Synthesis, intramolecular cyclization and anti-inflammatory activity of substituted 2-(2-(Furan-2-carbonyl)hydrazono)-4-oxobutanoic Acids published by Ural Federal University eISSN 2411-1414 chimicatechnoacta.ru ARTICLE 2023, vol. 10(1), No. 202310102 DOI: 10.15826/chimtech.2023.10.1.02 1 of 8 Synthesis, intramolecular cyclization and anti-inflammatory activity of substituted 2-(2-(Furan-2- carbonyl)hydrazono)-4-oxobutanoic acids Sergei N. Igidov ab , Dmitriy V. Lipin c* , Aleksey Yu. Turyshev a , Svetlana V. Chashchina a, Daria A. Shipilovskikh d* , Ol’ga V. Zvereva a, Ksenia A. Mitusova e , Pavel S. Silaichev c , Nazim M. Igidov a a: Perm State Pharmaceutical Academy, Ministry of Health of the Russian Federation, Perm 614990, Russia b: Merck LLC, Moscow 115054, Russia c: Perm State National Research University, Perm 614990, Russia d: Perm National Research Polytechnic University, Perm 614990, Russia e: Peter the Great St. Petersburg Polytechnic University, St. Petersburg 195251, Russia * Corresponding author: lipindima@psu.ru (Dmitriy V. Lipin), shipilovskikh@psu.ru (Daria A. Shipilovskikh) This paper belongs to the MOSM2022 Special Issue. Abstract A method was proposed for the synthesis of substituted 2-(2-(furan-2-car- bonyl)hydrazono)-4-oxobutanoic acids by the reaction of substituted 2,4- dioxobut-2-enoic acids with furan-2-carbohydrazide. It was found that substituted 2-(2-(furan-2-carbonyl)hydrazono)-4-oxobutanoic acids un- dergo intramolecular cyclization in the presence of propionic anhydride to form the corresponding N'-(2-oxofuran-3(2H)-ylidene)furan-2-carbohy- drazides. The anti-inflammatory activity of the obtained compounds was studied. It was found that the obtained compounds have pronounced anti- inflammatory activity. Keywords dioxobutanoic acids 2-hydrazono-4-oxobutanoic acids 3-hydrazonofuran-2(3H)-ones anti-inflammatory activity drugs Received: 07.11.22 Revised: 08.12.22 Accepted: 08.12.22 Available online: 16.12.22 Key findings ● A synthesis method for obtained to produce methyl-2-(2-(furan-2-carbonyl)hydrazono)-4-oxobutanoic acids and N'- (2-oxofuran-3(2H)-ylidene]furan-2-carbohydrazides. ● Sixteen new biologically active compounds have been obtained and described. ● It was found that some of the compounds obtained have a significant anti-inflammatory effect. © 2022, the Authors. This article is published in open access under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). 1. Introduction The priority direction in pharmaceuticals and medical chemistry is the development and creation of new dosage forms with low toxicity [1–7]. The main cause is the chaotic usage of medicines, which leads to a loss of their efficiency. The main problem of drug development now is the choice of suitable frameworks that would make it possible to transform compounds at various stages of synthesis. Derivatives of 3-imino- and 3-hydrazonofuran-2(3H)- one are excellent for this role because of their chemical availability, scalability of synthetic methods [8–12] and high reactivity [13–17]. Derivatives of 3-imino- and 3-hy- drazonofuran-2(3H)-ones are capable of interacting with various nucleophilic reagents to form acyclic structures preserving the pharmacophore fragment of 2,4-dioxobu- tanoic acid [18–27]. Previously, we proposed a simple method for the prepara- tion of 3-hydrazinylidenefuran-2(3Н)-one derivatives by in- tramolecular cyclization of substituted 2-(2-(4-R-benzoyl)hy- drazono)-4-oxobutanoic acids in the presence of acetic or pro- pionic anhydride [28, 29]. Furthermore, this method was ap- plied to the synthesis of 3-(imino(thien-2-yl))furan-2(3H)- ones derivatives, which include the pharmacophore fragment, Gewald aminothiophene [30] (Scheme 1). It was found that 2- (2-(4-R-benzoyl)hydrazono)-4-oxobutanoic and 2-(thiophen- 2-ylamino)-4-oxobut-2-enoic acids and their derivativities ex- hibit analgesic [31, 32], anti-inflammatory [16] antimicrobial activity [24] and photoluminescent properties [33, 34]. We continue to search for new biologically active com- pounds with low toxicity [35] and expand the methods for the synthesis of 2,4-dioxobutanoic acid and 3-hydrazonofu- ran-2(3H)-one derivatives. http://chimicatechnoacta.ru/ https://doi.org/10.15826/chimtech.2023.10.1.02 mailto:lipindima@psu.ru mailto:shipilovskikh@psu.ru http://creativecommons.org/licenses/by/4.0/ https://orcid.org/0000-0001-6006-168X https://orcid.org/0000-0003-2746-1395 https://orcid.org/0000-0003-3867-5305 https://orcid.org/0000-0001-6086-4300 https://orcid.org/0000-0002-3820-4899 https://orcid.org/0000-0002-2840-6809 https://orcid.org/0000-0003-0976-9951 https://crossmark.crossref.org/dialog/?doi=https://doi.org/10.15826/chimtech.2022.10.1.02&domain=pdf&date_stamp=2022-12-16 Chimica Techno Acta 2023, vol. 10(1), No. 202310103 ARTICLE 2 of 8 DOI: 10.15826/chimtech.2023.10.1.02 Scheme 1 Synthesis of 3-hydrazono- and 3-(imino(thien-2-yl))furan-2(3H)-ones. In this paper, synthesis and anti-inflammatory activity of new 2,4-dioxobutanoic acids derivatives are discussed. 