Green synthesis of structural analogs of favipiravir

Abstract

A series of 3-hydroxy-5-arylpyrazine-2-carboxamides, structural analogs of favipiravir, have been successfully synthesized using a green and sustainable method through a one-pot condensation reaction of arylglyoxals 1a–i and 2-aminopropanediamide 2 in an alkaline solution under heating conditions. The reaction is temperature-sensitive; when conducted at 80 °C, 5-aryl substituted pyrazine derivatives were predominantly obtained. In reactions with arylglyoxals 1a, 1d, 1h, and 1i, temperatures exceeding 80 °C produced a mixture of two regioisomeric pyrazine derivatives with significant efficiency. This method is highly desirable due to its short reaction time, simple purification of products, and the use of water as an eco-friendly solvent.

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1. Introduction

Viruses, as microscopic infectious agents, are small obligate intracellular parasites that possess either an RNA or DNA genome and an outer protein shell, which may be enveloped by a lipid layer.¹ Viral infections and their resulting epidemics, and pandemics are among the primary causes of high mortality.² RNA viruses, such as the influenza virus (H1N1),³ the highly pathogenic avian influenza virus (H5N1),^4,5 Zika,⁶ the Ebola virus (EBOV),^7,8 severe acute respiratory syndrome coronavirus (SARS-CoV-1),⁹ and COVID-19 (SARS-CoV-2)^10–13 are highly transmissible and lead to significant public health issues, along with considerable morbidity and mortality. Thus, to prevent the further spread of RNA viruses, the development of more potent therapeutic agents with activity against a broad spectrum of such pathogens is essential.

1,4-Pyrazine-3-carboxamide-based antiviral compounds have been under intensive study for the last 20 years.^2,14 Favipiravir (6-fluoro-3-hydroxypyrazine-2-carboxamide, T-705), a synthetic analog of 1,4-pyrazine-3-carboxamide, is an antiviral drug that inhibits the RNA-dependent RNA polymerase of influenza virus. It is effective against a variety of RNA viruses but not against DNA viruses.^2,15–20 In recent years, favipiravir has also been actively used against COVID-19.²¹

Favipiravir, a 3-OH substituted pyrazine derivative, exhibits acidic properties and can tautomerize to the keto form, as shown in Scheme 1.²² Favipiravir, a nucleobase analog, is a prodrug; its active form is favipiravir-RTP, a nucleoside analog. The nucleobase analog favipiravir first undergoes metabolic activation through phosphoribosylation to form ribofuranosyl-5′-monophosphate (Favipiravir-RMP, T-705-RMP), which is then converted through intracellular phosphorylation into its ribofuranosyl-5′-triphosphate metabolite (Favipiravir-RTP, T-705-RTP), most likely by a series of intracellular enzymes (Scheme 1).^23–25 The fluoro group in the structure enhances favipiravir's binding energy with RNA polymerase.²⁶ Literature suggests that the nitrogen atom undergoing phosphoribosylation is a promising target for structural modifications (Fig. 1).²³ However, attempts to obtain the favipiravir riboside or the monophosphate revealed that its bond is prone to cleavage and the compound exhibited poor solubility.²⁷

Scheme 1 Formation of the active metabolite of favipiravir (T-705-RTP) from favipiravir (T-705).

Fig. 1 Structural analogs of favipiravir.

Favipiravir (T-705) was first synthesized by Furuta and co-workers²⁸ (Japanese Toyama Chemical Co., Ltd) in 2000 in a seven-step process from 3-aminopyrazine-2-carboxylic acid. This approach had a poor overall yield of 0.44% (Scheme 2), but a second approach starting with aminomalonic acid diethyl ester and proceeding through a series of sequential reactions, improved the yield to 17%.²⁹ Current research is focused on finding more efficient and practical ways to synthesize favipiravir (Scheme 3).^30–46 Classical synthetic methods for producing favipiravir are thoroughly detailed in three recent reviews by Y. Titova,²⁷ N. Al Bujuq,⁴³ and N. Qin.⁴⁶

Scheme 2 Favipiravir synthesis according to the strategy developed by Y. Furuta et al. (Toyama Chemical Co., Ltd).²⁸

Scheme 3 Synthetic methods for the preparation of favipiravir (T-705).

Structural analogs of favipiravir are also under study for antiviral activity. Of particular interest are the non-fluorinated T-705 analog (T-1105; 3-hydroxy-2-pyrazinecarboxamide) and it's active nucleoside 5′-triphosphate form (T-1105-RTP) (Fig. 1). T-1105 has shown promising results in the treatment of influenza virus H1N1and other RNA viruses.^47–49 The antiviral activity of T-1105 and it's activated form T-1105-RTP depends on the cell lines. For example, T-1105 showed higher antiviral activity in MDCK cells. However, antiviral activity of T-1105-RTP was not detected in the three cell lines, A549, Vero cells HEK293T cells.⁴⁹ Also its ribonucleoside analog T-1106 (3,4-dihydro-3-oxo-4-β-d-ribofuranosyl-2-pyrazinecarboxamide) has showed potent antiviral activity against RNA viruses without significant toxicity to mammalian cells.^50–55 A number of in vitro and in vivo studies have shown an even higher efficacy of T-1105 and T-1106 compared to that of favipiravir.^17,56 Synthesis of the new bioactive derivative of favipiravir, (E)-N-(4-cyanobenzylidene)-6-fluoro-3-hydroxypyrazine-2-carboxamide (cyanorona-20), was reported in 2021. Cyanorona-20 exhibited very significant anti-COVID-19 activity and interestingly demonstrated approximately 209- and 45-fold anti-SARS-CoV-2 selectivity/potency compared to favipiravir and remdesivir, respectively.⁵⁷

