Synthesis and Biological Activity of 4-(Pyridin-3-yl)-2-hydroxy-4-oxobut-2-enoic Acid Derivatives

Alena L. Oleshchuk; Zarina T. Shulgau; Tulegen M. Seilkhanov; Alexey S. Vasilchenko; Samat A. Talipov; Ivan V. Kulakov

doi:10.1055/s-0037-1610738

Synlett, Table of Contents

Synlett 2020; 31(02): 165-170
DOI: 10.1055/s-0037-1610738

letter

Synthesis and Biological Activity of 4-(Pyridin-3-yl)-2-hydroxy-4-oxobut-2-enoic Acid Derivatives

Alena L. Oleshchuk

^aOmsk F. M. Dostoevsky State University, 55a Mira Ave., Omsk 644077, Russian Federation

^fInstitute of Chemistry, Tyumen State University, 15a Perekopskaya St., Tyumen 625003, Russian Federation Email: i.v.kulakov@utmn.ru

,

Zarina T. Shulgau

^bRepublican State Enterprise ‘National Center for Biotechnology’ under the Science Committee of Ministry of Education and Science of the Republic of Kazakhstan, 13/5 Kurgalzhinskoye Road, Astana 010000, Kazakhstan

,

Tulegen M. Seilkhanov

^cKokshetau State University named after Sh. Ualikhanov, 76 Abay St., Kokshetau 020000, Kazakhstan

,

Alexey S. Vasilchenko

^dInstitute of Environmental and Agricultural Biology (X-Bio) , Tyumen State University, 23 Lenina St., Tyumen 625003, Russian Federation

,

Samat A. Talipov

^eInstitute of Bioorganic Chemistry, 83, Mirzo Ulughbek St., Tashkent 100125, Uzbekistan

,

Ivan V. Kulakov ∗

^fInstitute of Chemistry, Tyumen State University, 15a Perekopskaya St., Tyumen 625003, Russian Federation Email: i.v.kulakov@utmn.ru

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Abstract

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Abstract

Claisen condensation reaction of diethyl oxalate with 1-[4-(furan-2-yl)-2-methyl-5-nitro-6-phenylpyridin-3-yl]ethan-1-one afforded (Z)-4-[4-(furan-2-yl)-2-methyl-5-nitro-6-phenylpyridin-3-yl]-2-hydroxy-4-oxobut-2-enoic acid. The latter reacted with various binucleophiles to form the corresponding 3,4-dihydroquinoxaline-2(1H)-one, 3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one, and 1H-pyrazole derivatives. Biological screening of the obtained compounds revealed analgesic and antibacterial activity.

Key words

α,γ-diketo acids - 3,4-dihydroquinoxalin-2(1H)-ones - 3,4-dihydro-2H-benzo[b][1,4]oxazin-2-ones - 1H-pyrazoles - analgesic activity - antibacterial activity