2. Experimental IR spectra were recorded on an FSM-1202 instrument in vaseline oil. 1Н NMR spectra were obtained on a Bruker Avance III spectrometer (operating frequency of 400 MHz) in DMSO-d6, the internal standard was the residual signal of the deuterium solvent. Elemental analysis was performed on a LECO CHNS-932 instrument. The chemical purity of the compounds and the reactions progress were monitored by TLC on Sorbfil plates in the diethyl ether–benzene–acetone (10:9:1) system (de- tection in UV light and iodine vapor). Melting points were determined on an SMP40 apparatus. 2.1. General procedure for the synthesis of substi- tuted 2-(2-(furan-2-carbonyl)hydrazono)-4- oxobutanoic acids (3a–h) To a solution of 0.01 mol of furan-2-carboxylic acid hydra- zide 2 in 30 mL of acetonitrile was added 0.01 mol of 2,4- dioxobutanoic acid 1a–h. The resulting mixture was heated to 50 °C and kept for 5 min at this temperature. The solu- tion was cooled to 0 °C; the formed precipitate was filtered off and recrystallized from acetonitrile or 1,4-dioxane. 2.1.1. 5,5-Dimethyl-4-oxo-2-(2-(furan-2-carbonyl)hydra- zono)hexanoic acid (3а) Yield 1.96 g (70%), pale yellow crystals, m.p. 144–145 °С (MeCN). IR spectrum, ν, cm–1: 3324, 3204 br., 3119, 1717, 1676, 1595. 1Н NMR spectrum (DMSO-d6), δ, ppm: form A (24%): 1.16 s (3H, t-Bu), 4.04 s (2H, CH2), 6.62 dd (1H, Harom, JHH 3.5, 1.8 Hz), 7.02–7.95 m (2H, Harom), 11.09 br. s (1H, NH); form B (61%): 1.12 d (3H, t-Bu), 3.21 d (1H, C4H2, JHH 20.0 Hz), 3.35 d (1H, C4H2, JHH 20.0 Hz) , 6.56 dd (1H, JHH 3.5, 1.8 Hz), 7.03–7.95 m (2H, Harom, 1H, OH); form C (15%): 1.14 s (3H, t-Bu), 3.80 s (2H, CH2), 6.70 dt (1H, Harom, JHH 1.7, 0.8 Hz), 7.03–7.95 m (2H, Harom), 13.48 br. s (1H, NH). Found, %: С 55.74; H 5.73; N 10.03. C13H16N2O5. Calculated, %: С 55.71; H 5.75; N 10.00. 2.1.2. 4-Methylphenyl-2-(2-(furan-2-carbonyl)hydra- zono)-4-oxobutanoic acid (3b) Yield 2.29 g (73%), yellow crystals, m.p. 179–180 °С (1,4- dioxane). 1Н NMR spectrum (DMSO-d6), δ, ppm: form A (30%): 2.41 s (3Н, CH3), 4.52 s (2Н, СН2), 6.73 dd (1Н, Harom, JHH 3.4, 1.7 Hz), 7.14–7.99 m (6Н, Harom), 11.38 br. s (1Н, NH); form B (58 %): 2.30 с (3Н, CH3), 3.22 d (1Н, С4Н2, JHH 20.0 Hz), 3.32 d (1Н, С4Н2, JHH 20.0 Hz), 6.70 dd (1Н, JHH 3.5, 1.7 Hz), 7.14–7.98 m (6Н, Harom; 1Н, ОН); form C (12 %): 2.40 s (3Н, CH3), 4.29 s (2Н, СН2), 6.73 dd (1Н, Harom, JHH 3.4, 1.7 Hz), 7.14–7.99 m (6Н, Harom) 13.47 br. s (1Н, NH). Found, %: C 61.12; H 4.47; N 8.94. C16H14N2О5. Calculated, %: C 61.14; H 4.49; N 8.91. 2.1.3. (4-Ethylphenyl)-2-(2-(furan-2-carbonyl)hydra- zono)-4-oxobutanoic acid (3c) Yield 2.10 g (64%), yellow crystals, m.p. 143–144 °С (MeCN). IR spectrum, ν, cm–1: 3245, 3126, 1736, 1684, 1641, 1612. 1Н NMR spectrum (DMSO-d6), δ, ppm: form A (12%), 1.20 m (3Н, Me), 2.65 m (2H, CH2), 4.51 s (2H, CH2), 6.68 dd (1H, Harom, JHH 3.6, 1.8 Hz), 7.15–7.94 m (6H, Harom), 11.30 br. s (1H, NH); form B (81%), 1.20 m (3Н, Me), 3.20 d (1Н, С4Н2, JHH 20.0 Hz), 3.33 d (1Н, С4Н2, JHH 20.0 Hz), 2.65 m (2Н, CH2), 6.66 dd (1H, Harom, JHH 3.5, 1.6 Hz), 7.15– 7.94 m (7H, 6Harom and OH); form C (7%), 1.20 m (3H, Me), 2.64 m (2H, CH2), 4.23 s (2H, CH2), 6.71 dd (1H, Harom, JHH 3.6, 1.7 Hz), 7.15–7.94 m (6H, Harom), 13.83 br. s (1H, NH). Found, %: C 62.21; H 4.89; N 8.56. C17H16N2O5. Calculated, %: C 62.19; H 4.91; N 8.53. M 328.32. https://doi.org/10.15826/chimtech.2023.10.1.02 Chimica Techno Acta 2023, vol. 10(1), No. 202310103 ARTICLE 3 of 8 DOI: 10.15826/chimtech.2023.10.1.02 2.1.4. (4-Ethoxyphenyl)-2-(2-(furan-2-carbonyl)hydra- zono)-4-oxobutanoic acid (3d) Yield 2.89 g (84%), yellow crystals, m.p. 134–135 °С (MeCN). IR spectrum, ν, cm–1: 3232, 3121, 1744, 1652, 1641, 1607. 1Н NMR spectrum (DMSO-d6), δ, ppm: form A (47%), 1.33 m (3Н, Me ), 4.13 m (2H, CH2), 4.48 s (2H, CH2), 6.68 dd (1H, Harom, JHH 3.5, 1.8 Hz), 6.85–7.98 m (6H, Harom), 11.29 s (1H, NH); form B (32%), 1.33 m (3Н, Me), 3.21 d (1Н, С4Н2, JHH 20.0 Hz), 3.30 d (1Н, С4Н2, JHH 20.0 Hz), 4.13 m (2Н, CH2), 6.66 dd (1H, Harom, JHH 3.5, 1.8 Hz), 6.85–7.98 m (7H, 6Harom and OH); form C (21%), 1.33 m (3H, Me),4.13 m (2H, CH2), 4.24 s (2H, CH2), 6.71 m (1H, Harom, JHH 3.5, 1.8 Hz), 6.85–7.98 m (6H, Harom), 13.35 br. s (1H, NH). Found, %: C 59.32; H 4.69; N 8.17. C17H16N2O6. Calculated, %: C 59.30; H 4.68; N 8.14. M 344.32. 2.1.5. (4-Fluorophenyl)-2-(2-(furan-2-carbonyl)hydra- zono)-4-oxobutanoic acid (3e) Yield 2.32 g (73%), yellow crystals, m.p. 132–133 °C (MeCN). IR spectrum, ν, cm–1: 3237, 3131, 1741, 1683, 1617, 1585. 