In this study, we present the synthesis of novel structural analogs of favipiravir through an eco-friendly one-pot condensation reaction involving arylglyoxal monohydrates and 2-aminopropanediamide.

2. Results and discussion

Development of convenient protocols for synthesis of biologically active pyrazine scaffolds from simple raw materials is a key research area in heterocyclic chemistry and especially drug discovery programs. Synthetic routes for pyrazines may include different building blocks or conditions. In this work, we tried to synthesize the pyrazine ring, the central core of favipiravir, from the condensation reaction of arylglyoxalmonohydrates 1 with 2-aminopropanediamide 2 in the presence of aqueous sodium hydroxide solution.

For this purpose, the arylglyoxalmonohydrates 1a–i were prepared by oxidation of corresponding aryl methyl ketones with selenium dioxide according to standard literature procedure (Scheme 4).⁵⁸ 2-Aminopropanediamide 2 was synthesized using modified literature methods via the ammonolysis of the ester groups of diethylaminomalonate hydrochloride salt with a 25% ammonia solution at room temperature in methanol (Scheme 5).^59,60

Scheme 4 Synthesis of arylglyoxalmonohydrates.

Scheme 5 Synthesis of 2-aminopropanediamide.

Next, the reaction of phenylglyoxalmonohydrate (1a), and 2-aminopropanediamide (2) was selected as a model reaction. The condensation reaction of phenylglyoxalmonohydrate 1a (1.6 mmol), and 2-aminopropanediamide 2 (1.7 mmol) was carried out in water in the presence of sodium hydroxide under heating conditions. The reaction of 1a and 2 under basic conditions at 70 °C leads to the formation of sodium salt of 3a. Then acidification by acetic acid to afford 3a in 40% yield. We were pleased to find that this reaction is temperature-sensitive (Table 1). At 80 °C, the reaction also favors the formation of 3-hydroxy-5-phenylpyrazine-2-carboxamide 3a as main product in higher yield 55% (Table 1, entry 2), while temperatures exceeding 80 °C lead to a mixture of two possible regioisomeric pyrazine compounds with significant efficiency. At 90 °C, two regoisomeric compounds 3a and 4a were obtained in equal amounts (Table 1, entry 3). This indicates that temperature significantly affects the regioselectivity of the reaction. Two compounds were separated through crystallization from ethanol. The melting point of one of the products is in agreement with the value reported for the 3-hydroxy-6-phenylpyrazine-2-carboxamide (4a) with a melting point of 213 °C in the literature.⁶⁰ Consequently, another regioisomeric compound, with a melting point of 257 °C, corresponds to 3-hydroxy-5-phenylpyrazine-2-carboxamide (3a).

Table 1 Optimization of the reaction temperature

Entry	Temperature (°C)	Time (h)	Yield (%) 3a	Yield (%) 4a
1	70	2	40	—
2	80	2	55	10
3	90	2	30	30

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The electron-withdrawing ketone group in arylglyoxals enhances the electrophilicity of the aldehyde carbonyl group. This increased electrophilicity results in a quicker reaction of the aldehyde carbonyl with the more nucleophilic NH₂ group under kinetic conditions, favoring the formation of the product 3a. However, under thermodynamic conditions, both products 3a and 4a are generated as the reaction can progress to a more stable equilibrium. The proposed mechanism for the synthesis of 3-hydroxy-(5-aryl/6-aryl) pyrazine-2-carboxamides is shown in Scheme 6. The formation of product 3a versus 4a via two pathways depends not only on the relative electrophilicity of two carbonyl groups but also on the stability of the imine intermediates (A) and (B). Pathway 1, leading to product 3a, involves a less stable imine derivative (A), while pathway 2, leading to product 4a, proceeds through a more stable aryl imine (B).

Scheme 6 Plausible mechanism for the synthesis of 3-hydroxy-(5-aryl and 6-aryl) pyrazine-2-carboxamide derivatives.

With optimized reaction conditions in hand (reaction in alkaline water at 80 °C), the scope of the reaction was explored with various arylglyoxalmonohydrates (Scheme 7 and Table 2).

Scheme 7 Synthesis of 3-hydroxy-5-arylpyrazine-2-carboxamide derivatives in aqueous solution.

