was monitored by TLC. After completion of the reaction, the solvent was evaporated and residue was triturated with petroleum ether twice to obtain the crude product 4 which was recrystallised from ethanol [36].

5-(1'',3''-Diphenyl-4''-pyrazolyl)-2-phenyl-1,3,4-oxadiazole (4a)

Yield 90 %; m.p.: (Obs.) 136-137 °C, m.p.: (Lit.) 136-138 °C; TLC Rf = 0.61 [ethylacetate: hexane (3:7)]; 1H-NMR (400 MHz, CDCl3): δ = 8.71 (s, 1H, H-5''), 7.92-7.97 (m, 4H, H-2'''', H-6'''' & H-2', H-6'), 7.84 (d, 2H, J = 7.6 Hz, H-2''', H-6'''), 7.26-7.55 (m, 9H, H-3', H-4', H-5', H-Ph''' & H-Ph'''') ppm; 13C-NMR (100 MHz, CDCl3): δ = 164.0 (C, C-5), 159.9 (C, C-2), 152.0 (C, C-3''), 139.2 (C, C-1'''), 131.8 (C, C-1''''), 131.6 (CH, C-5''), 129.7 (CH, C-3'''', C-5''''), 129.4 (CH, C-4'), 129.1 (CH, C-3''', C-5'''), 129.0 (CH, C-4''''), 128.8 (CH, C-2'''', C-6''''), 128.3 (CH, C-2', C-6'), 127.6 (CH, C-4'''), 126.8 (CH, C-3', C-5'), 123.8 (C, C-1'), 119.5 (CH, C-2''', C-6'''), 106.5 (C, C-4'') ppm; FT-IR (KBr): transparent in the region of (N-H str.) and (C=O str.), 1250 (C-O str.) cm-1; MS (ESI): m/z = 365.2 (M+1)+; Anal. Calcd. for C23H16N4 O: C, 75.78; H, 4.39; N, 15.38. Found: C, 75.75; H, 4.37; N, 15.34.

5-(4''-Nitrophenyl)-2-phenyl-1,3,4-oxadiazole (4b)

Yield 88.5 %; m.p.: (Obs.) 209-210 °C, m.p.: (Lit.) 209-210 °C; TLC Rf = 0.75 [ethylacetate: hexane (3:7)]; 1H-NMR (400 MHz, DMSO-d6): δ = 8.33-8.48 (m, 4H, H-Ph''), 7.35-7.75 (m, 5H, H-Ph') ppm; 13C-NMR (100 MHz, DMSO-d6): δ = 162.1 (C, C-5), 160.7 (C, C-2), 148.9 (C, C-4''), 130.1 (CH, C-4'), 129.1 (C, C-1''), 128.7 (CH, C-2', C-6'), 127.0 (CH, C-3', C-5'), 126.5 (CH, C-2'', C-6''), 124.2 (CH, C-3'', C-5''), 123.9 (CH, C, C-1') ppm; FT-IR (KBr): transparent in the region of (N-H str.) and (C=O str.), 1543 (NO2 asymmetric str.), 1349 (NO2 symmetric str.), 1252 (C-O str.) cm-1; MS (ESI): m/z = 268.2 (M+1)+; Anal. Calcd. for C14H9N3O3: C, 62.87; H, 3.37; N, 15.72. Found: C, 62.85; H, 3.34; N, 15.71.

5-(4''-Bromophenyl)-2-phenyl-1,3,4-oxadiazole (4c)

Yield 88.1 %; m.p.: (Obs.) 167-168 °C, m.p.: (Lit.) 167 °C; TLC Rf = 0.81 [ethylacetate: hexane (3:7)]; 1H-NMR (400 MHz, DMSO-d6): δ = 8.01 (d, 2H, J = 7.2 Hz, H-2', H-6'), 7.38-7.80 (m, 7H, H-3', H-4', H-5' & H-Ph'') ppm; 13C-NMR (100 MHz, DMSO-d6): δ = 163.5 (C, C-5), 160.9 (C, C-2), 132.5 (CH, C-3'', C-5''), 129.8 (CH, C-4'), 128.9 (CH, C-2', C-6'), 128.1 (CH, C-2'', C-6''), 126.8 (CH, C-3', C-5'), 126.5 (C, C-1''), 124.0 (C, C-1'), 123.0 (C, C-4'') ppm; FT-IR (KBr): transparent in the region of (N-H str.) and (C=O str.), 1245 (C-O str.) cm-1; MS (ESI): m/z = 301.1 (M+1)+, 303.1 (M+2)+ in the ratio showing typical bromine isotope profile (1:1); Anal. Calcd. for C14H9BrN2O: C, 55.98; H, 3.00; N, 9.33. Found: C, 55.96; H, 2.98; N, 9.32.