1Н NMR spectrum (DMSO-d6), δ, ppm: form A (6%), 4.51 s (2Н, СН2), 6.71 m (1Н, Harom), 7.28–7.92 m (6Н, Harom), 11.30 br. s (1H, NH); form B (90%), 3.24 d (1Н, С4Н2, JHH 20.0 Hz), 3.30 d (1Н, С4Н2, JHH 20.0 Hz), 6.68 m (1Н, Harom), 7.28–7.92 m (7Н, 6Harom and ОН); form C (4%), 4.13 s (2H, CH2), 6.85 m (1H, Harom), 7.28–7.92 m (6H, Harom), 13.04 br. s (1H, NH). Found, %: C 56.63; H 3.46; N 8.82. C15H11FN2O5. Calculated, %: C 56.61; H 3.48; N 8.80. M 318.26. 2.1.6. 4-(4-Chlorophenyl)-2-(2-(furan-2-carbonyl)hy- drazono)-4-oxobutanoic acid (3f) Yield 2.58 g (77%), m.p. 182–183 °С (1,4-dioxane). IR spec- trum, ν, cm–1: 3237, 3131, 1741, 1683, 1617, 1585. 1Н NMR spectrum (DMSO-d6), δ, ppm: form A (9%), 4.49 s (2Н, СН2), 6.71 m (1Н, Harom), 7.22‒7.96 m (6Н, Harom), 11.43 br. s (1Н, NH); form B (86%), 3.21 d (1Н, С4Н2, JHH 20.0 Hz), 3.30 d (1Н, С4Н2, JHH 20.0 Hz), 6.69 m (1Н, Harom), 7.22‒7.96 m (7Н, 6Нarom and ОН); form C (5%), 4.31 s (2Н, СН2), 6.84 m (1Н, Harom), 7.22‒7.96 m (6Н, Harom), 13.50 br. s (1Н, NH). Found, %: C 53.85; H 3.29; N 8.39. C15H11ClN2О5. Calculated, %: C 53.83; H 3.31; N 8.37. 2.1.7. 2-(2-(Furan-2-carbonyl)hydrazono)-4-(naphtha- len-1-yl)-4-oxobutanoic acid (3g) Yield 2.38 g (68%), yellow crystals, m.p. 199–200 °C (MeCN). IR spectrum, ν, cm–1: 3247, 3124, 1703, 1675, 1654, 1581. 1Н NMR spectrum (DMSO-d6), δ, ppm: form A (23%), 4.63 s (2Н, СН2), 6.71 m (1Н, Harom), 7.33–8.57 m (9Н, Harom), 11.44 br. s (1H, NH); form B (66%), 3.39 d (1Н, С4Н2, JHH 20.0 Hz), 3.44 d (1Н, С4Н2, JHH 20.0 Hz), 6.71 m (1Н, Harom), 7.33–8.57 m (10Н, 9Harom and ОН); form C (11%), 4.38 s (2H, CH2), 6.71 m (1H, Harom), 7.33– 8.57 m (9H, Harom), 13.52 br. s (1H, NH). Found, %: C 65.17; H 4.01; N 8.03. C19H14N2O5. Calculated, %: C 65.14; H 4.03; N 8.00. 2.1.8. 2-(2-(Furan-2-carbonyl)hydrazono)-4-(naphtha- len-2-yl)-4-oxobutanoic acid (3h) Yield 2.49 g (71%), m.p. 198–199 °С (MeCN). IR spec- trum, ν, cm–1: 3251, 3118, 1705, 1681, 1649, 1583. 1Н NMR spectrum (DMSO-d6), δ, ppm: form A (13%), 4.69 s (2Н, СН2), 6.70 m (1Н, Harom), 7.47‒8.73 m (9Н, Harom), 11.33 br. s (1Н, NH); form B (81%), 3.34 d (1Н, С4Н2, JHH 20.0 Hz), 3.40 d (1Н, С4Н2, JHH 20.0 Hz), 6.70 m (1Н, Harom), 7.47‒8.73 m (10Н, 9Нarom and ОН); form C (6%), 4.42 s (2Н, СН2), 6.71 m (1Н, Harom), 7.33‒8.57 m (9Н, Harom) 13.77 br. s (1Н, NH). Found, %: C 65.13; H 4.05; N 8.02. C19H14N2О5. Calculated, %: C 65.14; H 4.03; N 8.00. 2.2. General procedure for the synthesis of N′-(2- oxofuran-3(2Н)-ylidene]furan-2-carbohydra- zides 4a–h Propionic anhydride (8 mL) was added to 0.01 mol of acid 3a–h. The resulting mixture was slowly heated with stir- ring to 150 °C and kept for 5 min at this temperature. The precipitate formed after cooling was filtered off, washed with anhydrous diethyl ether, and recrystallized from an- hydrous toluene or 1,4-dioxane. 2.2.1. N'-(5-(t-Butyl)-2-oxofuran-3(2Н)-ylidene)furan- 2-carbohydrazide (4а) Yield 1.36 g (52%), light yellow crystals, m.p. 215–216 °С (1,4-dioxane). IR spectrum, ν, см–1: 3186, 1793, 1699, 1663, 1622, 1592. 1Н NMR spectrum (DMSO-d6), δ, ppm: form A (88%): 1.22 s (9Н, t-Bu), 6.73 dd (1Н, JHH 3.6, 1.8 Hz), 6.83 s (1Н, СН), 7.52 dd (1Н, JHH 3.6, 0.7 Hz), 7.98 dd (1Н, JHH 1.8, 0.8 Hz), 11.63 br. s (1Н, NH): form B (12 %): 1.23 s (9Н, t-Bu), 6.28 s (1Н, СН), 6.76 dd (1Н, Нarom, JHH 3.6, 1.8 Hz), 7.39 d (1Н, JHH 3.6, 0.7 Hz), 8.02 dd (1Н, JHH 1.8, 0.8 Hz), 12.36 br. s (1Н, NH). Found, %: C 59.57; 5.35; N 10.66. C13H14N2О4. Calculated, %: C 59.54; H 5.38; N 10.68. 2.2.2. N'-(2-Oxo-5-(p-tolyl)furan-3(2H)-ylidene)furan- 2-carbohydrazide (4b) Yield 1.57 g (53%), yellow crystals, m.p. 258–259 °С (1,4- dioxane). IR spectrum, ν, cm–1: 3125, 1799, 1693, 1672, 1622. 1H NMR spectrum (DMSO-d6), δ, ppm: form A (100%): 2.41 s (3H, CH3), 6.72 dd (1H, HAr, JHH 3.5, 1.8 Hz), 7.36– 7.67 m (5H, Harom, 1H, CH), 7.98 d (1H, JHH 1.0 Hz), 11.89 br. s (1H, NH). Found, %: C 64.84; H 4.11; N 9.48. C16H12N2O4. Calculated, %: C 64.86; H 4.08; N 9.46. 2.2.3. N'-(5-(4-Ethylphenyl)-2-oxofuran-3(2Н)-yli- dene)furan-2-carbohydrazide (4c) Yield 1.89 g (61%), yellow crystals, m.p. 189–190 °С (tolu- ene). IR spectrum, ν, cm–1: 3132, 1806, 1697, 1666, 1616. 1Н NMR spectrum (DMSO-d6), δ, ppm: form A (25%), 1.22 m (3Н, СН3), 2.70 m (2Н, СН2), 6.78 dd (1Н, Harom, JHH 3.6, 1.8 Hz), 7.44 m (2Н, Harom), 7.45 s (1Н, СН), 7.59 d (1Н, Harom, JHH 3.4 Hz), 7.70 m (2Н, Harom), 8.04 d (1Н, Нarom, JHH 1.5 Hz), 11.83 br. s (1Н, NH); form B (75%), 1.22 m (3Н, СН3), 2.70 m (2Н, СН2), 6.80 dd (1Н, Harom, JHH 3.6, 1.8 Hz), 7.17 s (1Н, СН), 7.40 m (2Н, Harom), 7.70 d (1Н, Harom, JHH https://doi.org/10.15826/chimtech.2023.10.1.02 Chimica Techno Acta 2023, vol. 10(1), No. 202310103 ARTICLE 4 of 8 DOI: 10.15826/chimtech.2023.10.1.02 8.3 Hz), 7.78 d (2Н, Harom, JHH 8.3 Hz), 8.07 d (1Н, Harom, JHH 1.5 Hz), 12.53 br. s (1Н, NH). Found, %: C 49.87; H 2.53; N 7.73. C17H14N2О4. Calculated, %: C 65.80; H 4.55; N 9.03. 