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References

References and Notes
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20 (Z)-4-[4-(Furan-2-yl)-2-methyl-5-nitro-6-phenylpyridin-3-yl]-2-hydroxy-4-oxobut-2-enoic Acid (4) To a freshly prepared sodium n-butoxide, prepared from sodium metal (920 mg, 4.0 mmol) dissolved in anhydrous n-BuOH (0.9 mL), was added diethyl oxalate (730 mg, 5.0 mmol) in anhydrous Et₂O (30 mL). To this mixture was added with stirring a solution of 1-[4-(furan-2-yl)-2-methyl-5-nitro-6-phenylpyridin-3-yl]ethan-1-one (3, 1.0 g, 3.0 mmol) in anhydrous benzene (2 mL). The reaction mixture was reflux for 6 h. The formed yellow precipitate of diketo ester salt was filtered and dissolved in 0.03 N NaOH (250 mL). The mixture was vigorously stirred for 3 h at room temperature, then was acidified with concentrated HCl (to pH 3–4). The resulting precipitate was filtered, washed with water, and air-dried. Recrystallization from mixture of 2-propanol–water (3:1) afforded the light brown crystals; yield 970 mg (82%); mp 120–122 °С. IR: ν_max = 3559 (OH), 1719 (C=O), 1538, 1354 (NO₂) cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 2.71 (s, 3 H, –CH₃), 6.35 (s, 1 H, =CH), 6.53 (d, J = 5.0 Hz, 1 H, H-4′ Fur), 6.78 (d, J = 3.1 Hz, 1 H, H-3′ Fur), 7.49–7.52 (m, 3 H, H-3′,4′,5′ Ph), 7.56 (br s, 1 H, H-5′ Fur), 7.62–7.64 (m, 2 H, H-2′,6′ Ph) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 23.36 (–CH₃), 103.50, 112.79, 115.10, 128.04, 128.93, 129.46, 130.39, 134.87, 142.34, 142.91, 145.88, 151.61, 157.14, 162.61, 166.88 (COOH), 194.07 (C=O) ppm. Anal. Calcd for C₂₀H₁₄N₂O₇: C, 60.92; H, 3.58; N, 7.10; O, 28.40. Found: C, 60.61; H, 3.32; N, 7.01; O, 28.11.
21 X-ray Structural Study X-ray structural study was performed at room temperature on a CCD diffractometer ‘Xcalibur, Oxford Diffraction’. The structure was solved by direct method and refined anisotropically with full-matrix method of least squares by all reflections using the SHELXL software suite. The hydrogen atom positions were calculated geometrically and refined according to the ‘rider’ model. The positions of hydrogen atoms belonging to hydroxyl groups were refined isotropically. The crystals of compound 4 (C₂₀H₁₄N₂O₇, M 394.34) were monoclinic, space group P21/c; a = 11.4931(3), b = 10.3438(2), c = 17.2566(4) Å; V = 1947.74(8) Å³; Z = 4; d _calcd = 1.406 g/cm³. A total of 33424 reflections were collected (θ _max 76.145°), including 4040 independent, R _int = 0.0476. The final values of probability factors were R = 0.0417 (for 3243 reflections with I > 2σ(I)), wR = 0.1155, S = 1.022 for all reflections. The complete crystallographic dataset was submitted to the Cambridge Crystallographic Data Center (deposit CCDC 1935337).
22 (Z)-3-{2-[4-(Furan-2-yl)-2-methyl-5-nitro-6-phenylpyridin-3-yl]-2-oxoethylidene}-3,4-dihydroquinoxalin-2(1H)-one (5a) A mixture both of compound 4 (200 mg, 0.5 mmol) and o-phenylenediamine (1 equiv, 54 mg, 0.5 mmol) in 2-propanol (2 mL) was stirred for 3 h at 60–80°C and then left to cool. The formed yellow precipitate was filtered, washed with 2-propanol, and air-dried. The crude product was purified by recrystallized from a mixture of 2-propanol–dichloromethane (5:1); yield 210 mg (90%); bright-yellow crystals; mp 258–260 °C. IR: ν_max = 1677–1611 (C=O), 1536, 1374 (NO₂) cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 2.70 (s, 3 H, –CH₃), 6.23 (s, 1 H, =CH), 6.43 (br s, 1 H, H-4′ Fur), 6.76 (d, J = 3.05 Hz, 1 H, H-3′ Fur), 7.12 (d, J = 7.63 Hz, 1 H, H-5′′ Ar), 7.21 (dd, J = 14.5 Hz, 8.39 Hz, 2 H, H-6′′,7′′ Ar), 7.30 (d, J = 7.60 Hz, 1 H, H-8′′ Ar), 7.48 (br s, 4 H, H-3′,4′,5′ Ph, H-5′ Fur), 7.61–7.63 (m, 2 H, H-2′,6′ Ph), 10.50 (s, 1 H, CONH), 13.48 (s, 1 H, NH) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 23.32 (–CH₃), 95.02, 112.25, 114.51, 115.92, 116.53, 124.21, 125.08, 128.03, 128.82, 129.91, 133.43, 142.49, 143.96, 145.02, 145.26, 150.36, 156.72, 192.79 (C=O) ppm. Anal. Calcd for C₂₆H₁₈N₄O₅: C, 66.95; H, 3.89; N, 12.01; O, 17.15. Found: C, 66.75; H, 3.64; N, 12.33; O, 17.29.