Table 2 One-pot synthesis of 3-hydroxy-5-arylpyrazine-2-carboxamides^a

Entry	Reactant	Product^b	Time (h)	Yield^c (%)	m.p. (°C)
a Reaction conditions: arylglyoxalmonohydrates (1.6 mmol), aminomalonamide (1.7 mmol), aqueous sodium hydroxide solution (12.5 N, 1 mL), 6 mL water at 80 °C, then glacial acetic acid (1 mL).b Yield of products 4a, 4d, 4h, and 4i at reaction temperature above 80 °C.c Yield of the isolated product after recrystallization.d Decompose before melting.
1			2	55	256–257
2			2	30^b	210–213 (ref. 60 213–216)
3			2	65	238–240
4			2	60	254–255 (Dec.)^d
5			2	45	219–220
6			2	15^b	236–238 (Dec.)^d
7			2.5	48	275–278
8			2	72	269–270 (Dec.)^d
9			2	68	266–270 (Dec.)^d
10			2	48	217–220
11			2	15^b	200–204
12			2	50	225–226 (Dec.)^d
13			2	12^b	198–199

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The structure of novel 3-hydroxy-5-arylpyrazine-2-carboxamide derivatives was confirmed using FT-IR, ¹H NMR, and ¹³C NMR spectroscopy. For example, the FT-IR spectrum of 3-hydroxy-5-arylpyrazine-2-carboxamide 3a confirmed the presence of the functional groups OH and NH₂ at 3435, 3264, 3211 cm⁻¹, along with the amide carbonyl (NH–C=O) exhibiting a strong absorption band around 1666 cm⁻¹. The ¹H NMR spectrum of 3a displayed the aromatic protons of phenyl ring at 7.59–8.17 ppm, the CH proton of pyrazine ring at 8.76 ppm, and the NH₂ protons at 8.42 and 8.82 ppm as two singlets, with the OH proton at 13.59 ppm. The partial double bond character of the carbon–nitrogen bond in the amide group results in restricted rotation, making the two NH₂ protons of chemically distinct and leading to separate NMR signals. On the other hand, the two NH NMR signals of ortho hydroxy carboxamide would likely appear at different chemical shifts due to intramolecular hydrogen bonding and the different environments of the amide protons. The ¹³C NMR spectrum further confirmed the product by the presence of an amide carbonyl signal at 170.1 ppm, and C-3 of pyrazine ring at 168.6 ppm.

3. Conclusions

In summary, we presented a simple and eco-friendly method for synthesizing structural analogs of favipiravir through a one-pot condensation reaction of 2-aminopropanediamide and arylglyoxals in an aqueous alkaline solution upon heating. The reaction is sensitive to temperature. At 80 °C, the main product is 3-hydroxy-5-phenylpyrazine-2-carboxamide; however, in some instances, temperatures exceeding 80 °C result in a mixture of two regioisomeric pyrazine compounds with comparable efficiency.

4. Experimental

4.1. General

The ¹H and ¹³C NMR spectra were recorded using Varian INOVA 500 MHz or Bruker 250 MHz NMR spectrometers. The IR spectra were recorded on a Bruker PS-15 spectrometer. The melting points were measured on an electrothermal 9100 apparatus in open capillaries without correction. The elemental analyses were performed on a Carlo-Erba 1104 CHN analyzer. All the commercial reagents were used without prior purification.

4.2. Preparation of 2-aminopropanediamide 2

Diethyl aminomalonate hydrochloride (1.5 g, 7 mmol) was dissolved in methanol (2 mL) and added to a 25% ammonia solution (14 mL) while kept in an ice bath (0 °C). The mixture was stirred for 15 min at 0 °C, followed by 24 h at room temperature. The resulting precipitate was filtered and washed with 25% ammonia solution. 2-Aminopropanediamide (aminomalonamide) was obtained as a white powder with a yield of 67% (0.56 g).

mp 188–189 °C (ref. 60 187–188 (Dec.)); IR (KBr): [small upsilon, Greek, macron] = 3358, 3312, 3211 (NH₂), 2892 (C–H), 1686 (C=O), 1658, 1286 (C–N) cm⁻¹; ¹H NMR (DMSO-d₆, 250 MHz): δ = 2.88 (s, 1H, CH), 3.74 (s, 2H, NH₂), 7.21 (s, 2H, (C=O)NH₂), 7.40 (s, 2H, (C=O)NH₂) ppm; ¹³C NMR (DMSO-d₆, 62 MHz): δ = 58.6 (CH), 172.2 (C=O) ppm.

4.3. Typical procedure for the synthesis of 3-hydroxy-5-arylpyrazine-2-carboxamides 3a–i

Powdered aminomalonamide 2 (200 mg, 1.7 mmol) was added to a solution of phenylglyoxalmonohydrates 1a (250 mg, 1.6 mmol) in water (6 mL) at 80 °C with stirring. Then, a 12.5 N aqueous sodium hydroxide solution (1 mL) was added dropwise to the reaction mixture. Within a few minutes of stirring, the semi-solid mixture was obtained. Upon completion of the reaction (1 h), the reaction mixture cooled to room temperature and glacial acetic acid (1 mL) was added drop-wise while stirring. After the reaction was complete, the precipitated solid was filtered, washed with water and acetone, respectively, and air-dried. Ethanol was then added to the crude solid product and refluxed. Part of the solid dissolved in ethanol, and the residue was separated by filtration. This compound, with a melting point of 257 °C, was consistent with 3-hydroxy-5-phenylpyrazine-2-carboxamide 3a. The filtrate is also allowed to cool. The resulting crystals was filtered. This compound, with a melting point of 213 °C, was consistent with 3-hydroxy-6-arylpyrazine-2-carboxamide 4a. In the reaction of arylglyoxalmonohydrates 1a, 1d, 1h, and 1i with aminomalonamide 2 at 80–85 °C, 6-aryl substituted pyrazine derivatives were obtained in significant yields, while in other cases, 6-aryl substituted pyrazine derivatives formed only in trace amounts.

