3'-aroyl-4'-hydroxy-1'-(2-hydroxyaryl)-2h-spiro[naphtho[1,2-b]furan-3,2'-pyrrole]-2,5'(1'h)-diones and 3'-aroyl-4'-hydroxy-1'-(2-hydroxyaryl)-2h-spiro[naphtho[2,1-b]furan-1,2'-pyrrole]-2,5'(1'h)-diones

Abstract

FIELD: chemistry.SUBSTANCE: invention relates to compounds 3'-aroyl-4'-hydroxy-1'-(2-hydroxyaryl)-2H-spiro[naphthophuran-pyrrole]-2,5'(1'H)-diones of formulaswhere R = H, Cl, Br, Me; R'=H, OH; Ar = Ph, C6H4C1-4, C6H4Br-4, C6H4Me-4, C6H4OMe-4, C6H4F-4.EFFECT: obtaining new compounds 3'aroyl-4'hydroxy-1'-(2-hydroxyaryl)-2H-spiro[naphthophuran-pyrrole]-2,5'(1'H)-diones with antimicrobial and growth-regulating activity, which can be used as stocks for the synthesis of heterocyclic systems.1 cl, 2 tbl, 21 ex

Description

[0001] 3'-Aroyl-4'-hydroxy-1'-(2-hydroxyaryl)-2H-spiro[naphtho[1,2-b]furan-3,2'-pyrrole]-2,5'(1'H)-diones and 3'-aroyl-4'-hydroxy-1'-(2-hydroxyaryl)-2H-spiro[naphtho[2,1-b]furan-1,2'-pyrrole]-2,5'(1'H)-diones

[0002] The invention relates to the field of organic chemistry, namely to new biologically active individual compounds of the spiro[naphthopuran-pyrrole] class, namely 3'-aroyl-4'-hydroxy-1'-(2-hydroxyaryl)-2H-spiro[naphthopuran-pyrrole]-2,5'(1'H)-diones of the formulas:

[0003]

[0004] where R=H, Cl, Br, Me; R'=H, OH; Ar=Ph, C6H4C1-4, C6H4Br-4, C6H4Me-4,

[0005] C6H4OMe-4, C6H4F-4, possessing biological activity, which allows us to suggest their use as starting products for the synthesis of new heterocyclic systems, in pharmacology and in medicine as drugs with an antimicrobial effect.

[0006] Structural analogs of the claimed compounds are known - derivatives of spiro[1-benzofuran-3,2'-pyrroles] (N. M. Tutynina, I. L. Racheva, V. A. Maslivets, Z. G. Aliyev, A. N. Maslivets / Five-membered 2,3-dioxoheterocycles XCI. Interaction of 3-acyl-1H-pyrrolo[2,1-c][1,4]benzoxazine-1,2,4-triones with dimedone. Crystal and molecular structure of substituted spiro[1-benzofuran-3,2'-pyrrole] / / ZhOrKh. - 2013. - Vol. 49. - No. 1. - P. 101-104. [N. M. Tutynina, NL Racheva, V. A. Maslivets, Z. G. Aliev, AN Maslivets / Five-membered 2,3-dioxoheterocycles: XCI. Reaction of 3-aroyl-1H-pyrrolo[2,1-c][1,4]benzoxazine-1,2,4-triones with dimedone. Crystalline and molecular structure of 3'-benzoyl-4'-hydroxy-1'-(2-hydroxyphenyl)-6,6-dimethy1-6,7-dihydrospiro[1-benzofuran-3,2'-pyrrole]-2,4,5'(1'H,5H)-trione / / Russian Journal of Organic Chemistry. - 2013. - Vol. 49. - No. 1. - P. 95-98. - DOI: 10.1134 / S1070428013010168]) general formula:

[0007]

[0008] where Ar=Ph, C6H4OMe-4, C6H4Br-4, CeH4NO2-4, C6H4OEt-4, C6H4F-4

[0009] The antibacterial drug dioxidine [Padeyskaya E.N. Antibacterial drug dioxidine: features of biological action and importance in the therapy of various forms of purulent infection / / Infections and antimicrobial therapy. - 2001. - No. 5. - P. 105-155] and the antifungal drug fluconazole [Shilova IB, Gus'kova T.A., Glushkov R.G. Modern drags for treating dermatomycosis / / Pharmaceutical Chemistry Journal. - 2004. - V. 38. - No. 4. - P. 175-180.], which are widely used in medical practice and are analogous in action, were chosen as the standards for comparison of antimicrobial efficacy.

