Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 17  |  Issue : 2  |  Page : 104-108

Synthesis and biological activity of some new fused pyrazole-c-nucleosides


1 Chemistry of Natural and Microbial Products Department, National Research Center, Giza, Egypt
2 Department of Chemistry, Faculty of Science, El-Menoufia University, Shebin El-Koom, Egypt

Date of Submission15-Dec-2017
Date of Acceptance18-Feb-2018
Date of Web Publication6-Sep-2018

Correspondence Address:
Samy A El-Assaly
Department of the Chemistry of Natural and Microbial Products, National Research Centre, 33 El Bohoth St, PO Box 12622, Dokki, Giza
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/epj.epj_4_18

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  Abstract 

Background and objectives Owing to the high antiviral, antibiotic, antitumor, and antifungal activities associated with various C-nucleosides, much attention has been paid on the synthesis of this class of compounds. We synthesized new pyrazole-C-nucleosides through one-pot reaction of open sugar, phenyl hydrazine hydrochloride, and different bases in presence of acetic acid and sodium acetate as a catalyst. These nucleosides, containing pyrazole moiety, have been marked as biologically active compounds.

Keywords: chemotherapeutic effects, one-pot synthesis, pyrazole-C-nucleosides


How to cite this article:
El-Assaly SA, Ismail AHA, Sobaih SA, El-Naggar TB. Synthesis and biological activity of some new fused pyrazole-c-nucleosides. Egypt Pharmaceut J 2018;17:104-8

How to cite this URL:
El-Assaly SA, Ismail AHA, Sobaih SA, El-Naggar TB. Synthesis and biological activity of some new fused pyrazole-c-nucleosides. Egypt Pharmaceut J [serial online] 2018 [cited 2018 Oct 16];17:104-8. Available from: http://www.epj.eg.net/text.asp?2018/17/2/104/240670


  Introduction Top


Among the wide variety of pyrazole derivatives that have been explored for developing potential pharmacologically active compounds, pyrazoles fused with different heterocycles, that are known to contribute to various chemotherapeutic effects have emerged as antimicrobial [1],[2], antifungal [3], and antiviral agents [4]. In addition, some fused pyrazole derivatives were reported to induce various antileukemic [5], antitumor [6],[7] and antiproliferative [8],[9] activities. Moreover, fused pyrazole-C-nucleosides have strong biological activities against many diseases. So we prepared new nucleosides through one-pot synthesis of three compounds (one sugar and two bases).


  Materials and methods Top


Chemistry

All melting points were measured on an electrothermal melting point apparatus and are uncorrected. The infrared spectra were recorded in potassium bromide pellets on a Pye Unicam (Cambridge, England) SP 3–300 or Shimadzu (Shimadzu, Tokyo, Japan) FT-IR 8101 PC infrared spectrophotometer. The 1H-NMR (300 MHz) and 13C-NMR (75 MHz) spectra were recorded in DMSO-d6 on a GEMINI-200 spectrometer using TMS as the internal reference. Results are expressed in ppm and coupling constants (J) in Hertz. Mass spectra were measured on a GCMS-QP 1000 EX spectrometer at 70 eV. Elemental analyses were carried out at the Micro analytical Center of Cairo University, Giza, Egypt.

General procedure for the preparation of compounds (2a–d)

To a solution of sugar, containing d(+) mannose, d(+) glucose, d(+) arabinose, and d(+) xylose (0.01 mol), in water (100 ml), the base 5-amino uracil and 5-amino 6-methyl uracil (0.01 mol), phenyl hydrazine hydrochloride (7.2 g; 0.05 mol), acetic acid (6 ml, 60%), and 0.5-g sodium acetate were added. The reaction mixture was heated at 60°C on a water bath for 2–3 h. The reaction mixture was cooled and yellow precipitate was filtered off, and washed successively with ethyl acetate. The compounds gave one spot on thin layer chromatography (TLC).

3-(1, 2, 3-Trihydroxypropyl)-1-phenyl-4,8-dihydropyrazolo [3,4-b]pyrimido [5,4-e] [1,4]oxazin-7(1H)-one (2a)

2a was recrystallized from methanol-ethylacetate as a yellow needle, m. p. 180–183°C, with molecular formula C16H14N5O5 (mol. wt. 356.13 mg). 1H-NMR (DMSO) δ: 3.42 (m, 2H, H-3′), 3.48 (m, 1H, H-2′), 3.88 (d, 1H, H-1′), 4.35 (m, 1H, OH), 4.89 (m, 1H, OH), 5.22 (t, 1H, OH), 6.22 (dd, 1H, CH), 6.81–7.26 (m, 5H, Ar-H), 10.1 (s, 1H, NH); yield 80%, m. p. 58–59°C; IR: 3190–3300 (3OH), 3150 (NH), 1724 (C=O), and 1605 (C=N).