4.3.1. 3-Hydroxy-5-phenylpyrazine-2-carboxamides 3a. Yield: 189 mg (55%); brown powder; mp 256–257 °C; IR (KBr): [small upsilon, Greek, macron] = 3435, 3264, 3206 (NH₂, OH), 1666 (C=O) cm⁻¹; ¹H NMR (500 MHz, DMSO-d₆): δ = 7.54–7.55 (m, 3H, Ar–H), 8.15–8.16 (m, 2H, Ar–H), 8.42–8.82 (s, 2H, NH₂), 8.75 (s, 1H, pyrazine H), 13.59 (s, 1H, OH) ppm; ¹³C NMR (62 MHz, DMSO-d₆): δ = 125.76, 127.41, 129.19, 130.25, 139.86, 142.78, 154.00, 168.64 (C–OH), 170.12 (C=O) ppm; anal. calcd for C₁₁H₉N₃O₂: C, 61.39; H, 4.22; N, 19.53. Found: C, 61.42; H, 4.36; N, 19.80.

4.3.2. 3-Hydroxy-6-phenylpyrazine-2-carboxamide 4a. Yield: 35 mg (10%); yellow powder; mp 210–213 °C (ref. 60 213–216 °C); IR (KBr): [small upsilon, Greek, macron] = 3433 (OH), 3266, 3210 (NH₂, OH), 1665 (C=O) cm⁻¹; ¹H NMR (500 MHz, DMSO-d₆): δ = 7.46–7.48 (m, 1H, Ar–H), 7.49–7.55 (m, 2H, Ar–H), 8.15–8.16 (m, 2H, Ar–H), 8.42 and 8.82 (s, 2H, NH₂), 8.76 (s, 1H, pyrazine H), 13.55 (s, 1H, OH) ppm; ¹³C NMR (62 MHz, DMSO-d₆): δ = 127.69, 128.00, 129.41, 130.92, 135.74, 153.64, 162.62 (C–OH), 169.87(C=O) ppm; anal. calcd for C₁₁H₉N₃O₂: C, 61.39; H, 4.22; N, 19.53. Found: C, 61.41; H, 4.32; N, 19.79.

4.3.3. 5-(4-Bromophenyl)-3-hydroxypyrazine-2-carboxamide 3b. Yield: 207 mg (65%); yellow powder; mp 238–240 °C; IR (KBr): [small upsilon, Greek, macron] = 3566, 3248, 3211 (NH₂, OH), 1630 (C=O) cm⁻¹; ¹H NMR (250 MHz, DMSO-d₆): δ = 7.69–7.73 (m, 2H, Ar–H), 8.06–8.10 (m, 2H, Ar–H), 8.39 (s, 1H, pyrazine H), 8.75 and 8.79 (s, 2H, NH₂), 13.60 (s, 1H, OH) ppm; ¹³C NMR (62 MHz, DMSO-d₆): δ = 121.62, 125.13, 129.72, 131.89, 132.49, 134.33, 152.73, 161.43 (C–OH), 170.08 (C=O) ppm; anal. calcd for C₁₁H₈BrN₃O₂: C, 44.92; H, 2.74; N, 14.29. Found: C, 44.95; H, 2.89; N, 14.46.

4.3.4. 5-(4-Chlorophenyl)-3-hydroxypyrazine-2-carboxamide 3c. Yield: 202 mg (60%); green powder; mp 254–255 °C (Dec.); IR (KBr): [small upsilon, Greek, macron] = 3442, 3278, 3211 (NH₂, OH), 1666 (C=O) cm^{−1; 1}H NMR (500 MHz, DMSO-d₆): δ = 7.60 (s, 1H, Ar–H), 7.62 (s, 1H, Ar–H), 8.19 (s, 1H, Ar–H), 8.20 (s, 1H, Ar–H), 8.44 and 8.84 (s, 2H, NH₂), 8.78 (s, 1H,pyrazine H), 13.58 (s, 1H, OH) ppm; ¹³C NMR (62 MHz, DMSO-d₆): δ = 129.57, 132.90, 134.06, 136.23, 152.84, 161.51 (C–OH), 170.20 (C=O) ppm; anal. calcd for C₁₁H₈ClN₃O₂: C, 52.92; H, 3.23; N, 16.83. Found: C, 53.15; H, 3.38; N, 16.99.