2.2.4. N'-(5-(4-Ethoxyphenyl)-2-oxofuran-3(2Н)-yli- dene)furan-2-carbohydrazide (4d) Yield 1.89 g (58%), yellow crystals, mp. 259–260 °C (1,4-dioxane). IR spectrum, ν, cm–1: 3123, 3118, 1811, 1694, 1662, 1615. 1Н NMR spectrum (DMSO-d6), δ, ppm: form A (47%): 1.37 t (3Н, СН3 , JHH 7.0 Hz), 4.15 m (2H, CH2), 6.77 dd (1H, Harom, JHH 3.5, 1.8 Hz), 7.40 s (1H, CH), 7.58 d (1H, Harom, JHH 3.5 Hz), 7.72 m (2H, Harom), 7.80 m (2H, Harom), 8.03 d (1H, Harom, JHH 1.5 Hz), 11.75 br. s (1H, NH): form B (75%): 1.37 t (3H, CH3, JHH 7.0 Hz), 4.15 m (2H, CH2), 6.79 dd (1H, Harom, JHH 3.5, 1.8 Hz), 7.06 s (1H, CH), 7.09 m (2H, Harom), 7.14 m (2H, Harom), 7.42 d (1H, Harom, JHH 3.5 Hz), 8.06 m (1H, Harom), 12.50 br. s (1H, NH). Found, %: C 62.55; 4.35; N 8.61. C17H14N2O5. Calculated, %: C 62.57; H 4.32; N 8.59. 2.2.5. N'-(5-(4-Fluorophenyl)-2-oxofuran-3(2H)-yli- dene)furan-2-carbohydrazide (4e) Yield 1.89 g (63%), yellow crystals, mp. 287–288 °С (1,4-diox- ane). IR spectrum, ν, cm–1: 3116, 1808, 1662, 1615. 1H NMR spectrum (DMSO-d6), δ, ppm: form A (16%), 6.75 dd (1H, Harom, JHH 3.6, 1.7 Hz), 7.42 m (2H, Harom), 7.49 s (1H, CH), 7.56 m (1H, Harom), 7.82 m (2H, Harom), 8.00 m (1H, Harom), 11.77 br. s (1H, NH); form B (84%): 6.80 dd (1H, Harom, JHH 3.6, 1.7 Hz), 7.17 s (1H, CH), 7.38 m (2H, Harom), 7.43 dd (1H, Harom, JHH 3.5, 0.6 Hz) , 7.76 m (2H, Harom), 8.07 dd (1H, Harom, JHH 1.6, 0.6 Hz), 12.54 s (1H, NH). Found, %: C 60.04; H3.00; N 9.35. C15H9N2O4. Calculated, %: C 60.01; H 3.02; N 9.33. 2.2.6. N'-(5-(4-Chlorophenyl)-2-oxofuran-3(2H)-yli- dene)furan-2-carbohydrazide (4f) Yield 2.34 g (74%), yellow crystals, mp. 268–269 °C (1,4-diox- ane). IR spectrum, ν, cm–1: 1619, 1694, 1776, 3137. 1Н NMR spectrum (DMSO-d6), δ, ppm: form A (16%): 6.78 dd (1Н, Нarom, JHH 3.6, 1.7 Hz), 7.50 s (1H, CH), 7.59 m (1H, Harom), 7.63 m (2H, Harom), 7.88 m (2H, Harom), 8.04 m (1H, Harom), 11.75 br. s (1H, NH). form B (84%): 6.80 dd (1H, Harom, JHH 3.6, 1.7 Hz), 7.17 s (1H, CH), 7.38 m (2H, Harom), 7.43 dd (1H, Harom, JHH 3.5, 0.6 Hz), 7.76 m (2H, Harom), 8.07 dd (1H, Harom, JHH 1.6, 0.6 Hz), 12.54 s (1H, NH). Found, %: C 56.87; H 2.88; N 8.87. C15H9N2O4. Calculated, %: C 56.89; H 2.86; N 8.85. 2.2.7. N'-(5-(Naphthalene-1-yl)-2-oxofuran-3(2Н)-yli- dene)furan-2-carbohydrazide (4g) Yield 2.59 g (78%), yellow crystals, mp. 236–237 °С (1,4- dioxane). IR spectrum, ν, cm–1: 3163, 1808, 1660, 1612. 1Н NMR spectrum (DMSO-d6), δ, ppm: form A (100%): 6.77 dd (1Н, Нarom, JHH 3.6, 1.8 Hz), 7.60 s ( 1H, CH), 7.68 m (3H, Harom), 7.97 dd (1H, Harom, JHH 7.3, 1.2 Hz), 8.02 dd (1H, Harom, JHH 1.7, 0.8 Hz), 8.08 dd (1H, Harom, JHH 3.4 , 1.1 Hz), 8.16 m (1H, Harom), 8.42 m (1H, Harom), 11.96 br. s (1H, NH). Found, %: C 68.65; H 3.66; N 8.44. C19H12N2O4. Calculated, %: C 68.67; H 3.64; N 8.43. 2.2.8. N'-(5-(Naphthalene-2-yl)-2-oxofuran-3(2Н)-yli- dene)furan-2-carbohydrazide (4h) Yield 2.79 g (84%), yellow crystals, mp. 264–265 °С (1,4- dioxane). IR spectrum, ν, cm–1: 3137, 1805, 1662, 1617. 1Н NMR spectrum (DMSO-d6), δ, ppm: form A (100%): 6.79 dd (1Н, Нarom, JHH 3.6, 1.8 Hz), 7.64 m (3H, Harom), 7.68 s (1H, CH), 7.79 dd (1H, Harom, JHH 3.7, 1.7 Hz), 8.01 m (1H, Harom), 8.05 m (1H, Harom, JHH 1.7, 0.8 Hz), 8.12 m (2H, Harom), 8.39 d (1H, Harom, JHH 0.9 Hz), 11.91 br. s (1H, NH). Found, %: C 68.69; H 3.67; N 8.42. C19H12N2O4. Calculated, %: C 68.67; H 3.64; N 8.43. 2.3. Anti-inflammatory activity Anti-inflammatory activity tests were carried out at the Perm State Pharmaceutical Academy. The study was per- formed on rats of both sexes (the group included 6 ani- mals) weighing 210–240 g on a model of acute inflamma- tory edema caused by subplantar injection of 0.1 ml of 1% aqueous solution of carrageenan into the hind paw of a rat. An increase in the volume of the foot, indicating the development of edema, was assessed oncometrically [36] before and 3 hours after the administration of carragee- nan. The test substances were administered orally at a dose of 50 mg/kg 1 hour before the administration of the phlogogenic agent. Animals that did not receive the drug served as controls. Statistical processing was carried out according to the Student's method. The effect of inhibition of inflammation was determined as a percentage of the control level. The presence of anti-inflammatory action was judged by the severity of inhibition of the inflamma- tory response. Scheme 2 Synthesis of 4-R-2-(2-(furan-2-ylcarbonyl)hydrazono)-4-oxobutanoic acids 3a–h. https://doi.org/10.15826/chimtech.2023.10.1.02 Chimica Techno Acta 2023, vol. 10(1), No. 202310103 ARTICLE 5 of 8 DOI: 10.15826/chimtech.2023.10.1.02 Scheme 3 Synthesis of N'-(2-oxofuran-3(2Н)-ylidene)furan-2-carbohydrazides 4a–h. All applicable international, national, and/or institu- tional guidelines for the care and use of animals were fol- lowed. 