[0010] Growth-regulating activity was studied in relation to Chlorella vulgaris microalgae cells in BG-11 medium [Touloupakis, E.; Tartari, G.; Zittelli, GC; Torzillo, G. Growth and photosynthetic performance of Chlamydopodium fusi-forme cells cultivated in BG11 and Bristol media. J. Appl. Phycol. 2020, 32(1), 145-152. https: / / doi.org / 10.1007 / sl0811-019-01900-y] under aseptic conditions.

[0011] The objective of the invention is to search for substances with antimicrobial and growth-regulating effects against C. vulgaris in a series of spiro[naphthofuran-pyrrole] derivatives and to expand the arsenal of means of influencing a living organism.

[0012] The set task is achieved by obtaining 3'-aroyl-4'-hydroxy-1'-(2-hydroxyaryl)-2H-spiro[naphtho[1,2-b]furan-3,2'-pyrrole]-2,5'(1'H)-diones and 3'-aroyl-4'-hydroxy-1'-(2-hydroxyaryl)-2H-spiro[naphtho[2,1-b]furan-1,2'-pyrrole]-2,5'(1'H)-diones, which have antimicrobial and growth-regulating activity.

[0013] The claimed compounds are synthesized by reacting 3-aroylpyrrolo[2,1-c][1,4]benzoxazine-1,2,4-triones 1a-i with naphthols by boiling in toluene in a 1:1 ratio for 1-2 hours, followed by isolation of the target product, according to the following scheme:

[0014]

[0015] 1, 2, 3: Ar=Ph, R=H, R'=H (a); Ar=C6H4Cl-4, R=H, R=H (6); Ar=C6H4Br-4, R=H, R=H (c); Ar=C6H4Me-4, R=H, R=H (r); Ar=C6H4OMe-4, R=H, R=H (d); Ar=C6H4F-4, R=H, R=H (e); Ar=Ph, R=Cl, R=H (l); Ar=Ph, R=Br, R=H (h); Ar=Ph, R=Me, R=H (and), Ar=Ph, R=H,

[0016] R=ОН (к).

[0017] The process is carried out by boiling, and anhydrous toluene is used as a solvent.

[0018] The invention is illustrated by the following examples.

[0019] Example 1. Preparation of 3'-benzoyl-4'-hydroxy-1'-(2-hydroxyphenyl)-2H-spiro[naphtho[1,2-b]furan-3,2'-pyrrole]-2,5 | (HY)-dione (2a).

[0020] 1.0 mmol of 1-naphthol was added to a solution of 1.0 mmol of pyrroledione (1a) in 5 ml of anhydrous toluene. The reaction mixture was refluxed for 1-2 hours (until the violet color of the starting compound 1a disappeared), and the formed precipitate was filtered off. Yield 82%, mp 217-220°C (decomp.).

[0021] Connection (2a) C 28 H 17 NO6.

[0022] Found, %: C 72.56; H 3.72; N 3.03.

[0023] Calculated, %: C 72.57; H 3.70; N 3.02.

[0024] Compound (2a) is a yellow crystalline substance, readily soluble in acetone, DMSO, 1,4-dioxane, sparingly soluble in dichloromethane, acetonitrile, toluene, chloroform, insoluble in alkanes and water. Stable when stored under normal conditions.

[0025] IR spectrum taken as a paste in vaseline oil: 3161, 1814, 1708, 1666 cm -1 .

[0026] NMR spectrum 1 H (400 MHz, DMSO-d6, δ, ppm): 6.65-6.77 m (2H аром ), 6.98-7.08 m (2N аром ), 7.44-7.52 m (2Nаром ), 7.54-7.69 m (5N аром ), 7.75-7.82 m (2N аром ), 7.87-7.99 m (2N аром ), 9.86 units (1H, OH фенол ). The hydrogen atom of the enol hydroxyl group is not visible due to strong broadening. NMR spectrum 13 C (100 MHz, DMSO-v6, δ, ppm): 69.9 (C 5 с пиро ), 116.5, 117.1, 117.6, 118.6,

[0027] 119.0, 120.5, 121.2, 121.3, 123.8, 127.1, 127.6, 128.1 (2C), 128.2, 128.4, 128.8 (2C), 130.0, 133.0, 134.5, 136.9, 150.0, 153.6, 153.8, 165.4, 173.3, 188.4 (COPh).