23 (Z)-3-{2-[4-(Furan-2-yl)-2-methyl-5-nitro-6-phenylpyridin-3-yl]-2-oxoethylidene}-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (5b) Compound 5b was obtained from compound 4 (160 mg, 0.4 mmol) and o-aminophenol (1 equiv, 44 mg, 0.4 mmol) analogously to the procedure for preparation of compound 5a; yield 150 mg (78%); bright-yellow crystals; mp 216–218 °С. IR: ν_max = 1761–1624 (C=O), 1561, 1351 (NO₂) cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 2.69 (s, 3 H, –CH₃), 6.23 (s, 1 H, =CH), 6.48 (br s, 1 H, H-4′ Fur), 6.75 (d, J = 3.05 Hz, 1 H, H-3′ Fur), 7.20–7.27 (m, 4 H, H-5′′,6′′,7′′,8′′ Ar), 7.50 (br s, 4 H, H-3′,4′,5′ Ph, H-5′ Fur), 7.62–7.64 (m, 2 H, H-2′,6′ Ph), 12.75 (s, 1 H, NH) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 23.31 (–CH₃), 98.30, 112.40, 114.59, 116.20, 117.26, 122.96, 124.81, 125.98, 128.00, 128.82, 130.00, 132.77, 135.36, 139.13, 141.39, 142.45, 143.58, 145.43, 150.61, 155.13, 156.71, 194.11 (C=O) ppm. Anal. Calcd for C₂₆H₁₇N₃O₆: C, 66.81; H, 3.67; N, 8.99; O, 20.54. Found: C, 66.98; H, 3.87; N, 8.73; O, 20.31
24 (Z)-3-{2-[4-(furan-2-yl)-2-methyl-5-nitro-6-phenylpyridin-3-yl]-2-oxoethylidene}-7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (5c) Yield 160 mg (80%); bright-yellow crystals; mp 290–292 °C. IR: ν_max = 1771 (C=O), 1575, 1340 (NO₂) cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 2.69 (s, 3 H, –CH₃), 6.31 (s, 1 H, =CH), 6.51 (br s, 1 H, H-4′ Fur), 6.77 (d, J = 3.10 Hz, 1 H, H-3′ Fur), 7.28–7.30 (m, 1 H, H-5′′ Ar), 7.51–7.52 (m, 4 H, H-3′,4′,5′ Ph, H-5′ Fur), 7.62–7.64 (m, 2 H, H-2′,6′ Ph), 8.13 (s, 1 H, H-8′′ Ar), 8.18 (d, J = 6.10 Hz, 1 H, H-6′′ Ar), 12.59 (s, 1 H, NH) ppm. ¹³C NMR (101 MHz, DMSO-d ₆): δ = 23.31 (–CH₃), 98.30, 112.40, 114.59, 116.20, 117.26, 122.96, 124.81, 125.98, 128.00, 128.82, 129.24, 130.00, 132.77, 135.36, 139.13, 141.39, 142.45, 143.58, 145.43, 150.61, 155.13, 156.71, 194.11 (C=O) ppm. Anal. Calcd for C₂₆H₁₆N₄O₈: C, 60.94; H, 3.15; N, 10.93; O, 24.98. Found: C, 60.65; H, 3.39; N, 10.74; O, 24.76
25 Synthesis of 1H-Pyrazole-3-carboxylic Acids 6a,b – General Method To a solution of compound 4 (200 mg, 0.5 mmol) in ethanol (2 mL) was added with stirring of the corresponding hydrazine (4 equiv). The reaction mixture was stirred for 3 h at 50–60 °C and then left to cool. The formed precipitate was filtered, washed with ethanol, and air-dried. Recrystallization from ethanol afforded the pyrazole derivatives 6a,b.
26 5-[4-(Furan-2-yl)-2-methyl-5-nitro-6-phenylpyridin-3-yl]-1H-pyrazole-3-carboxylic Acid (6a) Yield 174 mg (89%); light-yellow crystals; mp 212–215 °С. IR: ν_max = 3356,2 (OH), 3166,2 (N–H), 1656 (C=O), 1531, 1340 (NO₂) cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 2.43 (s, 3 H, –CH₃), 6.05 (d, J = 4.58 Hz, 1 H, H-4′ Fur), 6.36 (br s, 1 H, H-3′ Fur), 6.50 (s, 1 H, H-4 pyrazole), 7.53–7.55 (m, 6 H, H-2′,3′,4′,5′,6′ Ph, H-5′ Fur), 7.77 (1 H, s, NH) ppm. ¹³C NMR (101 MHz, DMSO-d ₆): δ = 23.93 (–CH₃), 106.49, 112.16, 114.57, 127.81, 128.76, 129.79, 130.67, 135.69, 142.41, 143.60, 144.45, 145.46, 149.05, 160.55, 163.26 (–COOH) ppm. Anal. Calcd (%) for C₂₀H₁₄N₄O₅: C, 61.54; H, 3.62; N, 14.35; O, 20.49. Found (%): C, 61.77; H, 3.85; N, 14.71; O, 20.78.