4.3.5. 5-(4-Fluorophenyl)-3-hydroxypyrazine-2-carboxamide 3d. Yield: 154 mg (45%); orange powder; mp 219–220 °C; IR (KBr): [small upsilon, Greek, macron] = 3445, 3277, 3211 (NH₂, OH),1673 (C=O) cm⁻¹; ¹H NMR (250 MHz, DMSO-d₆): δ = 7.24–7.35 (m, 2H, Ar–H), 8.14–8.20 (m, 2H, Ar–H), 8.40 (s, 1H, pyrazine H), 8.71 and 8.85 (m, 2H, NH₂), 13.52 (s, 1H, OH) ppm; ¹³C NMR (62 MHz, DMSO-d₆): δ = 116.63, 128.58, 130.18, 130.32, 132.68, 153.02, 162.26 (C–OH), 166.22 (C–F), 170.23 (C=O) ppm; anal. calcd for C₁₁H₈FN₃O₂: C, 56.65; H, 3.46; N, 18.02. Found: C, 56.72; H, 3.61; N, 18.25.

4.3.6. 6-(4-Fluorophenyl)-3-hydroxypyrazine-2-carboxamide 4d. Yield: 52 mg (15%); yellow powder; mp 236–238 °C (Dec.); IR (KBr): [small upsilon, Greek, macron] = 3444, 3280, 3210 (NH₂, OH), 1671 (C=O) cm⁻¹; ¹H NMR (250 MHz, DMSO-d₆): δ = 7.29–7.36 (m, 2H, Ar–H), 8.21 (s, 2H, Ar–H), 8.42 (s, 1H, pyrazine H), 8.76–8.80 (s, 2H, NH₂), 13.58 (s, 1H, OH) ppm; ¹³C NMR (62 MHz, DMSO-d₆): δ = 116.68, 128.58, 130.35, 131.77, 132.73, 153.03, 161.51 (C–OH), 166.24 (C–F), 170.23 (C=O) ppm; anal. calcd for C₁₁H₈FN₃O₂: C, 56.65; H, 3.46; N, 18.02. Found: C, 56.68; H, 3.62; N, 18.32.

4.3.7. 3-Hydroxy-5-(4-nitrophenyl)pyrazine-2-carboxamide 3e. Yield: 158 mg (48%); dark brown powder; mp 275–278 °C; IR (KBr): [small upsilon, Greek, macron] = 3418 (NH₂, OH), 1669 (C=O) cm⁻¹; ¹H NMR (250 MHz, DMSO-d₆): δ = 7.50–8.54 (m, 7H, Ar–H, pyrazine H, NH₂), 8.89 (s, 1H, OH) ppm; ¹³C NMR (62 MHz, DMSO-d₆): δ = 122.92, 125.31, 128.74, 130.83, 132.90, 154.60, 161.75 (C–OH), 167.14 (C–NO₂), 170.06 (C=O) ppm; anal. calcd for C₁₁H₈N₄O₄: C, 50.77; H, 3.10; N, 21.53. Found: C, 50.60; H, 3.20; N, 21.70.

4.3.8. 3-Hydroxy-5-(p-tolyl)pyrazine-2-carboxamide 3f. Yield: 249 mg (72%); light orange powder; mp 269–270 °C (Dec.); IR (KBr): [small upsilon, Greek, macron] = 3428, 3274, 3212 (NH₂, OH), 1662(C=O) cm⁻¹; ¹H NMR (250 MHz, DMSO-d₆): δ = 2.32 (s, 3H, CH₃), 7.24–7.27 (d, J = 7.5 Hz, 2H, Ar–H), 8.03–8.06 (d, J = 7.5 Hz, 2H, Ar–H), 8.37 (s, 1H, pyrazine H), 8.71–8.83 (m, 2H, NH₂) 13.38 (s, 1H, OH) ppm; ¹³C NMR (62 MHz, DMSO-d₆): δ = 21.25 (CH₃), 126.23, 127.75, 130.11, 132.41, 138.75, 141.33, 159.79, 161.51 (C–OH), 170.22 (C=O) ppm; anal. calcd for C₁₂H₁₁N₃O₂: C, 62.87; H, 4.84; N, 18.33. Found: C, 62.90; H, 4.94; N, 18.50.

4.3.9. 3-Hydroxy-5-(4-methoxyphenyl)pyrazine-2-carboxamide 3g. Yield: 229 mg (68%); green powder; mp 266–270 °C (Dec.); IR (KBr): [small upsilon, Greek, macron] = 3450, 3271 (OH, NH₂), 1610 (C=O) cm⁻¹; ¹H NMR (250 MHz, DMSO-d₆): δ = 3.81 (s, 3H, OCH₃), 6.97–7.00 (d, J = 7.5 Hz, 1H, Ar–H), 7.03–7.06 (d, J = 7.5 Hz, 1H, Ar–H), 8.07 (s, 1H, Ar–H), 8.11 (s, 1H, Ar–H), 8.30 (s, 1H, pyrazine H), 8.68–8.85 (m, 2H, NH₂), 13.34 (s, 1H, OH) ppm; ¹³C NMR (62 MHz, DMSO-d₆): δ = 55.82 (OCH₃), 114.57, 128.15, 129.47, 131.63, 141.14, 153.76, 161.96 (C–OH), 169.42 (C–OCH₃), 170.30 (C=O) ppm; anal. calcd for C₁₂H₁₁N₃O₃: C, 58.77; H, 4.52; N, 17.13. Found: C, 58.85; H, 4.67; N, 17.40.