[0028] Example 2. Preparation of 4'-hydroxy-1'-(2-hydroxyphenyl)-3'-(4-chlorobenzoyl)-2H-spiro[naphtho[1,2-b]furan-3,2'-pyrrole]-2,5'(1'H)-dione (2b).

[0029] 1.0 mmol of 1-naphthol was added to a solution of 1.0 mmol of pyrroledione (1b) in 5 ml of anhydrous toluene. The reaction mixture was refluxed for 1-2 hours (until the violet color of the starting compound 1b disappeared), and the formed precipitate was filtered off. Yield 76%, mp 239-241°C (decomp.).

[0030] Connection (2b) C 28 H 16 ClNO6.

[0031] Found, %: C 67.57; H 3.27; N 2.81.

[0032] Calculated, %: C 67.55; H 3.24; N 2.81.

[0033] Compound (26) is a yellow crystalline substance, readily soluble in acetone, DMSO, 1,4-dioxane, sparingly soluble in dichloromethane, acetonitrile, toluene, chloroform, insoluble in alkanes and water. Stable when stored under normal conditions.

[0034] IR spectrum taken as a paste in vaseline oil: 3152, 1809, 1708, 1671 cm -1 .

[0035] NMR spectrum 1 H (400 MHz, DMSO-d6, δ, ppm): 6.65-6.71 m (1H аром ), 6.73 D.D (1N аром , J 8.3 Hz), 6.96-7.07 m (2H аром ), 7.51-7.69 m (6N аром ), 7.76-7.85 m (2N аром ), 7.87-7.99 m (2N аром ), 9.85 units (1H, OH фенол ). The hydrogen atom of the enol hydroxyl group is not visible due to strong broadening. NMR spectrum 13 C (100 MHz, DMSO-d6, δ, ppm): 69.8 (C 5спиро ), 116.5, 117.1,

[0036] 117.1, 118.5, 119.0, 120.5, 121.2, 121.3, 123.8, 127.1, 127.6, 128.2, 128.3 (2C), 128.4, 130.0, 130.6 (2C), 134.5, 135.6, 137.8, 150.0, 153.8, 154.4, 165.3, 173.3, 187.1 (COAr).

[0037] Example 3. Preparation of 3'-(4-bromobenzoyl)-4'-hydroxy1'(2-hydroxyphenyl)-2H-spiro[naphtho[1,2-b]furan-3,2'-pyrrole]-2,5'(1'H)-Dione (2c).

[0038] 1.0 mmol of 1-naphthol was added to a solution of 1.0 mmol of pyrroledione (1c) in 5 ml of anhydrous toluene. The reaction mixture was refluxed for 1-2 hours (until the violet color of the starting compound 1c disappeared), and the formed precipitate was filtered off. Yield 76%, mp 239-241°C (decomp.).

[0039] Connection (2v) C 28 N 16 B rNO6.

[0040] Found, %: C 62.04; H 2.98; N 2.55.

[0041] Calculated, %: From 62.01; H 2.97; N 2.58.

[0042] Compound (2b) is a yellow crystalline solid, readily soluble in acetone, DMSO, and 1,4-dioxane; sparingly soluble in dichloromethane, acetonitrile, toluene, and chloroform; insoluble in alkanes and water. Stable when stored under normal conditions.

[0043] IR spectrum taken as a paste in vaseline oil: 3068, 1814, 1713, 1667 cm -1 .

[0044] NMR spectrum 1 H (400 MHz, DMSO-d6, δ, ppm): 6.66-6.77 m (2H аром ), 6.98-7.07 m (2N аром ), 7.55-7.77 m (8N аром ), 7.89-7.97 m (2N аром ), 9.87 units (1H, OH фенол ). The hydrogen atom of the enol hydroxyl group is not visible due to strong broadening. NMR spectrum 13 C (100 MHz, DMSO-d6, δ, ppm): 69.8 (C 5 с pyro), 116.5, 117.0, 117.1, 118.6, 119.0, 120.5, 121.2, 121.3, 123.8, 126.9, 127.1, 127.6, 128.2, 128.4, 130.0, 130.7(2С), 131.2(2С), 134.5, 135.9, 150.0, 153.8, 154.3, 165.3, 173.3, 187.3 (COAr).

