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Short Note

2-Furyl-6-nitro-1,2,4-triazolo [1,5-a]pyrimidin-7-one

Chemical Engineering Institute, Ural Federal University, 19 Mira St., 620002 Yekaterinburg, Russia
*
Author to whom correspondence should be addressed.
Molbank 2023, 2023(1), M1563; https://doi.org/10.3390/M1563
Received: 27 December 2022 / Revised: 16 January 2023 / Accepted: 19 January 2023 / Published: 23 January 2023
(This article belongs to the Section Organic Synthesis)

Abstract

:
A sodium salt of 2-(fur-2-yl)-6-nitro-1,2,4-triazolo[1,5-a]pyrimidin-7-one as a close structural analogue of ZM-241385 was obtained. This heterocycle can serve as an effector for A2a adenosine receptors and possesses antiseptic activity. The structures of compounds were confirmed based on the data of 1H, 13C NMR spectroscopy, IR spectroscopy, and an elemental analysis. The structure of sodium salt 2-furyl-6-nitro-1,2,4-triazolo[1,5-a]pyrimidin-7-one was confirmed by an X-ray diffraction analysis.

1. Introduction

Sepsis and septic shock are major healthcare problems affecting millions of people around the world each year and killing as many as one in four (and often more) [1,2,3]. Similar to polytrauma, acute myocardial infarction, or stroke, early identification and appropriate management in the initial hours after sepsis develops improves outcomes. The causative agents of sepsis are bacteria (95% of cases), fungi, viruses, and protozoa. Most often, sepsis develops as a complication of diseases such as abdominal trauma, perforation of an intestinal ulcer, pyelonephritis, pneumonia, and severe influenza. The secondary complications of influenza include viral or bacterial pneumonia, pulmonary distress syndrome, and septic shock, which are difficult to treat, including due to late detection, on the one hand, as well as the presence of aggravating factors in the form of an unfavorable premorbid patient background, on the other.
Recently, the European Society of Intensive Care Medicine and the Society of Critical Care Medicine revised the definitions for sepsis and septic shock. Sepsis is now defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Septic shock is a subset of sepsis with circulatory and cellular/metabolic dysfunction associated with a higher risk of mortality [4].
Modern chemotherapy for septic conditions based on broad-spectrum antibiotics [5] and steroids [6] has limited potential, as mortality in sepsis can reach 30% and more than 50% in septic shock. It is clear that novel molecules with a different mechanism of action should be found to fight septic conditions.
It has previously been shown that inflammation is reduced during the activation of adenosine A2a receptor (A2a AR), and the use of synthetic analogues of adenosine increases survival in sepsis. Moreover, A2A AR gene-deficient mice are susceptible to the minimum damaging impacts that stimulate inflammation. In particular, the level of cytokine production is increased, tissues are damaged, and even the death of male species is observed; at the same time, there is no such effect under the action of the same stimuli on wild-type mice [7]. Additionally, we found that nitro-containing derivatives of azoloazine series possessed anti-septic activity in vivo [8]. They could also serve as structural analogues of known effectors for A2a AR, such as 1,2,4-triazolo[1,5-a][1,2,4]triazine ZM 241385 [9]. The further development of more potent effectors for A2a AR with antiseptic activity relies on docking studies towards the active site of this receptor. This task requires optimizing the structural geometry of potential ligands by an X-ray analysis of appropriate crystal samples.
In this communication, we report the synthesis of a sodium salt of 2-(fur-2-yl)-6-nitro-1,2,4-triazolo[1,5-a]pyrimidin-7-one (A), a close structural analogue of ZM-241385 (Scheme 1). This heterocycle (A) can serve as an effector for A2a AR and possesses antiseptic activity. We obtained a crystal sample of azolopyrimidine (A) that was suitable for X-ray analysis and determined the geometry of this molecule.