3. Results and Discussion Substituted 2-[2-(furan-2-ylcarbonyl)hydrazono]-4-oxobu- tanoic acids 3a–h were obtained in 64–84% yields by the re- action of corresponding 2,4-dioxobutanoic acids 1a–h with furan-2-carbohydrazide 2 in acetonitrile at 50 °C (Scheme 2). Compounds 3a–h are crystalline yellow substances, easily soluble in chloroform, DMSO, and when heated, in toluene, di- oxane, and ethanol, and insoluble in water and alkanes. The IR spectra of compounds 3a–h contain an absorption band at 1703–1744 cm–1, which is characteristic of the stretching vibrations of the carbonyl amide group, and ab- sorption bands at 3119–3131 and 3204–3251 cm–1, which are characteristic of the stretching vibrations of the amino group. The 1H NMR spectra (DMSO-d6) of compounds 3a–h in the tautomeric form A are characterized by singlet signals of the NH protons (11.09–11.44 ppm) and CH2 (4.04– 4.69 ppm) groups. Form B is characterized by the presence in the spectrum of a doublet of protons of the CH2 group at 3.30‒3.44 and 3.20‒3.39 ppm, and for form C, singlets of the NH protons (13.04‒13.83 ppm) and CH2 (3.80‒4.42 ppm). The spectral data of compounds 3a–h are in good agreement with the corresponding spectral data of alkyl 4-oxo-4-aryl-2- [2-(arylcarbonyl)hydrazinylidene]butanoates, which have a similar structure and also exist in three forms [37]. Intramolecular cyclization of acids 3a–h occurs upon slow heating to 150 °С in propionic anhydride and led to the formation of substituted N'-(2-oxofuran-3(2H)-ylidene)fu- ran-2-carbohydrazides 4a–h (Scheme 3). Compounds 4a–h, obtained in 52–84% yields, are yellow crystalline sub- stances, readily soluble in DMSO, when heated – in toluene and ethanol, and insoluble in water and alkanes. The IR spectra of compounds 4a–h contain an absorption band in the region 1776–1811 cm–1, which is characteristic of the stretching vibrations of the lactone carbonyl of the furan- 2(3H)-one ring, and an absorption band in the region 3116– 3186 cm–1, which is characteristic of the stretching vibra- tions of the amino group. According to 1Н NMR data in DMSO-d6, compounds 4a, 4c–f are present as two geometric isomers A and B. The spectra of the isomers are character- ized by the presence of signals of the NH groups [11.63‒ 11.83 (E–A) and 12.36‒12.54 ppm (Z–B)]. Compounds 4b, 4g, 4h exist only as the E-isomer, δ(NH) 11.89‒11.96 ppm. The spectral data of compounds 4a–h are in good agree- ment with the corresponding spectral data of N-[5-aryl-2- oxofuran-3(2H)-ylidene]-4-methylbenzohydrazides, which have a similar structure [28]. Some of the obtained compounds were examined for anti- inflammatory activity. It is shown in Table 1 that compounds 3e, g and 4d, f, g have a pronounced anti-inflammatory effect, surpassing the effect of the comparison drug nimesulide. Table 1 Anti-inflammatory activity of substances 3a, c–e, g. Compound Increase in foot volume after 3 hours (%) Braking swelling after 3 h, % 3a 57.59±3.54 13.36 3c 44.12±3.22*,** 33.62 3d 55.91±5.82 15.89 3e 26.71±5.47* 59.82 3g 30.49±3.55* 54.13 Nimesulide 33.90±6.78* 48.99 Control 66.47±10.19 – * – the difference is reduced compared to the decrease at р<0.05; ** – the difference is significant compared with nimesulide at p<0.05. Table 2 Anti-inflammatory activity of substances 4a, b, d–h. Compound Increase in foot volume after 3 hours (%) Braking swelling after 3 h, % 4a 41.32±3.26* 37.84 4b 39.61±1.73* 40.41 4d 28.96±5.58* 56.43 4e 45.34±3.62*,** 31.79 4f 24.04±5.68* 63.83 4g 24.29±3.73* 63.45 4h 114.76±16.45* –72.64 Nimesulide 33.90±6.78* 48.99 Control 66.47±10.19 – * – the difference is reduced compared to the decrease at р<0.05; ** – the difference is significant compared with nimesulide at p<0.05. https://doi.org/10.15826/chimtech.2023.10.1.02 Chimica Techno Acta 2023, vol. 10(1), No. 202310103 ARTICLE 6 of 8 DOI: 10.15826/chimtech.2023.10.1.02 Figure 1 The structure of the 3a, с–e, g compounds. Figure 2 The structure of the 4a, b, d–h compounds. 4. Limitations We have received new methyl-2-(2-(furan-2-carbonyl)hy- drazono)-4-oxobutanoic acids with yields of 64–84% and N'-(2-oxofuran-3(2H)-ylidene]furan-2-carbohydrazides with yields of 52–84%, after recrystallization of the ob- tained compounds, yields are significantly reduced. In the course of our further research, we are going to improve the purification method in order to achieve a significantly higher yield of the product. 