3-(1, 2, 3-Trihydroxypropyl)-1-phenyl,5-methyl-4,8-dihydropyrazolo [3,4-b]pyrimido [5,4-e] [1,4]oxazin-7(1H)-one (2b)

2b was recrystallized from methanol-ethylacetate as a yellow needle, m. p. 193–196°C, with molecular formula C17H16N5O5 (mol. wt. 370.16 mg), 1H-NMR (DMSO) δ: 3.31 (m, 2H, H-3′), 3.42 (m, 1H, H-2′), 3.7 (d, 1H, H-1′), 4.25 (m, 1H, OH), 4.32 (m, 1H, OH), 5.11 (t, 1H, OH), 6.10 (dd, 1H, CH), 6.51–7.81 (m, 5H, Ar-H), 11.2 (s, 1H, NH); yield 83%, m. p. 71–72°C; IR: 3200–3310 (3OH) 3143 (NH), 1712 (C=O), and 1612 (C=N).

3-(1, 2, 3-Trihydroxypropyl)-1-phenyl-4,8-dihydropyrazolo [3,4-b]pyrimido [5,4-e] [1,4]oxazin-7(1H)-one (2c)

2c was recrystallized from ethanol as a white needle, m. p. 190–192°C, with molecular formula C15H12N5O4 (mol. wt. 326.14). 1H-NMR (DMSO) δ: 3.47 (m, 1H, H-2′), 3.56 (d, 1H, H-1′), 4.33 (m, 1H, OH), 4.46 (m, 1H, OH), 6.71–7.26 (m, 9H, Ar-H), 10.1 (s, 1H, NH). 13C-NMR (DMSO) δ: 73 (C-2′), 79 (C-1′), 114, 120, 129 (Ar-C), 145 (CN), 150 (CO) and 211 (C=O).

3-(1,2-Dihydroxyethyl)-1-phenyl, 3-methyl-4,8-dihydropyrazolo [3,4-b]pyrimido [5,4-e] [1,4]oxazin-7(1H)-one (2d)

2d was recrystallized from ethanol as a white needle, m. p. 188–189°C, with molecular formula C16H14N5O4 (mol. wt. 340.13). 1H-NMR (DMSO) δ: 3.49 (m, 1H, H-2′), 3.63 (d, 1H, H-1′), 4.12 (m, 1H, OH), 4.42 (m, 1H, OH), 6.63–7.22 (m, 9H, Ar-H), 10.65 (s, 1H, NH). 13C-NMR (DMSO) δ: 50(CH3), 76 (C-2′), 78 (C-1′), 115, 119, 127 (Ar-C), 144 (CN), 151 (CO), and 212 (C=O).

General procedure for the preparation of compounds (3a–d)

To a solution of the sugar d(+) mannose, glucose, arabinose, and xylose (0.01 mol) in water (100 ml), the base (2-amino imidazole) (0.01 mol), phenyl hydrazine hydrochloride (7.2 g; 0.05 mol), acetic acid (6 ml, 60%), and 0.5 g sodium acetate were added. The reaction mixture was heated at 60°C on a water bath for 2–3 h. The reaction mixture was cooled and yellow precipitate was filtered off, and washed successively with ethyl acetate. The compounds gave one spot on TLC.

3-(1, 2, 3-Trihydroxypropyl)-1-phenyl-pyrazolo- [2,3-b])benzimidazole) (3a)

3a was recrystallized from methanol as a yellow needle, m. p. 185–187°C, with molecular formula C19H17N5O3 (mol. wt. 363.17). 1H-NMR (DMSO) δ: 3.25 (m, 2H, H-3′), 3.47 (m, 1H, H-2′), 3.70 (d, 1H, H-1′), 4.33 (m, 1H, OH), 4.53 (m, 1H, OH), 4.76 (t, 1H, OH), 6.81–7.36 (m, 9H, Ar-H), 10.1 (s, 1H, NH), EI, MS: m/z (%)=(363 M+, 75); yield 80%, m. p. 58–59°C; IR: 318–3310 (3OH), 3140 (NH), and 1602 (C=N).