2. Results

The 2-furyl-6-nitro-1,2,4-triazolo[1,5-a]pyrimidin-7-one A was obtained by a two-step reaction scheme starting from aminoazole 1 and ethoxymethylenenitroacetate 2 (Scheme 2).
In the first step, an equimolar mixture of glacial acetic acid and dry pyridine was used as a solvent for the cyclocondensation of azole 1 and nitrocompound 2. It was found that the isolated product is a pyridinium salt of nitroazoloazine 3, which was confirmed by 1H and 13C NMR analysis (characteristic peaks of pyridine ring in downfield). This can be explained by a strong NH-acidity of the azoloazine scaffold due to the electron-withdrawing effect of the nitro group on the π-deficiency of the heterocyclic system. Subsequent treatment of the pyridinium salt 3 with aqueous solution NaOH resulted in the sodium salt of 2-(fur-2-yl)-6-nitrotriazolo[1,5-a]pyrimidin-7-one A in a good yield (70%). It should be noted that sodium salt A has good solubility in aqueous media, which is important for biological studies.
All compounds were fully characterized by NMR, IR spectroscopy, and elemental analysis (Figures S1–S4, Supplementary Materials). The structure of sodium salt of 2-(fur-2-yl)-6-nitrotriazolo[1,5-a]pyrimidin-7-one A was confirmed by an X-ray diffraction analysis (Figure 1). According to the XRD data, the compound is crystallized in the non-centrosymmetric space group as a hydrate (1:1). In the result of the various anion–cationic interactions, the salt forms the complicated 3D structure; however, any shortened π-π-contacts between heterocycles in the crystal are not observed.

3. Materials and Methods

Commercial reagents were obtained from Sigma-Aldrich Merck Life Science LLC Valovaya Str. 35, floor 6 Moscow 115054, Russian Federation, Acros Organics Thermo Fisher Scientific Geel—Belgium, or Alfa Aesar Thermo Fisher (Kandel) GmbH Erlenbachweg 2 76870, Kandel Germany and used without any preprocessing. All workup and purification procedures were carried out using analytical-grade solvents. One-dimensional 1H and 13C NMR spectra were acquired on a Bruker DRX-400 instrument (400 and 101 MHz, respectively) utilizing DMSO-d6 as a solvent and an external reference. Chemical shifts are expressed in δ (parts per million, ppm) values, and coupling constants are expressed in herts (Hz). The following abbreviations are used for the multiplicity of NMR signals: s, singlet; d, doublet; t, triplet; dd, doublet of doublet; and m, multiplet. The IR spectra were recorded on a Bruker α spectrometer equipped with a ZnSe ATR accessory. The elemental analysis was performed on a PerkinElmer PE 2400 elemental analyzer. Melting points were determined on a Stuart SMP3 (Staffordshire, UK) and are uncorrected. High-resolution mass spectra were obtained using an Agilent 1290 Infinity II high-performance liquid chromatography system equipped with a UV diode array detector and a tandem quadrupole time-of-flight accurate mass detector (Agilent 6545, Agilent Technologies Inc., Santa Clara, CA, USA). 3-(Furan-2-yl)-1H-1,2,4-triazol-5-amine (1) was prepared according to a literature procedure [10].