5. Conclusions New derivatives of 2-(2-(furan-2-carbonyl)hydrazono)-4- oxobutanoic acids and N'-(2-oxofuran-3(2H)-ylidene)fu- ran-2-carbohydrazides were obtained. It was found that some of the obtained compounds (3e, 4g and 4f) exhibited significant anti-inflammatory activity, reliably exceeding the effect of a referral drug nimesulide. Compounds 3 and 4 have LD50 > 1500 mg/kg and, according to the drug tox- icity classification [38], belong to the V class (practically non-toxic substances). ● Supplementary materials No supplementary materials are available. ● Funding This study was performed under financial support by the “Rational Use of the Earth Interior” Perm Scientific Educa- tional Center 2023 and the Ministry of Science and Higher Education of the Russian Federation FSEG-2022-0012. ● Acknowledgments None. ● Author contributions Conceptualization: D.A.S., N.M.I. Data curation: S.N.I., D.V.L. A.Yu.T. Formal Analysis: D.V.L., P.S.S. Funding acquisition: D.A.S., N.M.I. Investigation: S.N.I., D.V.L. A.Yu.T. S.V.C. O.V.Z. K.M. Methodology: S.N.I., A.Yu.T. S.V.C. O.V.Z. K.M. Project administration: D.A.S., N.M.I. Resources: D.A.S., N.M.I. Supervision: D.A.S., N.M.I. Validation: D.V.L., D.A.S., P.S.S., N.M.I. Visualization: D.V.L., P.S.S. Writing – original draft: D.V.L., D.A.S., P.S.S. Writing – review & editing: D.V.L., D.A.S. ● Conflict of interest The authors declare no conflict of interest. ● Additional information Author IDs: Sergei N. Igidov, Scopus ID 57679291500; Dmitriy V. Lipin, Scopus ID 57414727200; Aleksey Yu. Turyshev, Scopus ID 57431693900; Daria A. Shipilovskikh, Scopus ID 57193555475; Pavel S. Silaichev, Scopus ID 8521794900; Ksenia A. Mitusova, Scopus ID 57203920295; Nazim M. Igidov, Scopus ID 6701786062. Websites: Perm State Pharmaceutical Academy, http://pfa.ru; Perm State National Research University, http://en.psu.ru; Perm National Research Polytechnic University, https://pstu.ru/en; Peter the Great St. Petersburg Polytechnic University, https://english.spbstu.ru. References 1. Bouz G, Dolezal M. Advances in Antifungal Drug Develop- ment: An Up-To-Date Mini Review. Pharmaceutic. 2021;14(12):1312. doi:10.3390/ph14121312 2. Huang L, Yang J, Wang T, Gao J, Xu D. Engineering of small- molecule lipidic prodrugs as novel nanomedicines for en- hanced drug delivery. Nanobiotechnol. 2022;20(1):49. doi:10.1186/s12951-022-01257-4 3. Jhinjharia D, Kaushik AC, Sahi S. Chapter 3 – Advances in structure-based drug design. Bioinform Pharm Sci. 2021:55. doi:10.1016/B978-0-12-821748-1.00009-9 4. Samy KE, Gampe C. Medicinal chemistry strategies to extend duration of action of inhaled drugs for intracellular targets. Bioorg Med Chem Lett. 2022;62:128627. doi:10.1016/j.bmcl.2022.128627 5. Zhao R, Fu J, Zhu L, Chen Y, Liu B. Designing strategies of small-molecule compounds for modulating non-coding RNAs in cancer therapy. J Hematol Oncol. 2022;15(1):14. doi:10.1186/s13045-022-01230-6 https://doi.org/10.15826/chimtech.2023.10.1.02 https://www.scopus.com/authid/detail.uri?authorId=57679291500 https://www.scopus.com/authid/detail.uri?authorId=57414727200 https://www.scopus.com/authid/detail.uri?authorId=57431693900 https://www.scopus.com/authid/detail.uri?authorId=57193555475 https://www.scopus.com/authid/detail.uri?authorId=8521794900 https://www.scopus.com/authid/detail.uri?authorId=57203920295 https://www.scopus.com/authid/detail.uri?authorId=6701786062 http://pfa.ru/ http://en.psu.ru/ https://pstu.ru/en https://english.spbstu.ru/ https://doi.org/10.3390/ph14121312 https://doi.org/10.1186/s12951-022-01257-4 https://doi.org/10.1016/B978-0-12-821748-1.00009-9 https://doi.org/10.1016/j.bmcl.2022.128627 https://doi.org/10.1186/s13045-022-01230-6 Chimica Techno Acta 2023, vol. 10(1), No. 202310103 ARTICLE 7 of 8 DOI: 10.15826/chimtech.2023.10.1.02 6. Ivashchenko AA, Mitkin OD, Jones JC, Nikitin AV, Koryakova AG, Ryakhovskiy A, Karapetian RN, Kravchenko DV, Ala- dinskiy V, Leneva IA, Falynskova IN, Glubokova EA. Non-rigid diarylmethyl analogs of baloxavir as cap-dependent endonu- clease inhibitors of influenza viruses. J Med Chem. 2020;63:9403. doi:10.1021/acs.jmedchem.0c00565 7. Babushkina AA, Dogadina AV, Egorov DM, Piterskaia JL, Shtro AA, Nikolaeva YV, Galochkina AV, Kornev AA, Boitsov VM. Ef- ficient synthesis and evaluation of antiviral and antitumor activity of novel 3-phosphonylated thiazolo[3,2-a]oxopyrim- idines. Med Chem Res. 2021;30:2203–2215. doi:10.1007/s00044-021-02801-x 8. Mayorova OA, Yegorova AY. 13C and 1H NMR study of azo cou- pling products from diazonium salts and furan-2-(3H)-ones. Magn Res Chem. 2015;10:853. doi:10.1002/mrc.4270 9. Igidov SN, Turyshev AYu, Makhmudov RR, Shipilovskikh DA, Igi- dov NM, Shipilovskikh SA. Synthesis, Intramolecular Cyclization, and Analgesic Activity of Substituted 2-[2-(Furancarbonyl)hydra- zinylydene]-4-oxobutanoic Acids. Russ J Gen Chem. 2022;92(9):1629–1636. doi:10.1134/S1070363222090067 10. Gavkus DN, Maiorova OA, Borisov MY, Egorova AY. Azo cou- pling of 5-substituted furan-2(3H)-ones and 1H-pyrrol-2(3H)- ones with arene(hetarene)diazonium salts. Russ J Org Chem. 2012;48:1229–1232. doi:10.1134/s107042801209014x 11. Ali A, Khalid M, Abid S, Tahir MN, Iqbal J, Ashfaq M, Kanwal F, Lu C, Rehman MF. Green synthesis, SC-XRD, non-covalent interactive potential and electronic communication via DFT exploration of pyridine-based hydrazone. Crystals. 