5-(4''-Methoxyphenyl)-2-phenyl-1,3,4-oxadiazole (4d)

Yield 91 %; m.p.: (Obs.) 150-151 °C, m.p.: (Lit.) 150 °C; TLC Rf = 0.73 [ethylacetate: hexane (3:7)]; 1H-NMR (400 MHz, CDCl3): δ = 7.35- 8.10 (m, 7H, H-2'', H-6'' & H-Ph'), 7.12 (d, 2H, J = 8.5 Hz, H-3'', H-5''),3.84 (s, 3H, 4''-OCH3) ppm; 13C-NMR (100 MHz, DMSO-d6): δ = 162.4 (C, C-5), 160.1 (C, C-2), 159.7 (C, C-4''), 130.0 (CH, C-4'), 128.7 (CH, C-2'', C-6''), 128.4 (CH, C-2', C-6'), 126.9 (CH, C-3', C-5'), 124.2 (C, C-1'), 120.8 (C, C-1''), 114.8 (CH, C-3'', C-5''), 55.3 (OCH3) ppm; FTIR (KBr): transparent in the region of (N-H str.) and (C=O str.), 1249 (C-O str.) cm-1; MS (ESI): m/z = 253.2 (M+1)+; Anal. Calcd. for C15H12 N2O2: C, 71.37; H, 4.76; N, 11.10. Found: C, 71.36; H, 4.75; N, 11.09.

5-(4''-Methylphenyl)-2-phenyl-1,3,4-oxadiazole (4e)

Yield 90.2 %; m.p.: (Obs.) 148-149 °C, m.p.: (Lit.) 148 °C; TLC Rf = 0.77 [ethylacetate: hexane (3:7)]; 1H-NMR (400 MHz, CDCl3): δ = 7.45- 8.05 (m, 7H, H-2'', H-6'' & H-Ph'), 7.28 (d, 2H, J = 8.4 Hz, H-3'', H-5''), 2.40 (s, 3H, 4''-CH3) ppm; 13C-NMR (100 MHz, CDCl3): δ = 165.4 (C, C-5), 160.5 (C, C-2), 144.2 (C, C-4''), 130.2 (CH, C-2'', C-6''), 129.7 (CH, C-4'), 128.6 (CH, C-2', C-6'), 127.1 (CH, C-3', C-5'), 127.0 (CH, C-3'', C-5''), 123.9 (C, C-1'), 120.3 (C, C-1''), 21.7 (CH3) ppm; FT-IR (KBr): transparent in the region of (N-H str.) and (C=O str.), 1253 (C-O str.) cm-1; MS (ESI): m/z = 237.3 (M+1)+; Anal. Calcd. for C15H12N2O : C, 76.17; H, 5.08; N, 11.85. Found: C, 76.16; H, 5.05; N, 11.84.

2-Phenyl-5-(thien-2''-yl)-1,3,4-oxadiazole (4f)

Yield 87.9 %; m.p.: 110-111 °C; TLC Rf = 0.75 [ethylacetate: hexane (3:7)]; 1H-NMR (400 MHz, CDCl3): δ = 8.12 (d, 2H, J = 6.9 Hz, H-2', H-6'), 7.18-7.84 (m, 6H, H-3', H-4', H-5' & H-3'', H-4'', H-5'') ppm; 13C-NMR (100 MHz, CDCl3): δ = 164.0 (C, C-5), 160.9 (C, C-2), 131.8 (CH, C-5''), 130.2 (CH, C-3''), 129.8 (CH, C-4'), 129.1 (CH, C-2', C-6'), 128.2 (CH, C-4''), 127.0 (CH, C-3', C-5'), 125.2 (C, C-2''), 123.7 (C, C-1') ppm; FT-IR (KBr): transparent in the region of (N-H str.) and (C=O str.), 1246 (C-O str.) cm-1; MS (ESI): m/z = 229.0 (M+1)+; Anal. Calcd. for C12H8N2OS: C, 63.16; H, 3.51; N, 12.28. Found: C, 63.14; H, 3.48; N, 12.26.

5-(Fur-2''-yl)-2-phenyl-1,3,4-oxadiazole (4g)

Yield 85.9 %; m.p.: (Obs.) 103-104 °C, m.p.: (Lit.) 103 °C; TLC Rf = 0.64 [ethylacetate: hexane (3:7)]; 1H-NMR (400 MHz, CDCl3): δ = 8.10 (d, 2H, J = 7.0 Hz, H-2', H-6'), 7.12-7.88 (m, 6H, H-3', H-4', H-5' & H-3'', H-4'', H-5'') ppm; 13C-NMR (100 MHz, DMSO-d6): δ = 164.3 (C, C-5), 159.8 (C, C-2), 133.4 (CH, C-5''), 130.1 (CH, C-4'), 128.8 (CH, C-2', C-6'), 128.5 (C, C-2''), 127.1 (CH, C-3', C-5'), 123.9 (C, C-1'), 114.8 (CH, C-3''), 114.5 (CH, C-4'') ppm; FT-IR (KBr): transparent in the region of (N-H str.) and (C=O str.), 1244 (C-O str.) cm-1; MS (ESI): m/z = 213.1 (M+1)+; Anal. Calcd. for C12H8N2O2: C, 67.89; H, 3.77; N, 13.20. Found: C, 67.86; H, 3.75; N, 13.18.