3-(1, 2, 3-Trihydroxypropyl)-3-methyl,1-phenyl-pyrazolo- [2,3-b])benzimidazole) (3b)

3b was recrystallized from methanol as a yellow needle, m. p.178–180°C, with molecular formula C20H19N5O3 (mol. wt. 377.16). 1H-NMR (DMSO) δ: 3.25 (m, 2H, H-3′), 3.47 (m, 1H, H-2′), 3.70 (d, 1H, H-1′), 4.33 (m, 1H, OH), 4.53 (m, 1H, OH), 4.76 (t, 1H, OH), 6.81–7.36 (m, 9H, Ar-H), 10.1 (s, 1H, NH).,EI, MS: m/z (%)=(363 M+, 75); yield 80%; m. p. 58–59°C; IR: 3200–3320 (3OH), 3150 (NH), and 1605 (C=N).

3-(1,2-Dihydroxyethyl)-1-phenyl-pyrazolo- [2,3-b])benzimidazole) (3c)

3c was recrystallized from methanol as a yellow needle, m. p. 175–176°C, with molecular formula C18H15N5O2 (mol. wt. 333.11). 1H-NMR (DMSO) δ: 3.25 (m, 2H, H-3′), 3.47 (m, 1H, H-2′), 3.70 (d, 1H, H-1′), 4.33 (m, 1H, OH), 4.53 (m, 1H, OH), 4.76 (t, 1H, OH), 6.81–7.36 (m, 9H, Ar-H), 10.1 (s, 1H, NH), EI, MS: m/z (%)=(363 M+, 75); yield 80%; m. p. 58–59°C; IR: 3235–3300 (2OH), 3221 (NH), and 1611 (C=N).

3-(1,2-Dihydroxyethyl)-3-methyl,1-phenyl-pyrazolo- [3,4-b])benzimidazole (3d)

3d was recrystallized from methanol as a yellow needle, m. p. 173–175°C., with molecular formula C19H17N5O2 (mol. wt. 347.14). 1H-NMR (DMSO) δ: 3.37 (m, 1H, H-2′), 3.70 (d, 1H, H-1′) 4.33 (m, 1H, OH), 4.76 (t, 1H, OH), 6.81–7.36 (m, 9H, Ar-H), 10.1 (s, 1H, NH). 13C-NMR (DMSO) δ: 73 (C-2′), 79 (C-1′), 111, 114, 119, 128, 150 (Ar-C); yield 80%; m. p. 58–59°C; IR: 3190–3286 (2OH), 3166 (NH), and 1603 (C=N).

Biological activity

The potential target for antiviral chemotherapy is the reverse transcription step in hepatitis B virus (HBV) life cycle [10],[11],[12],[13],[14]. The minus strand of HBV is synthesized by reverse transcription of pregenome using the endogenous viral reverse transcriptase. It is shown that reverse transcription enzyme leads to incorporate nucleotide analogues more efficient than cellular DNA polymerase [15],[16],[17]. These nucleotide analogues are competitive inhibitors of the reverse transcriptase with the nucleosides pool in the cells cytoplasm in minus strand synthesis.

The recent development of nucleoside analogues has represented a breakthrough in the research for selective antiviral activities. Among these agents, for example, Lamivudine acts as a retroviral inhibitor [18]. It has activity against HBV replication both in vitro and in vivo.

Calculation of 50% inhibitory concentration of antiviral drugs, 50% cytotoxic effect, and selective index

The 50% inhibitory concentration of antiviral drugs (IC50) was determined by interpolation from the plots of amount of DNA copies versus antiviral drug concentration. The 50% cytotoxic effect (CC50) was calculated from the average viability of the cells with concentration of drugs. The selective index could be calculated as CC50/IC50.


  Results and discussion Top


In this work, 5-amino, 6-methyl uracil reacted with sugars and phenyl hydrazine hydrochloride to give fused pyrazole-C-nucleosides. Thus, 5-amino uracil reacts with d(+) mannose, d(+) glucose, d(+) arbinose, d(+) xylose, and phenyl hydrazine hydrochloride to give 2a–d. It should be noted that the products form with multicomponent reactions in one step via Michael addition (Scheme 1).

Moreover, 2-amino, 4-methyl imidazole reacted with d(+) mannose, d(+) glucose, d(+) arbinose, d(+) xylose, and phenyl hydrazine hydrochloride in the presence of aqueous acetic acid to give 3a–d (Scheme 2).


  Conclusion Top


The result of the antiviral screening against HBV of selected compounds indicated that compounds 2a, 2b, 2c, 2d, 3a, 3b, 4c, and 3d showed low inhibition and high cytotoxicity with selective indices 3.25–7.49 ([Table 1]): CC50, IC50, and selective index of compounds 2a, 2b, 2c, 2d, 3a, 3b, 4c, and 3d.
Table 1 Calculation of 50% inhibitory concentration of antiviral drugs, 50% cytotoxic effect, and selective index

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Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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    Figures

  [Scheme 1], [Scheme 2]
 
 
    Tables

  [Table 1]



 

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