2020;10(9):778. doi:10.3390/cryst10090778 12. Khalid M, Ali A, Abid S, Tahir MN, Khan MU, Ashfaq M, Imran M, Ahmad A. Facile ultrasound-based synthesis, sc-xrd, dft exploration of the substituted acyl-hydrazones: an experi- mental and theoretical slant towards supramolecular chemis- try. Chem Sel. 2020;5(47):14844–14856. doi:10.1002/slct.202003589 13. Gorbunova IA, Sharavyeva YuO, Makhmudov RR, Shipilov- skikh DA, Shadrin VM, Pulina NA, Shipilovskikh SA. Synthesis and antinociceptive activity of substituted 2-(3-cyano-4,5,6,7- tetrahydrobenzo[b]thiophene-2-ylamino)-4-oxobut-2-eno- ates. Russ J Gen Chem. 2022;92(10):1–8. doi:10.1134/S1070363222100048 14. Shipilovskikh SA, Rubtsov AE. One-Pot Synthesis of Thieno[3,2-e]pyrrolo[1,2-a]pyrimidine Derivative Scaffold: A Valuable Source of PARP-1 Inhibitors. J Org Chem. 2019;84:15788. doi:10.1021/acs.joc.9b00711 15. Sayed HH, Hashem AI, Yousif NM, ElSayed WA. Conversion of 3-Arylazo-5-phenyl-2(3H)-furanones into other heterocycles of anticipated biological activity. Arch Pharm. 2007;6:315. doi:10.1002/ardp.200700043 16. Siutkina AI, Sharavyeva YO, Chashchina SV, Shipilovskikh SA, Igidov NM. Synthesis and anti-inflammatory activity of N′- substituted 2-[2-(diarylmethylene)hydrazinyl]-5,5-dimethyl- 4-oxohex-2-enehydrazides. Russ Chem Bull. 2022;71:496– 501. doi:10.1007/s11172-022-3439-9 17. Kargar H, Fallah-Mehrjardi M, Behjatmanesh-Ardakani R, Munawar KS, Ashfaq M, Tahir MN. Diverse coordination of isoniazid hydrazone Schiff base ligand towards iron(III): Syn- thesis, characterization, SC-XRD, HSA, QTAIM, MEP, NCI, NBO and DFT study. J Mol Struct. 2022;1250(2):131691. doi:10.1016/j.molstruc.2021.131691 18. Fernández-García Y, Horst S, Bassetto M, Brancale A, Neyts J, Rogolino D, Sechi M, Carcelli M, Günther S, Rocha-Pereira J. Diketo acids inhibit the cap-snatching endonuclease of sev- eral Bunyavirales. Antivir Res. 2020;183:104947. doi:10.1016/j.antiviral.2020.104947 19. Joksimović N, Janković N, Davidović G, Bugarčić Z. 2,4-Diketo esters: Crucial intermediates for drug discovery. Bioorg Chem. 2020;105:104343. doi:10.1016/j.bioorg.2020.104343 20. Nair V, Okello M. Integrase Inhibitor Prodrugs: Approaches to Enhancing the Anti-HIV Activity of β-Diketo Acids. Molecules. 2015;20:12623. doi:10.3390/molecules200712623 21. Sharma H, Sanchez TW, Neamati N, Detorio M, Schinazi RF, Cheng X, Buolamwini JK. Synthesis, docking, and biological studies of phenanthrene β-diketo acids as novel HIV-1 inte- grase inhibitors. Bioorg Med Chem Lett. 2013;23:6146. doi:10.1016/j.bmcl.2013.09.009 22. Bobrovskaya OV, Russkih AA, Yankin AN, Dmitriev MV, Bunev AS, Gein VL. Straightforward synthesis of novel spiroether deriva. Synth. Commun. 2021;51:1731. doi:10.1080/00397911.2021.1903930 23. Sobin FV, Pulina NA, Lipatnikov KV, Starkova AV, Yushkova TA, Naugol’nykh EA. Synthesis and Hemostatic, Anti-Inflam- matory, and Anthelminthic Activity of 2-hydroxy-4-oxo-4- (thien-2-yl)but-2-enoic Acid Derivatives. Pharm Chem J. 2021;54:1003. doi:10.1007/s11094-021-02310-6 24. Pulina NA, Kuznetsov AS, Krasnova AI, Novikova VV. Synthe- sis, Antimicrobial Activity, and Behavioral Response Effects of N-Substituted 4-Aryl-2-Hydroxy-4-Oxobut-2-Enoic acid hy- drazides and their metal complexes. Pharm Chem J. 2019;53:220. doi:10.1007/s11094-019-01983-4 25. Gein VL, Zamaraeva TM, Gorgopina EV, Dmitriev MV. A four- component Biginelli reaction: new opportunities for the syn- thesis of functionalized pyrimidines. Chem Heterocycl Compd. 