5-(1'',3''-Diphenyl-4''-pyrazolyl)-2-(4'-methylphenyl)-1,3,4- oxadiazole (4h)

Yield 88.6 %; m.p.: 145-146 °C; TLC Rf = 0.57 [ethylacetate: hexane (3:7)]; 1H-NMR (400 MHz, CDCl3): δ = 8.61 (s, 1H, H-5''), 7.75-7.87 (m, 6H, H-2''', H-6''', H-2'''', H-6'''' & H-2', H-6'), 7.18-7.47 (m, 8H, H-3', H-5', H-Ph''' & H-Ph''''), 2.34 (s, 3H, 4'-CH3) ppm; 13C-NMR (100 MHz, CDCl3): δ = 163.9 (C, C-5), 162.3 (C, C-2), 151.9 (C, C-3''), 142.3 (C, C-4'), 139.3 (C, C-1'''), 132.0 (C, C-1''''), 131.7 (CH, C-5''), 129.6 (CH, C-2', C-6'), 129.5 (CH, C-3'''', C-5''''), 129.2 (CH, C-3''', C-5'''), 128.9 (CH, C-4''''), 128.8 (CH, C-2'''', C-6''''), 127.6 (CH, C-3', C-5'), 127.3 (CH, C-4'''), 120.5 (C, C-1'), 119.4 (CH, C-2''', C-6'''), 106.5 (C, C-4''), 21.3 (CH3) ppm; FT-IR (KBr): transparent in the region of (N-H str.) and (C=O str.), 1252 (C-O str.) cm-1; MS (ESI): m/z = 379.1 (M+1)+; Anal. Calcd. for C24H18N4O: C, 76.17; H, 4.76; N, 14.81. Found: C, 76.16; H, 4.74; N, 14.79.

2-(4'-Methylphenyl)-5-(4''-Nitrophenyl)-1,3,4-oxadiazole (4i)

Yield 90.2 %; m.p.: 168-169 °C; TLC Rf = 0.69 [ethylacetate: hexane (3:7)]; 1H-NMR (400 MHz, DMSO-d6): δ = 8.36-8.44 (m, 4H, H-Ph''), 8.03 (d, 2H, J = 8.2 Hz, H-2', H-6'), 7.41 (d, 2H, J = 8.1 Hz, H-3', H-5'), 2.34 (s, 3H, 4'-CH3) ppm; 13C-NMR (100 MHz, DMSO-d6): δ = 164.9 (C, C-2), 162.3 (C, C-5), 149.0 (C, C-4''), 142.5 (C, C-4'), 129.8 (CH, C-2', C-6'), 129.0 (C, C-1''), 127.8 (CH, C-3', C-5'), 126.7 (CH, C-2'', C-6''), 124.4 (CH, C-3'', C-5''), 120.2 (C, C-1'), 21.2 (CH3) ppm; FTIR (KBr): transparent in the region of (N-H str.) and (C=O str.), 1545 (NO2 asymmetric str.), 1347 (NO2 symmetric str.), 1255 (C-O str.) cm-1; MS (ESI): m/z = 282.1 (M+1)+; Anal. Calcd. for C15H11N3O3: C, 64.03; H, 3.91; N, 14.94. Found: C, 64.02; H, 3.90; N, 14.92.

5-(4''-Bromophenyl)-2-(4'-methylphenyl)-1,3,4-oxadiazole (4j)

Yield 87 %; m.p.: 205-206 °C; TLC Rf = 0.75 [ethylacetate: hexane (3:7)]; 1H-NMR (400 MHz, CDCl3): δ = 7.82-8.02 (m, 4H, H-2'', H-6'' & H-2', H-6'), 7.69 (d, 2H, J = 8.4 Hz, H-3'', H-5''), 7.35 (d, 2H, J = 7.9 Hz, H-3', H-5'), 2.46 (s, 3H, 4'-CH3) ppm; 13C-NMR (100 MHz, CDCl3): δ = 164.9 (C, C-2), 163.6 (C, C-5), 142.5 (C, C-4'), 132.4 (CH, C-3'', C-5''), 129.8 (CH, C-2', C-6'), 128.3 (CH, C-2'', C-6''), 126.9 (CH, C-3', C-5'), 126.3 (C, C-1''), 122.9 (C, C-4''), 120.9 (C, C-1'), 21.7 (CH3) ppm; FT-IR (KBr): transparent in the region of (N-H str.) and (C=O str.), 1248 (C-O str.) cm-1; MS (ESI): m/z = 315.2 (M+1)+, 317.1 (M+2)+ in the ratio showing typical bromine isotope profile (1:1); Anal. Calcd. for C15H11BrN2O: C, 57.29; H, 3.50; N, 8.91. Found: C, 57.28; H, 3.48; N, 8.89.

5-(4''-Methoxyphenyl)-2-(4'-methylphenyl)-1,3,4-oxadiazole (4k)

Yield 88.7 %; m.p.: (Obs.) 148-149 °C, m.p.: (Lit.) 148-150 °C; TLC Rf = 0.67 [ethylacetate: hexane (3:7)]; 1H-NMR (400 MHz, CDCl3): δ 7.68-8.00 (m, 4H, H-2'', H-6'' & H-2', H-6'), 7.40 (d, 2H, J = 8.0 Hz, H-3', H-5'), 7.11 (d, 2H, J = 8.3 Hz, H-3'', H-5''), 3.84 (s, 3H, 4''-OCH3), 2.44 (s, 3H, 4'-CH3) ppm; 13C-NMR (100 MHz, DMSO-d6): δ 164.2 (C, C-2), 162.8 (C, C-5), 159.7 (C, C-4''), 142.7 (C, C-4'), 129.7 (CH, C-2', C-6'), 128.5 (CH, C-2'', C-6''), 127.3 (CH, C-3', C-5'), 121.2 (C, C-1'), 120.6 (C, C-1''), 114.5 (CH, C-3'', C-5''), 55.3 (OCH3), 21.2 (CH3) ppm; FT-IR (KBr): transparent in the region of (N-H str.) and (C=O str.), 1256 (C-O str.) cm-1; MS (ESI): m/z = 267.1 (M+1)+; Anal. Calcd. for C16H14N2O2: C, 72.15; H, 5.26; N, 10.52. Found: C, 72.14; H, 5.24; N, 10.49.