4.3.10. 3-Hydroxy-5-(naphthalen-2-yl)pyrazine-2-carboxamide 3h. Yield: 158 mg (48%); light yellow powder; mp 217–220 °C; IR (KBr): [small upsilon, Greek, macron] = 3439, 3275, 3213 (OH, NH₂), 1669 (C=O) cm⁻¹; ¹H NMR (250 MHz, DMSO-d₆): δ = 7.56–7.58 (m, 3H, Ar–H), 7.97–8.06 (m, 4H, Ar–H), 8.30 (s, 1H, pyrazine H), 8.78 and 8.94 (s, 2H, NH₂), 13.49 (s, 1H, OH) ppm; ¹³C NMR (62 MHz, DMSO-d₆): δ = 124.55, 125.23, 127.00, 127.30, 128.09, 128.78, 129.13, 132.86, 133.35, 134.36, 153.84, 161.74 (C–OH), 170.26 (C=O) ppm; anal. calcd for C₁₅H₁₁N₃O₂: C, 67.92; H, 4.18; N, 15.84. Found: C, 67.95; H, 4.30; N, 15.98.

4.3.11. 3-Hydroxy-6-(naphthalen-2-yl)pyrazine-2-carboxamide 4h. Yield: 50 mg (15%); mustard yellow powder; mp 200–204 °C; IR (KBr): [small upsilon, Greek, macron] = 3433, 3267, 3205 (OH, NH₂), 1671 (C=O) cm⁻¹; ¹H NMR (250 MHz, DMSO-d₆): δ = 7.45–8.30 (m, 8H, pyrazine H, Ar–H), 8.81–8.95 (s, 2H, NH₂), 13.54 (s, 1H, OH) ppm; ¹³C NMR (62 MHz, DMSO-d₆): δ = 124.53, 126.49, 129.74, 130.48, 130.95, 133.07, 134.36, 142.64, 153.84, 161.59 (C–OH), 170.25 (C=O) ppm; anal. calcd for C₁₅H₁₁N₃O₂: C, 67.92; H, 4.18; N, 15.84. Found: C, 67.85; H, 4.28; N, 16.12.

4.3.12. 5-([1,1′-Biphenyl]-4-yl)-3-hydroxypyrazine-2-carboxamide 3i. Yield: 160 mg (50%); bright orange powder; mp 225–226 °C (Dec.); IR (KBr): [small upsilon, Greek, macron] = 3444, 3282, 3058 (OH, NH₂), 1661(C=O) cm⁻¹; ¹H NMR (250 MHz, DMSO-d₆): δ = 7.47 (m, 3H, Ar–H), 7.73–7.83 (m, 5H, Ar–H), 8.23 (s, 1H, pyrazine H), 8.79 and 9.02 (s, 2H, NH₂), 13.20 (s, 1H, OH) ppm; ¹³C NMR (62 MHz, DMSO-d₆): δ = 126.15, 127.23, 127.66, 128.38, 129.49, 131.85, 134.92, 139.93, 140.45, 142.63, 154.63, 162.11 (C–OH), 170.09 (C=O) ppm; anal. calcd for C₁₇H₁₃N₃O₂: C, 70.09; H, 4.50; N, 14.42. Found: C, 70.22; H, 4.65; N, 14.59.

4.3.13. 6-([1,1′-Biphenyl]-4-yl)-3-hydroxypyrazine-2-carboxamide 4i. Yield: 39 mg (12%); yellow powder; mp 198–199 °C; IR (KBr): [small upsilon, Greek, macron] = 3441, 3279, 3056 (OH, NH₂), 1660 (C=O) cm⁻¹; ¹H NMR (250 MHz, DMSO-d₆): δ = 7.47 (m, 4H, Ar–H), 7.73 (m, 5H, Ar–H), 8.00 (s, 1H, pyrazine H), 8.24–8.40 (m, 1H, NH₂), 8.84–8.93 (m, 1H, NH₂), 13.54 (s, 1H, OH) ppm; ¹³C NMR (62 MHz, DMSO-d₆): δ = 126.49, 127.02, 129.41, 129.74, 130.48, 130.94, 134.36, 135.29, 142.64, 153.84, 161.59 (C–OH), 170.25 (C=O) ppm; anal. calcd for C₁₇H₁₃N₃O₂: C, 70.09; H, 4.50; N, 14.42. Found: C, 70.12; H, 4.64; N, 14.66.

Data availability

The data supporting the findings of this study are included in the ESI file.† Additional data will be available upon request.

Conflicts of interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

The authors acknowledge the Research Office of Azarbaijan Shahid Madani University for financial support with funding grant number: 1402/60.