3.1. Pyridinium 2-(Fur-2-yl)-6-nitro-1,2,4-triazolo[1,5-a]pyrimidin-7-One (3)

Ethyl ethoxymethylenenitroacetate 2 (0.01 mol, 1 equiv) was added to a stirred solution of the 3-(furan-2-yl)-1H-1,2,4-triazol-5-amine (1) (0.01 mol, 1 equiv) in a mixture of pyridine (8.5 mL) and glacial acetic acid (6.0 mL), and the resulting solution was stirred at reflux (145 °C oil bath temperature) for 6 h. The obtained precipitate was filtered off and washed with EtOH. Yellow powder (0.65 g, yield 60%), m.p. 225–226 °C. FT-IR (neat) νmax (cm−1): 1689 (C=O), 1616 (NO2), 1311 (NO2). 1H NMR (400 MHz, DMSO-d6) δ (ppm) 6.61 (1 H, dd, J = 3.4, 1.8 Hz, H-4′), 7.07 (1 H, d, J = 3.3 Hz, H-3′), 7.77 (1 H, d, J = 1.8 Hz, H-5′), 7.80–7.88 (2 H, m, H-3′’, H-5′’), 8.31 (1 H, t, J = 7.7 Hz, H-4′’), 8.83 (2 H, m, H-2′’, H-6′’), 9.04 (1 H, s, H-5). 13C{1H} NMR (100 MHz, DMSO-d6) δ (ppm) 111.0, 111.9, 123.6, 126.7, 143.3, 143.4, 144.6, 144.8, 144.9, 146.1, 150.3, 152.3, 155.1, 157.4. Anal. Calcd. for C14H10N6O4: C 51.54, H 3.09, N 25.76; found: 51.48, H 3.10, N 25.80. HRMS (ESI/Q-TOF), m/z: [M+H]+ Calcd for C14H10N6O4 327.0836; Found 327.0831.

3.2. 2-(Fur-2-yl)-6-nitro-1,2,4-triazolo[1,5-a]pyrimidin-7-one Sodium Salt (A)

Pyridinium salt 2-(fur-2-yl)-6-nitro-1,2,4-triazolo[1,5-a]pyrimidin-7-one 3 0.33 g (0.001 mol, 1 equiv) was added to the solution of 0.064 g (0.0016 mol, 1.6 equiv) of NaOH in 10 mL of H2O. The resulting suspension was refluxed for 10 min and cooled to 25 °C. The solid product that formed was collected by filtration and recrystallized from H2O. Yellow crystals (0.16 g, yield 60%), m.p. 259–261 °C. FT-IR (neat) νmax (cm−1): 3358 (H2O), 1661 (C=O), 1539 (NO2), 1256 (NO2). 1H NMR (400 MHz, DMSO-d6) δ (ppm) 6.66 (1 H, dd, J = 3.4, 1.8 Hz, H-4′), 7.10 (1 H, d, J = 3.4, Hz H-3′), 7.86 (1 H, d, J = 1.8 Hz, H-5′), 9.01 (1 H, s, H-5). 13C{1H} NMR (100 MHz, DMSO-d6) δ (ppm) 110.9, 111.9, 123.2, 144.5, 146.4, 150.9, 153.5, 155.6, 158.7. Anal. Calcd. for C9H4N5O4Na*H2O: C 37.64 H 2.11 N 24.39; found: C 37.73 H 2.09 N 24.42. HRMS (ESI/Q-TOF), m/z: [M+H]+ Calcd for C9H4N5NaO4 270.0233; Found 270.0232.
The XRD analysis was carried out using equipment from the Center for Joint Use “Spectroscopy and Analysis of Organic Compounds” at the Postovsky Institute of Organic Synthesis of the Russian Academy of Sciences (Ural Branch). The experiment was accomplished on the automated X-ray diffractometer «Xcalibur 3» with a CCD detector on standard procedure (MoKα-irradiation, graphite monochromator, ω-scans with 1⁰ step at T = 295(2) K). Empirical absorption correction was applied. The solution and refinement of the structures were accomplished using the Olex program package [11]. The structures were solved using the method of the intrinsic phases on the ShelXT program and refined on ShelXL in anisotropic approximation by the full-matrix least-squared method for non-hydrogen atoms [12]. The H-atoms were placed in the calculated positions and refined in isotropic approximation.
Crystal Data for C9H6N5NaO5 (M =287.18 g/mol): orthorhombic, space group P212121, a = 6.0608(9) Å, b = 13.231(2) Å, c = 13.608(2) Å, V = 1091.3(3) Å3, Z = 4, T = 295(2) K, μ(Mo Kα) = 0.177 mm−1, Dcalc = 1.748 g/cm3, 3615 reflections measured (7.36° ≤ 2Θ ≤ 54.17°), 2378 unique (Rint = 0.0766, Rsigma = 0.1364). These were used in all calculations. The final R1 = 0.0687 (I > 2σ(I)) and wR2 = 0.1840 (all data).
The XRD data were deposited in the Cambridge Structural Database with number CCDC 2232970. These data can be requested free of charge via www.ccdc.cam.ac.uk.