5-(4''-Methylphenyl)-2-(4'-methylphenyl)-1,3,4-oxadiazole (4l)

Yield 88 %; m.p.: (Obs.) 179-180 °C, m.p.: (Lit.) 179-180 °C; TLC Rf = 0.73 [ethylacetate: hexane (3:7)]; 1H-NMR (400 MHz, DMSO-d6): δ = 7.74-7.95 (m, 4H, H-2'', H-6'' & H-2', H-6'), 7.38 (d, 2H, J = 8.4 Hz, H-3', H-5'), 7.28 (d, 2H, J = 8.6 Hz, H-3'', H-5''), 2.45 (s, 6H, 4', 4''-CH3) ppm; 13C-NMR (100 MHz, DMSO-d6): δ = 166.8 (C, C-2), 165.9 (C, C-5), 144.7 (C, C-4''), 142.2 (C, C-4'), 130.1 (CH, C-2'', C-6''), 129.8 (CH, C-2', C-6'), 127.2 (CH, C-3'', C-5''), 127.0 (CH, C-3', C-5'), 120.3 (C, C-1''), 120.1 (C, C-1'), 21.7 (CH3), 21.3 (CH3) ppm; FT-IR (KBr): transparent in the region of (N-H str.) and (C=O str.), 1255 (C-O str.) cm-1; MS (ESI): m/z = 251.1 (M+1)+; Anal. Calcd. for C16H14N2O: C, 76.77; H, 5.60; N, 11.19. Found: C, 76.76; H, 5.59; N, 11.18.

2-(4'-Methylphenyl)-5-(thien-2''-yl)-1,3,4-oxadiazole (4m)

Yield 85 %; m.p.: 126-127 °C; TLC Rf = 0.72 [ethylacetate: hexane (3:7)]; 1H-NMR (400 MHz, DMSO-d6): δ = 8.06 (d, 2H, J = 8.1 Hz, H-2',H-6'), 7.28-7.98 (m, 5H, H-3'', H-4'', H-5'' & H-3', H-5'), 2.42 (s, 3H, 4'- CH3) ppm; 13C-NMR (100 MHz, DMSO-d6): δ = 165.9 (C, C-2), 164.4 (C, C-5), 142.3 (C, C-4'), 132.0 (CH, C-5''), 130.0 (CH, C-2', C-6'), 129.5 (CH, C-3''), 128.6 (CH, C-4''), 126.9 (C, C-2''), 126.8 (CH, C-3', C-5'), 120.6 (C, C-1'), 21.3 (CH3) ppm; FT-IR (KBr): transparent in the region of (N-H str.) and (C=O str.), 1249 (C-O str.) cm-1; MS (ESI): m/z = 243.3 (M+1)+; Anal. Calcd. for C13H10N2OS: C, 64.38; H, 4.13; N, 11.55. Found: C, 64.36; H, 4.10; N, 11.54.

5-(Fur-2''-yl)-2-(4'-methylphenyl)-1,3,4-oxadiazole (4n)

Yield 84.9 %; m.p.: (Obs.) 131-132 °C, m.p.: (Lit.) 131-132 °C; TLC Rf = 0.60 [ethylacetate: hexane (3:7)]; 1H-NMR (400 MHz, DMSO-d6): δ = 7.95 (d, 2H, J = 8.0 Hz, H-2', H-6'), 7.21-7.85 (m, 5H, H-3'', H-4'', H-5'' & H-3', H-5'), 2.44 (s, 3H, 4'-CH3) ppm; 13C-NMR (100 MHz, DMSO-d6): δ = 165.4 (C, C-2), 164.3 (C, C-5), 142.0 (C, C-4'), 133.5 (CH, C-5''), 129.9 (CH, C-2', C-6'), 128.6 (C, C-2''), 127.0 (CH, C-3', C-5'), 120.9 (C, C-1'), 115.2 (CH, C-3''), 113.8 (CH, C-4''), 21.3 (CH3) ppm; FT-IR (KBr): transparent in the region of (N-H str.) and (C=O str.), 1251 (C-O str.) cm-1; MS (ESI): m/z = 227.1 (M+1)+; Anal. Calcd. for C13H10N2O2: C, 69.00; H, 4.42; N, 12.38. Found: C, 69.00; H, 4.40; N, 12.37.

5-(1'',3''-Diphenyl-4''-pyrazolyl)-2-(4'-nitrophenyl)-1,3,4- oxadiazole (4o)

Yield 86.4 %; m.p.: 210-211 °C; TLC Rf = 0.60 [ethylacetate: hexane (3:7)]; 1H-NMR (400 MHz, DMSO-d6): δ = 9.38 (s, 1H, H-5''), 8.26-8.44 (m, 4H, H-Ph'), 7.42-8.03 (m, 10H, H-Ph''' & H-Ph'''') ppm; 13C-NMR (100 MHz, DMSO-d6): δ = 164.1 (C, C-5), 161.6 (C, C-2), 150.8 (C, C-3''), 149.0 (C, C-4'), 138.6 (C, C-1'''), 131.4 (C, C-1''''), 131.1 (CH, C-5''), 129.4 (CH, C-2', C-6'), 128.9 (CH, C-3'''', C-5''''), 128.8 (CH, C-3''', C-5'''), 128.7 (CH, C-4''''), 128.4 (CH, C-2'''', C-6''''), 127.9 (CH, C-4'''), 127.2 (C, C-1'), 124.3 (CH, C-3', C-5'), 118.9 (CH, C-2''', C-6'''), 105.5 (C, C-4'') ppm; FT-IR (KBr): transparent in the region of (N-H str.) and (C=O str.), 1256 (C-O str.) cm-1; MS (ESI): m/z = 410.1 (M+1)+; Anal. Calcd. for C23H15N5 O3: C, 67.46; H, 3.67; N, 17.11. Found: C, 67.44; H, 3.65; N, 17.10.