27 5-[4-(Furan-2-yl)-2-methyl-5-nitro-6-phenylpyridin-3-yl]-1-phenyl-1H-pyrazole-3-carboxylic Acid (6b) Yield 175 mg (75%); light-yellow crystals; mp 215–217 °С. IR: ν_max = 1709 (C=O), 1536, 1368 (NO₂) cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 2.47 (s, 3 H, –CH₃), 6.17 (d, J = 4.60 Hz, 1 H, H-4′ Fur), 6.40 (br s, 1 H, H-3′ Fur), 7.06 (s, 1 H, H-4 pyrazole), 7.15 (d, J = 7.63 Hz, 2 H, H-2′′,6′′ Ph), 7.29–7.37 (m, 4 H, H-4′ Ph, H-3′′,4′′,5′′ Ph), 7.45–7.51 (m, 3 H, H-3′,5′ Ph, H-5′ Fur), 7.62 (d, J = 7.70 Hz, 2 H, H-2′,6′ Ph) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 24.32 (–CH₃), 77.31, 77.63, 112.51, 112.71, 114.83, 121.88, 124.15, 128.28, 129.16, 129.29, 129.49, 130.55, 132.37, 135.41, 138.54, 139.53, 142.99, 143.86, 144.02, 145.59, 160.29, 165.82 (–COOH) ppm. Anal. Calcd for C₂₆H₁₈N₄O₅: C, 66.95; H, 3.89; N, 12.01; O, 17.15. Found: C, 66.79; H, 3.71; N, 12.25; O, 17.27.
28 The Study of Analgesic Activity The study was performed on mice by recording the specific pain reaction of writhing (characteristic movements of animals, including contractions of abdominal musculature alternating with relaxation, extension of hind limbs, and arching of back), caused by intraperitoneal injection of 0.75% acetic acid (0.1 mL per 10 g of body weight). The number of writhings for each animal was counted during the subsequent 15 min (using groups of 5 animals). The analgesic effect was determined from the decrease in number of writhings, expressed as percentage relative to the control. The studied compounds were introduced in the amount of 100 mg/kg body weight as a suspension in drinking water into the stomach by using a feeding tube at 30 min prior to the intraperitoneal injection of acetic acid. The reference drug was metamizole sodium (analgin), which was introduced by analogous scheme in the amount of 100 mg/kg body weight. The control animals received analogous volume of drinking water.^30,31
29 The Study of Antibacterial Activity Samples of the studied chemicals were diluted in 1 mL of DMSO (Sigma). After which a series of twofold dilutions in DMSO were prepared. Determination of the minimum inhibitory concentration (MIC) was carried out by conventional broth microdilution methods based on the Clinical and Laboratory Standards Institute (CLSI). The overnight cultures of the Gram-positive S. aureus FDA 209 P and Gram-negative E. coli K12 test strains were diluted in LB- broth (Sigma-Aldrich, USA) in order to obtain 10⁶ CFU/mL. Prepared inoculums were mixed with twofold dilutions of chemicals and incubated for 24 h in 96-wells microtiter plate (Costar 3595, Corning corp, USA). After incubation, the optical density of planktonic cells was assessed by reading the absorbance data at 620 nm using spectrophotometer Multiscan GO (Thermo Scientific). Antimicrobial activity of chemicals was indicated by the minimal inhibitory concentration, which was defined as the lowest dose at which no visible growth was detected. Determination of bactericidal activity was performed by plating of the treated bacteria from the wells on LB-agar (Sigma-Aldrich, USA). Following incubation, CFU counting was conducted.³²
30 Mironov AN, Bunatyan ND, Vasiljev AN, Verstakova OL, Zhuravleva MV, Lepakhin VK, Korobov NV, Merkulov VA, Orekhov SN, Sakaeva IV, Uteshev DB, Yavorsky AN. Guidelines for Conducting Preclinical Studies of Drugs (in Russian), Vol. 1. Griff and K; Moscow: 2012: 746
31 All experimental work with laboratory animals was performed according to the generally accepted bioethics principles for work involving laboratory animals, in accordance with the European Convention for the Protection of Vertebrate Animals Used for Experimental and other Scientific Purposes (ETS 123); Strasbourg, 1986.
32 Mironov AN, Bunatyan ND, Vasiljev AN, Verstakova OL, Zhuravleva MV, Lepakhin VK, Korobov NV, Merkulov VA, Orekhov SN, Sakaeva IV, Uteshev DB, Yavorsky AN. Guidelines for Conducting Preclinical Studies of Drugs (in Russian), Vol. 1. Griff and K; Moscow: 2012: 509

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