2020;56:339. doi:10.1007/s10593-020-02665-w 26. Gein VL, Zamaraeva TM, Buzmakova NA, Rudakova IP, Dmitriev MV. Structure and Analgesic Activity of 13-(N- Aryl(N,N-Diethyl)Aminocarbonyl)-9-Methyl-11-Thioxo-8-Oxa- 10,12-Diazatricyclo[7.3.1.02,7]Trideca-2,4,6-Trienes and Their 10-N-Phenyl derivatives. Pharm Chem J. 2018;52:515. doi:10.1007/s11094-018-1851-0 27. Ashfaq M, Munawar K Shahzad BG, Ali A, Tahir MN, Ahmed G, Ramalingam A, Alam MM, Imran M, Sambandam S, Munir B. Single crystal inspection, Hirshfeld surface investigation and DFT study of a novel derivative of 4-fluoroaniline: 4-((4- fluorophenyl)amino)-4-oxobutanoic acid (BFAOB). J Iran Chem Soc. 2022;19(5):1953–1961. doi:10.1007/s13738-021-02432-4 28. Denisova EI, Lipin DV, Parkhoma KY., Devyatkin IO, Shipilov- skikh DA, Chashchina SV, Makhmudov RR, Igidov NM, Ship- ilovskikh SA. Synthesis, Intramolecular Cyclization, and An- tinociceptive Activity of Substituted 2-[2-(4-Nitrobenzoyl)hy- drazinylidene]-4-oxobut-2-enoic Acids. Russ J Org Chem. 2021;57:1955. doi:10.1134/s1070428021120083 29. Lipin DV, Denisova EI, Devyatkin IО, Okoneshnikova ЕА, Shipilovskikh DA, Makhmudov RR, Igidov NM, Shipilovskikh SA. Synthesis and Antinociceptive Activity of Substituted 5- (het)aryl-3-(4-methylbenzoyl)hydrazono-3H-furan-2-ones. Russ J Gen Chem. 2020;91:809. doi:10.1134/S1070363221120161 30. Gorbunova IA, Shipilovskikh DA, Rubtsov AE, Shipilovskikh SA. Synthesis and Intramolecular Cyclization of Substituted 4-(Het)aryl-4-oxo-2-thienylaminobut-2-enoic Acids Contain- ing Nitrile Group in the Thiophene Ring. Russ J Gen Chem. 2021;91:1623. doi:10.1134/S1070363221090048 31. Shipilovskikh SA, Makhmudov RR, Lupach DYu, Pavlov PT, Babushkina EV, Rubtsov AE. Synthesis and analgesic activity of substituted 4-(het)aryl-4-oxo-2-thienylaminobut-2-enoic acids. Pharm Chem J. 2013;47(7):366–370. doi:10.1007/s11094-013-0960-z 32. Sharavyeva YuO, Siutkina AI, Chashchina SV, Novikova VV, Makhmudov RR, Shipilovskikh SA. Synthesis, analgesic and antimicrobial activity of substituted 2-(3-cyano-4,5,6,7-tetra- hydrobenzo[b]thiophen-2-ylamino)-4-oxo-4-phenylbut-2-en- oates. Russ Chem Bull. 2022;71(3):538. doi:10.1007/s11172-022-3445-y 33. Gunina E, Zhestkij N, Bachinin S, Fisenko SP, Shipilovskikh DA, Milichko VA, Shipilovskikh SA. The influence of substi- tutes on the room temperature photoluminescence of 2- amino-4-oxobut-2-enoic acid molecular crystals. Photonics Nanostruct. 2022;48:100990. doi:10.1016/j.photonics.2021.100990 34. Zhestkij NA, Gunina EV, Fisenko SP, A.E. Rubtsov AE, Ship- ilovskikh DA, Milichko VA, Shipilovskikh SA. Synthesis of https://doi.org/10.15826/chimtech.2023.10.1.02 https://doi.org/10.1021/acs.jmedchem.0c00565 https://doi.org/10.1007/s00044-021-02801-x https://doi.org/10.1002/mrc.4270 https://doi.org/10.1134/S1070363222090067 https://doi.org/10.1134/s107042801209014x https://doi.org/10.3390/cryst10090778 https://doi.org/10.1002/slct.202003589 https://doi.org/10.1134/S1070363222100048 https://doi.org/10.1021/acs.joc.9b00711 https://doi.org/10.1002/ardp.200700043 https://doi.org/10.1007/s11172-022-3439-9 https://doi.org/10.1016/j.molstruc.2021.131691 https://doi.org/10.1016/j.antiviral.2020.104947 https://doi.org/10.1016/j.bioorg.2020.104343 https://doi.org/10.3390/molecules200712623 https://doi.org/10.1016/j.bmcl.2013.09.009 https://doi.org/10.1080/00397911.2021.1903930 https://doi.org/10.1007/s11094-021-02310-6 https://doi.org/10.1007/s11094-019-01983-4 https://doi.org/10.1007/s10593-020-02665-w https://doi.org/10.1007/s11094-018-1851-0 https://doi.org/10.1007/s13738-021-02432-4 https://doi.org/10.1134/s1070428021120083 https://doi.org/10.1134/S1070363221120161 https://doi.org/10.1134/S1070363221090048 https://doi.org/10.1007/s11094-013-0960-z https://doi.org/10.1007/s11172-022-3445-y https://doi.org/10.1016/j.photonics.2021.100990 Chimica Techno Acta 2023, vol. 10(1), No. 202310103 ARTICLE 8 of 8 DOI: 10.15826/chimtech.2023.10.1.02 highly stable luminescent molecular crystals based on (E)-2- ((3-(ethoxycarbonyl)-5-methyl-4-phenylthiophen-2- yl)amino)-4-oxo-4-(p-tolyl)but-2-enoic acid. Chimica Techno Acta. 2021;8(4):20218411. doi:10.15826/chimtech.2021.8.4.11 35. Siutkina AI, Chashchina SV, Kizimova IA, Igidov NM, Makhmudov RR, Shipilovskikh SA. Synthesis and Biological Activity of Substituted 2-[2-(Diphenylmethylene)hydrazinyl]- 5,5-dimethyl-4-oxohex-2-enoates. Russ J Org Chem. 2021;57(11):1874. doi:10.1134/S1070428021110105 36. Mironov AN, Bunatyan ND. Metodicheskie ukazaniya po provedeniyu doklinicheskih issledovanij lekarstvennyh sredstv [Guidelines for conducting preclinical studies of med- icines]. Moscow: Grif i K; 2012. 944 p. Russian. 37. Kizimova IA, Igidov NM, Kiselev MA, Ivanov DV, Syutkina AI. Reactions of N'-[2-Oxo-5-R-furan-3(2H)-ylidene]acylhydra- zides with Primary and Secondary Alcohols. Russ J Gen Chem. 2020;90(5):815–821. doi:10.1134/s1070363220050096 38. Izmerov NF, Sanotskii IV, Sidorov KK. Parametry toksikome- trii promyshlennykh yadov pri odnokratnom vozdeistvii [Pa- rameters of Toxicometry of Industrial Poisons at a Single Ex- posure]. Moscow: Meditsina; 1977. 196 p. Russian. https://doi.org/10.15826/chimtech.2023.10.1.02 https://doi.org/10.15826/chimtech.2021.8.4.11 https://doi.org/10.1134/S1070428021110105 https://doi.org/10.1134/s1070363220050096