2-(4'-Nitrophenyl)-5-(4''-nitrophenyl)-1,3,4-oxadiazole (4p)

Yield 89 %; m.p.: (Obs.) 127-128 °C, m.p.: (Lit.) 127-129 °C; TLC Rf = 0.68 [ethylacetate: hexane (3:7)]; 1H-NMR (400 MHz, DMSO-d6): δ = 8.32-8.54 (m, 8H, H-Ph' & H-Ph'') ppm; 13C-NMR (100 MHz, DMSO-d6): δ = 163.1 (C, C-2), 162.6 (C, C-5), 149.3 (C, C-4'), 149.1 (C, C-4''), 130.1 (C, C-1''), 129.3 (C, C-1'), 127.2 (CH, C-2', C-6'), 126.9 (CH, C-2'', C-6''), 124.6 (CH, C-3', C-5'), 124.4 (CH, C-3'', C-5'') ppm; FT-IR (KBr): transparent in the region of (N-H str.) and (C=O str.), 1546 (NO2 asymmetric str.), 1351 (NO2 symmetric str.), 1257 (C-O str.) cm-1; MS (ESI): m/z = 313.0 (M+1)+; Anal. Calcd. for C14H8N4O5: C, 53.85; H, 2.56; N, 17.95. Found: C, 53.83; H, 2.54; N, 17.93.

5-(4''-Bromophenyl)-2-(4'-nitrophenyl)-1,3,4-oxadiazole (4q)

Yield 85 %; m.p.: 197-198 °C; TLC Rf = 0.74 [ethylacetate: hexane (3:7)]; 1H-NMR (400 MHz, DMSO-d6): δ = 8.39-8.46 (m, 4H, H-Ph'), 7.63-7.81 (m, 4H, H-Ph'') ppm; 13C-NMR (100 MHz, DMSO-d6): δ = 163.6 (C, C-5), 163.2 (C, C-2), 148.8 (C, C-4'), 132.3 (CH, C-3'', C-5''), 129.8 (C, C-1'), 128.4 (CH, C-2'', C-6''), 127.3 (CH, C-2', C-6'), 126.3 (C, C-1''), 124.3 (CH, C-3', C-5'), 122.9 (C, C-4'') ppm; FT-IR (KBr): transparent in the region of (N-H str.) and (C=O str.), 1250 (C-O str.) cm-1; MS (ESI): m/z = 346.1 (M+1)+, 348.1 (M+2)+ in the ratio showing typical bromine isotope profile (1:1); Anal. Calcd. for C14H8BrN3O3: C,48.68; H, 2.32; N, 12.17. Found: C, 48.66; H, 2.30; N, 12.14.

5-(4''-Methoxyphenyl)-2-(4'-nitrophenyl)-1,3,4-oxadiazole (4r)

Yield 90 %; m.p.: 176-177 °C; TLC Rf = 0.66 [ethylacetate: hexane (3:7)]; 1H-NMR (400 MHz, DMSO-d6): δ = 8.37-8.46 (m, 4H, H-Ph'), 8.10 (d, 2H, J = 8.4 Hz, H-2'', H-6''), 7.15 (d, 2H, J = 8.2 Hz, H-3'', H-5''), 3.90 (s, 3H, 4''-OCH3) ppm; 13C-NMR (100 MHz, DMSO-d6): δ = 162.3 (C, C-5), 162.1 (C, C-2), 159.6 (C, C-4''), 149.1 (C, C-4'), 129.1 (C, C-1'), 128.6 (CH, C-2'', C-6''), 127.6 (CH, C-2', C-6'), 124.3 (CH, C-3', C-5'), 120.9 (C, C-1''), 114.6 (CH, C-3'', C-5''), 55.3 (OCH3) ppm; FT-IR (KBr): transparent in the region of (N-H str.) and (C=O str.), 1248 (C-O str.) cm-1; MS (ESI): m/z = 298.2 (M+1)+; Anal. Calcd. for C15H11N3O4: C, 60.56; H, 3.70; N, 14.13. Found: C, 60.54; H, 3.69; N, 14.11.

5-(4''-Methylphenyl)-2-(4'-nitrophenyl)-1,3,4-oxadiazole (4s)

Yield 87.9 %; m.p.: 188-189 °C; TLC Rf = 0.70 [ethylacetate: hexane (3:7)]; 1H-NMR (400 MHz, CDCl3): δ = 8.31-8.42 (m, 4H, H-Ph'), 8.05 (d, 2H, J = 8.4 Hz, H-2'', H-6''), 7.37 (d, 2H, J = 8.2 Hz, H-3'', H-5''), 2.46 (s, 3H, 4''-CH3) ppm; 13C-NMR (100 MHz, CDCl3): δ = 165.7 (C, C-5), 162.6 (C, C-2), 149.5 (C, C-4'), 143.1 (C, C-4''), 130.0 (CH, C-2'', C-6''), 129.0 (C, C-1'), 127.7 (CH, C-2', C-6'), 127.1 (CH, C-3'', C-5''), 124.4 (CH, C-3', C-5'), 120.5 (C, C-1''), 21.8 (CH3) ppm; FT-IR (KBr): transparent in the region of (N-H str.) and (C=O str.), 1254 (C-O str.) cm-1; MS (ESI): m/z = 282.3 (M+1)+; Anal. Calcd. for C15H11N3O3: C, 63.99; H, 3.91; N, 14.93. Found: C, 63.97; H, 3.89; N, 14.91.