4. Conclusions

To summarize, ZM-241385 structural analogue, 2-(fur-2-yl)-6-nitro-1,2,4-triazolo[1,5-a]pyrimidin-7-one sodium salt A was synthesized. The synthesis was characterized by simplicity and the availability of the reagents. The structure of the synthesized compounds is unambiguously confirmed by the set of spectral data. The prepared structural analogue of ZM-241385 may be further used in medicine for the treatment of sepsis.

Supplementary Materials

Figures S1–S2: 1H and 13C NMR spectra of compounds 3, A; Figures S3–S4: IR spectra of compounds 3, A; Figures S5–S6: HRMS chromatogram with mass spectrum of compounds 3, A.

Author Contributions

Synthesis, V.V.F. and K.V.S.; methodology, E.N.U. and V.L.R.; writing—original draft preparation, V.V.F. and K.V.S.; writing—review and editing, E.N.U. and V.L.R.; crystallographic investigation, P.A.S. and R.A.D.; project administration, V.L.R. All authors have read and agreed to the published version of the manuscript.

Funding

The research funding from the Ministry of Science and Higher Education of the Russian Federation (Ural Federal University Program of Development within the Priority-2030 Program) is gratefully acknowledged.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data are contained within the article.

Acknowledgments

The team of authors would like to thank the Laboratory for Comprehensive Research and Expert Evaluation of Organic Materials under the direction of O.S. Eltsov.

Conflicts of Interest

The authors declare no conflict of interest.

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Scheme 1. The structure of the sodium salt 2-furyl-6-nitro-1,2,4-triazolo[1,5-a]pyrimidin-7-one (A) and ZM-241385.
Scheme 1. The structure of the sodium salt 2-furyl-6-nitro-1,2,4-triazolo[1,5-a]pyrimidin-7-one (A) and ZM-241385.
Molbank 2023 m1563 sch001
Scheme 2. Synthesis of 2-furyl-6-nitro-1,2,4-triazolo[1,5-a]pyrimidin-7-one sodium salt A.
Scheme 2. Synthesis of 2-furyl-6-nitro-1,2,4-triazolo[1,5-a]pyrimidin-7-one sodium salt A.
Molbank 2023 m1563 sch002
Figure 1. The molecule of compound A in the thermal ellipsoids of the 50% probability level and contacts with nearest atoms.
Figure 1. The molecule of compound A in the thermal ellipsoids of the 50% probability level and contacts with nearest atoms.
Molbank 2023 m1563 g001
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MDPI and ACS Style

Fedotov, V.V.; Savateev, K.V.; Ulomsky, E.N.; Drokin, R.A.; Slepukhin, P.A.; Rusinov, V.L. 2-Furyl-6-nitro-1,2,4-triazolo [1,5-a]pyrimidin-7-one. Molbank 2023, 2023, M1563. https://doi.org/10.3390/M1563

AMA Style

Fedotov VV, Savateev KV, Ulomsky EN, Drokin RA, Slepukhin PA, Rusinov VL. 2-Furyl-6-nitro-1,2,4-triazolo [1,5-a]pyrimidin-7-one. Molbank. 2023; 2023(1):M1563. https://doi.org/10.3390/M1563

Chicago/Turabian Style

Fedotov, Victor V., Konstantin V. Savateev, Evgeny N. Ulomsky, Roman A. Drokin, Pavel A. Slepukhin, and Vladimir L. Rusinov. 2023. "2-Furyl-6-nitro-1,2,4-triazolo [1,5-a]pyrimidin-7-one" Molbank 2023, no. 1: M1563. https://doi.org/10.3390/M1563

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