References

1. S. Baron, Medical Microbiology, The University of Texas Medical Branch at Galveston, Galveston, 4th edn, 1996.
2. I. D. Konstantinova, V. L. Andronova, I. V. Fateev and R. S. Esipov, Acta Nat., 2022, 14, 16.
3. A. D. Iuliano, K. M. Roguski, H. H. Chang, D. J. Muscatello, R. Palekar, S. Tempia and C. Cohen, et al., Lancet, 2018, 391, 285.
4. S. Lai, Y. Qin, B. J. Cowling, X. Ren, N. A. Wardrop, M. Gilbert and H. Yu, et al., Lancet Infect. Dis., 2016, 16, e108.
5. J. Charostad, M. Rezaei Zadeh Rukerd, Sh. Mahmoudvand, D. Bashash, S. M. A. Hashemi, M. Nakhaie and K. Zandi, Trav. Med. Infect. Dis., 2023, 55, 102638.
6. H. Xia, X. P. Xie, C. Shan and P. Y. Shi, ACS Infect. Dis., 2018, 4, 656.
7. J. Kaner and S. Schaack, Glob. Health, 2016, 12, 53.
8. K. Izawa, J. L. Aceña, J. Wang, V. A. Soloshonok and H. Liu, Eur. J. Org. Chem., 2016, 8.
9. A. Likhacheva, Virtual Mentor, 2006, 8, 219.
10. F. S. Wu, B. Yu. Zhao, Y. M. Chen, W. Wang, Z. G. Song, Y. Hu, Z. W. Tao, J. H. Tian, Y. Y. Pei, M. L. Yuan, Y. L. Zhang, F. H. Dai, Y. Liu, Q. M. Wang, J. J. Zheng, L. Xu, E. C. Holmes and Y. Z. Zhang, Nature, 2020, 579, 265.
11. N. Zhu, D. Y. Zhang, W. L. Wang, X. W. Li, B. Yang, J. D. Song, X. Zhao, B. Y. Huang, W. F. Shi, R. J. Lu, P. H. Niu, F. X. Zhan, X. J. Ma, D. Y. Wang, W. B. Xu, G. Z. Wu, G. G. F. Gao and W. J. Tan, N. Engl. J. Med., 2020, 382, 727.
12. J.-Y. Li, Z. You, Q. Wang, Z.-J. Zhou, Y. Qiu, R. Luo and X.-Y. Ge, Microb. Infect., 2020, 22, 80.
13. D. S. Hui, E. I. Azhar, T. A. Madani, F. Ntoumi, R. Kock, O. Dar, G. Ippolito, T. D. Mchugh, Z. A. Memish, C. Drosten, A. Zumla and E. Petersen, Int. J. Infect. Dis., 2020, 91, 264.
14. W. A. E. Setyowati, Y. M. Syah, I. Ihsanawati and A. Alni, Moroccan J. Chem., 2022, 10, 288.
15. Y. Furuta, K. Takahashi, Y. Fukuda, M. Kuno, T. Kamiyama, K. Kozaki, N. Nomura, H. Egawa, S. Minami and Y. Watanabe, et al., Antimicrob. Agents Chemother., 2002, 46, 977.
16. Y. Furuta, K. Takahashi, K. Shiraki, K. Sakamoto, D. F. Smee, D. L. Barnard, B. B. Gowen, J. G. Julander and J. D. Morrey, Antivir. Res., 2009, 82, 95.
17. Y. Furuta, B. B. Gowen, K. Takahashi, K. Shiraki, D. F. Smee and D. L. Barnard, Antivir. Res., 2013, 1002, 446.
18. E. D. Clercq and G. Li, Clin. Microbiol. Rev., 2016, 29, 695.
19. Y. Furuta, T. Komeno and T. Nakamura, Proc. Jpn. Acad., Ser. B, 2017, 93, 449.
20. L. Delang, R. Abdelnabi and J. Neyts, Antivir. Res., 2018, 153, 85.
21. U. Agrawal, R. Raju and Z. F. Udwadia, Med. J. Armed Forces India, 2020, 76, 370.
22. A. El-Nahas and K. Hirao, J. Mol. Struct.: THEOCHEM, 1999, 459, 229.
23. H. Sangawa, T. Komeno, H. Nishikawa, A. Yoshida, K. Takahashi, N. Nomura and Y. Furuta, Antimicrob. Agents Chemother., 2013, 5711, 5202.
24. L. Naesens, L. W. Guddat, D. T. Keough, A. B. Kuilenburg, J. Meijer, J. V. Voorde and J. Balzarini, Mol. Pharmacol., 2013, 844, 615.
25. J. Xiao, G. Benedikt and C. Meier, Annu. Rep. Med. Chem., 2021, 57, 1.
26. L. Rhyman, M. Tursun, H. H. Abdallah, Y. S. Choong, C. Parlak, P. Kharkar and P. Ramasami, Phys. Sci. Rev., 2018, 3, 20170198.
27. Y. A. Titova and O. V. Fedorova, Chem. Heterocycl. Compd., 2020, 56, 659.
28. Y. Furuta and H. Egawa, WO2000/010569, 2000.
29. H. Egawa, Y. Furuta, J. Sugita, S. Uehara, S. Hamamoto and K. Yonezawa, WO2001/060834, 2001.
30. H. Egawa and Y. Furuta, PCT. Appl EP1112743 A1, 2001.