2-(4'-Nitrophenyl)-5-(thien-2''-yl)-1,3,4-oxadiazole (4t)

Yield 84.9 %; m.p.: 165-166 °C; TLC Rf = 0.57 [ethylacetate: hexane (3:7)]; 1H-NMR (400 MHz, DMSO-d6): δ = 8.35-8.46 (m, 4H, H-Ph'), 7.29-7.96 (m, 3H, H-3'', H-4'', H-5'') ppm; 13C-NMR (100 MHz, DMSO-d6): δ = 164.3 (C, C-5), 162.4 (C, C-2), 148.9 (C, C-4'), 133.5 (CH, C-5''), 131.6 (CH, C-3''), 130.6 (CH, C-4''), 128.7 (C, C-1'), 128.4 (C, C-2''), 127.7 (CH, C-2', C-6'), 124.3 (CH, C-3', C-5') ppm; FT-IR (KBr): transparent in the region of (N-H str.) and (C=O str.), 1248 (C-O str.) cm-1; MS (ESI): m/z = 274.0 (M+1)+; Anal. Calcd. for C12H7N3O3S: C, 52.75; H, 2.56; N, 15.38. Found: C, 52.73; H, 2.54; N, 15.36.

5-(Fur-2''-yl)-2-(4'-nitrophenyl)-1,3,4-oxadiazole (4u)

Yield 85.5 %; m.p.: 145-146 °C; TLC Rf = 0.55 [ethylacetate: hexane (3:7)]; 1H-NMR (400 MHz, DMSO-d6): δ = 8.31-8.49 (m, 4H, H-Ph'), 7.01-7.85 (m, 3H, H-3'', H-4'', H-5'') ppm; 13C-NMR (100 MHz, DMSO-d6): δ = 164.5 (C, C-5), 163.0 (C, C-2), 149.4 (C, C-4'), 133.8 (CH, C-5''), 129.7 (C, C-2''), 129.0 (C, C-1'), 127.8 (CH, C-2', C-6'), 124.4 (CH, C-3', C-5'), 114.6 (CH, C-3''), 114.0 (CH, C-4'') ppm; FTIR (KBr): transparent in the region of (N-H str.) and (C=O str.), 1249 (C-O str.) cm-1; MS (ESI): m/z = 258.1 (M+1)+; Anal. Calcd. for C12H7N3O4: C, 56.01; H, 2.72; N, 16.34. Found: C, 56.00; H, 2.71; N, 16.32.

Biological Activity

DNA photocleavage study

DNA photocleavage experiment was performed by taking 10 µL solution containing plasmid DNA in TE (Tris 10mM, EDTA 0.01mM, pH 8.0) buffer in the presence of 40 µg of synthesized compounds. The sample solution held in caps of polyethylene microcentrifuge tubes were placed directly on the surface of a trans-illuminator (8000 mW/cm) at 360 nm and were irradiated for 30 min at room temperature. After irradiation, samples were further incubated at 37°C for 1H. Irradiated samples were mixed with 6X loading dye containing 0.25 % bromophenol blue and 30 % glycerol. The samples were then analyzed by electrophoresis on a 0.8 % agarose horizontal slab gel in Tris-acetate EDTA buffer (40 mM Tris, 20 mM acetic acid, 1 mM EDTA, pH: 8.0). Untreated plasmid DNA was maintained as a control in each run of gel electrophoresis which was carried out at 5V/cm for 2.0 h. Gel was stained with ethidium bromide (1 µg/mL) and photographed under UV light [37]. To account the effect of synthesized compounds on DNA, the band intensities were analyzed using the MYImage Analysis software provided by Thermo Fisher Scientific Inc.

Results and Discussion

Chemistry

A variety of disubstituted-1,3,4-oxadiazoles had already been synthesized using different toxic reagents like phosphorus oxychloride [38], phosphorus pentaoxide [39] and acetic anhydride [40]. In the past few years, organic synthesis acquired various advantages such as shorter reaction time, higher regio-selectivity [41] and use of greener solvents or reagents with low toxicity profile. In this concern, organoiodine(III) reagents are well known for their non-toxic and eco-friendly behavior in organic synthesis [42,43]. Due to low toxicity and selective nature [44], they have also been extensively used for the synthesis of various heterocycles. In continuation of our interest to synthesize biological active azole derivatives, herein, we report the synthesis of some new 2,5-disubstituted-1,3,4-oxadiazoles by oxidative transformation of various newly synthesized hydrazones by iodobenzene diacetate (IBD), a hypervalent iodine (III) reagent in dichloromethane under mild reaction conditions.

The substituted aroylhydrazones 3 were obtained by the condensation of aroylhydrazines 1 with 3-aryl-1-phenyl-1H-pyrazole-4-carbaldehydes/benzaldehyde derivatives 2 in a mixture of ethanol and dichloromethane in presence of catalytic amount of concentrated sulfuric acid under reflux according to a literature method which was used to synthesize some different derivatives [45, 46]. The final products 4 were obtained in 84-91 % yields with high purity via oxidative cyclization of 3 by treating with 1.1 equivalent of IBD under mild conditions (Scheme 1). Although some 1,3,4-oxadiazole derivatives had been prepared via oxidation of a few substituted hydrazones such as N-acyl hydrazones [47] with 1.1 equivalent of iodobenzene diacetate in dichloromethane (DCM) at room temperature, in the present investigation total 42 compounds were prepared. The compounds were characterized on the basis of their FT-IR, 1H, 13C NMR and mass spectral data. The FT-IR spectra of compounds 3a-u showed absorption bands for –NH and –C=O stretching vibrations at 3427 and 1668 cm-1, respectively. In 1H NMR spectra, the compounds 3a, 3h and 3o displayed two characteristic signals due to 5'-H of pyrazole ring and N=CH at δ 8.96 and 8.61, respectively. A characteristic downfield signal at δ 11.76 was appeared due to the -NH proton and rest of the protons exhibited multiplet in the aromatic region. The chemical shifts in 13C NMR spectra of 3a, 3h and 3o (considering as representative cases) at δ 140.1-144.1, 126.6-127.5 and 160.9-163.4 correspond to N=CH, pyrazole-5' and carbonyl carbon atoms, respectively.

Medicinal-chemistry-Synthesis-substituted-aroylhydrazones

Scheme 1: Synthesis of substituted aroylhydrazones (3a-u) and oxadiazoles (4a-u).

The structures of final products 4a-u were established by comparing FT-IR, 1H and 13C NMR spectral data with those of the compounds 3a-u. The FT-IR spectra of 4 were found transparent in region of -NH and –C=O stretching and thus confirmed the successful oxidation of 3 into 4. Disappearance of chemical shifts at δ 8.38-8.72 (N=CH) and 11.70-12.14 (-NH) in 1H NMR spectra of the products (4a-u) confirmed the successful conversion of aroylhydrazones into 2,5-disubstituted-1,3,4-oxadiazoles. The 13C NMR spectra displayed signals at around δ 159.9, 164.0 for two oxadiazole carbons, however, signals at δ 152.0, 106.5 and 131.6 were appeared due to pyrazole ring carbons 3'', 4'' and 5'', respectively. In 13C NMR spectrum, disappearance of a characteristic signal in range of δ 140.1-144.1 due to N=CH functionality further confirmed the formation of oxadiazoles. The physical data of all the synthesized compounds 4 is given in the Table 1.

No.

R1

R2

Exact
Mass

m.p. (°C)

Reaction Time (min)

a

b

 

4a

H

image 

364.13

136-138

136-137

30-35

4b

 image

267.06

209-210

209-210

95

4c

image 

299.99

167

167-168

30

4d

 image

252.09

150

150-151

155

4e

image 

236.09

148

148-149

120

4f

 image

228.04

-----

110-111

30

4g

image 

212.06

103

103-104

45

4h

p-CH3

 image

378.15

-----

145-146

90

4i

image 

281.08

-----

168-169

100

4j

 image

314.01

-----

205-206

70

4k

 image

266.11

148-150

148-149

215

4l

 image

250.11

179-180

179-180

155

4m

 image

242.05

-----

126-127

150

4n

 image

226.07

131-132

131-132

165

4o

 p-NO2

 

 image

409.12

-----

210-211

70

4p

image 

312.05

127-129

127-128

90

4q

 image

344.97

-----

197-198

30

4r

image 

297.07

-----

176-177

190

4s

 image

281.08

-----

188-189

130

4t

 image

273.02

-----

165-166

70

4u

 image

257.04

-----

145-146

40

Table 1: Physical data of oxadiazoles (4).

The probable mechanism involved in synthesis of oxadiazole is given in Figure 1. The intermediate I is formed by the attack of hydrazone nitrogen on iodine of iodobenzene diacetate followed by elimination of acetate ion. The rate of reaction may depend upon the electron density on the carbon-a and carbon-b. Higher electro-positive character on carbon-b accelerates the attacking tendency of oxygen and the rate of reaction. Whereas, increased in positive charge on carbon-a reduces the attacking tendency of oxygen and hence retards the rate of reaction. On this basis, it is assumed that the presence of electron-withdrawing group at para position of phenyl ring (R2) facilitates the rate of reaction. On the other hand, electron-releasing group at para position of phenyl ring (R2) decreases rate of reaction by increasing the electron density at carbon-b.

Medicinal-chemistry-Proposed-mechanism-synthesis

Figure 1: Proposed mechanism for the synthesis of oxadiazoles 4.

On the other side, it is assumed that electron-withdrawing group attached to para position of phenyl ring (R1) decreases the electron density on carbon-a and thus facilitates the elimination of proton attached to nitrogen but retains the attacking tendency of oxygen to carbon-b. While electron-releasing group attached to para position at phenyl ring decreases the electro-positive character of carbon-a and rate of elimination of proton as a result the rate of reaction gets decreased. Thus, phenyl ring having electron-releasing group attached to either carbon-a or b decreases the rate of reaction (Figure 2).

Medicinal-chemistry-substitution-the-formation-oxadiazoles

Figure 2: Effect of substitution on the formation of oxadiazoles.