31. Y. Furuta, H. Egawa and N. Nomura, US Pat., US2002/0013316 A1, 2002.
32. T. Takamatsu and K. Yonezawa, WO2009/041473, 2009.
33. J. Z. T. Zheng, B. Feng, X. Gong, L. Kong, M. Chen, Y. Li, H. Niu, H. Zhou and S. Ding, State Intellectual Property Office of the P. R. C., CN102603658A, 2012.
34. J. Zheng, T. Zhang, C. Liu, B. Feng and Z. Li, State Intellectual Property Office of the P. R. C., CN102775358 A, 2012.
35. T. Zhang, L. Kong, Z. Li, H. Yuan and W. Xu, Chin. J. Pharm., 2013, 44, 841.
36. H. Wang, L. Xingzhou and W. Zhong, Chin. J. Pharm., 2014, 11, 1009.
37. F. Shi, Z. Li, L. Kong, Y. Xie, T. Zhang and W. Xu, Drug Discov. Ther., 2014, 8, 117.
38. K. Nakamura, T. Murakami, H. Naitou, N. Hanaki and K. Watanabe, US Pat., 20150051396A1, 2015.
39. W. Wang, M. Liu, X. Xiao and Q. Dai, Int. J. Pharm. Rev. Res., 2015, 42, 220.
40. F.-L. Liu, C.-Q. Li, H.-Y. Xiang and S. Feng, Chem. Pap., 2017, 71, 2153.
41. T. Zhang, M. Zhai, J. Ji, J. Zhang, Y. Tian and X. Liu, Bioorg. Med. Chem. Lett., 2017, 27, 2364.
42. Q. Guo, M. Xu, S. Guo, F. Zhu, Y. Xie and J. Shen, Chem. Pap., 2019, 73, 1043.
43. N. Al Bujuq, Synthesis, 2020, 52, 3735.
44. G. Fuentes, A. García, H. Cerecetto, G. Álvarez, M. Couto and A. Romero, Org. Biomol. Chem., 2023, 21, 3660.
45. H. Karatas, E. H. A. Hanashalshahaby, U. Catal, Y. E. Butun, E. Kurt, S. Gursel, A. Kaya and M. Guze, Chem. Pap., 2023, 77, 1695.
46. N. Qin, Q. Min, W. Hu and J. Compar, Chem, 2020, 4, 1.
47. (a) Y. Furuta and H. Egawa, PCT Int. Appl., WO2000010569A1, 2000; (b) Y. Furuta and H. Egawa, Chem. Abstr., 2000, 132, 194392.
48. Y. Furuta, K. Takahashi, K. Shiraki, K. Sakamoto, D. F. Smee, D. L. Barnard, B. B. Gowen, J. G. Julander and J. D. Morrey, Antivir. Res., 2009, 82, 95.
49. J. Huchting, E. Vanderlinden, R. V. Berwaer, C. Meier and L. Naesens, Antivir. Res., 2019, 167, 1.
50. K. Takahashi, Y. Furuta, Y. Fukuda, M. Kuno, T. Kamiyama, K. Kozaki, N. Nomura, H. Egawa, S. Minami and K. Shiraki, Antivir. Chem. Chemother., 2003, 14, 235.
51. Y. Furuta, K. Takahashi, Y. Fukuda, M. Kuno, T. Kamiyama, K. Kozaki, N. Nomura, H. Egawa, S. Minami, Y. Watanabe, H. Narita and K. Shiraki, Antimicrob. Agents Chemother., 2002, 46, 977.
52. Y. Furuta, K. Takahashi, M. Kuno-Maekawa, H. Sangawa, S. Uehara, K. Kozaki, N. Nomura, H. Egawa and K. Shiraki, Antimicrob. Agents Chemother., 2005, 49, 981.
53. J. G. Julander, K. Shafer, D. F. Smee, J. D. Morrey and Y. Furuta, Antimicrob. Agents Chemother., 2009, 53, 202.
54. B. B. Gowen, M. H. Wong, K. H. Jung, A. B. Sanders, M. Mendenhall, K. W. Bailey, Y. Furuta and R. W. Sidwell, Antimicrob. Agents Chemother., 2007, 51, 3168.
55. R. W. Sidwell, D. L. Barnard, C. W. Day, D. F. Smee, K. W. Bailey, M. H. Wong, J. D. Morrey and Y. Furuta, Antimicrob. Agents Chemother., 2007, 51, 845.
56. R. Abdelnabi, A. T. S. Morais, P. Leyssen, I. Imbert, S. Beaucourt, H. Blanc, M. Froeyen, M. Vignuzzi, B. Canard, J. Neyts and L. Delang, J. Virol., 2017, 91, 1.
57. A. M. Rabie, Chem. Pap., 2021, 75, 4669.
58. H. A. Riley and A. R. Gray, Org. Synth., 1935, 15, 67.
59. M. Botta, F. De Angelis and R. Nicoletti, J. Heterocycl. Chem., 1979, 16, 193.
60. R. G. Jones, J. Am. Chem. Soc., 1949, 71, 78.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d5ra02613j

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