Biological Evaluation

Plasmid DNA photocleavage study

The DNA photocleavage study was performed using agarose gel electrophoresis method and results are presented in Figures 3 and 4. There was a significant decrease in intensity of DNA band in case of aroylhydrazones and oxadiazoles as compared to the control DNA.

Medicinal-chemistry-Plasmid-DNA-photocleavage-hydrazones

Figure 3: Plasmid DNA photocleavage of hydrazones 3a-u. Lane 1: Control plasmid DNA+UV+DMSO, Lane 2: DNA+40 µg 3a, Lane 3: DNA+40 µg 3b, Lane 4: DNA+40 µg 3c, Lane 5: DNA+40 µg 3d, Lane 6: DNA+40 µg 3e, Lane 7: DNA+40 µg 3f, Lane 8: DNA+40 µg 3g, Lane 9: DNA+40 µg 3h, Lane 10: DNA+40 µg 3i, Lane 11: DNA+40 µg 3j, Lane 12: DNA+40 µg 3k, Lane 13: DNA+40 µg 3l, Lane 14: DNA+40 µg 3m, Lane 15: Control plasmid DNA+UV+DMSO, Lane 16: DNA+40 µg 3n, Lane 17: DNA+40 µg 3o, Lane 18: DNA+40 µg 3p, Lane 19: DNA+40 µg 3q, Lane 20: DNA+40 µg 3r, Lane 21: DNA+40 µg 3s, Lane 22: DNA+40 µg 3t, Lane 23: DNA+40 µg 3u, respectively. Values under each lane represent percentage contribution of Form I and II.

 

Medicinal-chemistry-Plasmid-DNA-photocleavage-oxadiazoles

Figure 4: Plasmid DNA photocleavage of oxadiazoles 4a-u. Lane 1: Control plasmid DNA+UV+DMSO, Lane 2: DNA+40 µg 4a, Lane 3: DNA+40 µg 4b, Lane 4: DNA+40 µg 4c, Lane 5: DNA+40 µg 4d, Lane 6: DNA+40 µg 4e, Lane 7: DNA+40 µg 4f, Lane 8: DNA+40 µg 4g, Lane 9: DNA+40 µg 4h, Lane 10: DNA+40 µg 4i, Lane 11: DNA+40 µg 4j, Lane 12: DNA+40 µg 4k, Lane 13: DNA+40 µg 4l, Lane 14: DNA+40 µg 4m, Lane 15: Control plasmid DNA+UV+DMSO, Lane 16: DNA+40 µg 4n, Lane 17: DNA+40 µg 4o, Lane 18: DNA+40 µg 4p, Lane 19: DNA+40 µg 4q, Lane 20: DNA+40 µg 4r, Lane 21: DNA+40 µg 4s, Lane 22: DNA+40 µg 4t, Lane 23: DNA+40 µg 4u, respectively. Values under each lane represent percentage contribution of Form I and II.

In case of substituted aroylhydrazones 3a-c, 3h, 3j, 3o-s (lane 2-4, 9, 11 and 17-21), decreased intensity of plasmid DNA as compared to control (lane 1) indicated the cleavage of DNA forms. In lane 11, 17-21 the compounds 3j and 3o-s were responsible for a complete fragmentation of supercoiled (Form I) into open circular (Form II) and linear (Form III) DNA. The intensity of Form III (linear form) was found to be increased in case of compounds 3a-c, 3h, 3j (lane 2-4, 9 and 11) while Form I (supercoiled DNA) was decreased. Moreover, an appearance of the Form III in between Form I and II was observed due to nicking of super coiled DNA. Aroylhydrazones were found to be more active cleaving agent causing fragmentation of plasmid DNA into linear (Form III) DNA.

Unsymmetrical oxadiazoles derivatives (4) also exhibited efficient DNA cleavage property as presented in Figure 4. On irradiation with UV light, the compounds 4a-b, 4d-h, 4s (lane 2-3, 5-9 and 21) were found to show cleavage of supercoiled (Form I) into open circular (Form II) DNA. In lane 12, the compound 4k containing methoxy group at para-position of phenyl ring (R2) was found to be the most effective cleaving agent which was particularly responsible for the complete fragmentation of plasmid DNA. It was found that compounds bearing electron-releasing substituent at para-position of phenyl ring (R2) increase the cleavage potential of oxadiazole compounds. Moreover, higher intensity of the Form II (open circular DNA) was observed in case of aroylhydrazones containing pyrazole moiety. Furthermore, para substitution on phenyl ring also increases the cleavage action of the aroylhydrazone compounds on the plasmid DNA.

Conclusion

In the present investigation, we reported the synthesis of total 21 unsymmetrical 1,3,4-oxadiazole derivatives via oxidative cyclization of their corresponding 21 aroylhydrazones using IBD under solvent conditions and thus explored potential utility of organoiodine(III) reagents on a variety of hydrazone derivatives bearing different electron-withdrawing as well as electron-donating group substituents. It has been observed that phenyl ring (R1) having electron-releasing group at para-position attached to carbon-a or b decreases the rate of reaction. Structures of the synthesized compounds were established on the basis of results obtained from their NMR spectral data. In DNA photocleavage study, it has been observed that compounds 3a-u and 4a-u have shown moderate DNA photocleavage activity. However, 3a-u, in particular, exhibited more photocleavage potential as compared to 4a-u.

Acknowledgements

The authors are grateful to the Chairman, Maharishi Markandeshwar University, Mullana, Ambala, Haryana for providing the necessary research facilities.

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