[0045] Example 4. Preparation of 4'-hydroxy-1'-(2-hydroxyphenyl)-3'-(4-methylbenzoyl)-2H-spiro[naphtho[1,2-b]furan-3,2'-pyrrole]-2,5'(1'H)-dione (2 g).

[0046] 1.0 mmol of 1-naphthol was added to a solution of 1.0 mmol of pyrroledione (1 g) in 5 ml of anhydrous toluene. The reaction mixture was refluxed for 1-2 hours (until the violet color of the starting compound (1 g) disappeared), and the formed precipitate was filtered off. Yield 82%, mp 232-233°C (decomp.).

[0047] Compound (2g) C 29 H 19 NO6.

[0048] Found, %: C 72.99; H 4.03; N 2.91.

[0049] Calculated, %: C 72.95; H 4.01; N 2.93.

[0050] The compound (2 g) is a yellow crystalline substance, readily soluble in acetone, DMSO, 1,4-dioxane, sparingly soluble in dichloromethane, acetonitrile, toluene, chloroform, and insoluble in alkanes and water. Stable when stored under normal conditions.

[0051] IR spectrum taken as a paste in vaseline oil: 3163, 1812, 1697, 1673 cm-1 .

[0052] NMR Spectrum 1 H (400 MHz, DMSO-d6, δ, ppm): 2.36 s (3H, Me), 6.66-6.76 m (2H аром ), 6.98-7.06 m (2H аром ), 7.26-7.31 m (2H аром , J 8.3 Hz), 7.54-7.64 m (4H аром ), 7.67-7.72 m (2H аром , J 8.3 Hz), 7.87-7.96 m (2H аром ), 9.85 ppm (1H, OH фенол ). The hydrogen atom of the enol hydroxyl group is not visible due to the strong broadening. NMR spectrum 13 C (100 MHz, DMSO-d6, δ, ppm): 21.1 (Me), 69.9 (C 5 с гафо ), 116.5, 117.0, 117.9, 118.6, 119.0, 120.5, 121.3, 121.3, 123.7, 127.0, 127.5, 128.2, 128.4, 128.7(C), 2.2(C), 130.0, 134.2, 134.5, 143.5, 150.0, 153.0, 153.8, 165.5, 173.3, 188.0 (COAr).

[0053] Example 5. Preparation of 4'-hydroxy1'(2-hydroxyphenyl)-3'-(4-methoxybenzoyl)-2H-spiro[naphtho[1,2-b]furan-3,2'-pyrrole]-2,5'(1'H)-dione (2D).

[0054] 1.0 mmol of 1-naphthol was added to a solution of 1.0 mmol of pyrroledione (1e) in 5 ml of anhydrous toluene. The reaction mixture was refluxed for 1-2 hours (until the violet color of the starting compound 1e disappeared), and the formed precipitate was filtered off. Yield 88%, mp 229-232°C (decomp.).

[0055] Connection (2d) C 29 H 19 NO7.

[0056] Found, %: C 70.57; H 3.89; N 2.86.

[0057] Calculated, %: C 70.59; H 3.88; N 2.84.

[0058] Compound (2d) is a yellow crystalline substance, readily soluble in acetone, DMSO, and 1,4-dioxane; sparingly soluble in dichloromethane, acetonitrile, toluene, and chloroform; insoluble in alkanes and water. Stable when stored under normal conditions.

[0059] IR spectrum taken as a paste in vaseline oil: 3166, 1818, 1707, 1651 cm -1 .

[0060] NMR spectrum 1 H (400 MHz, DMSO-d6, δ, ppm): 3.83 s (3H, OMe), 6.66-6.77 m (2H аром ), 6.97-7.06 m (4N аром), 7.54-7.64 m (4N аром ), 7.80 d (2N аром , J 8.8 Hz), 7.87-7.92 m (1H аром ), 7.92-7.97 m (1N аром ), 9.84 units (1H, OH фенол ), 12.45 us.s (1H, OH енол ). NMR spectrum 13 С (100 MHz, DMSO-d6, δ, ppm): 55.4(ОМе), 70.0 (С 5 с пиро ), 113.5(2С), 116.5, 117.0, 118.2, 118.6, 119.0, 120.5, 121.3(2С),

[0061] 123.7, 127.0, 127.5, 128.2, 128.4, 129.4, 130.0, 131.4(2C), 134.5, 150.0, 152.2,

[0062] 153.8, 163.3, 165.5, 173.3, 186.7 (SOAk).

[0063] Example 6. Preparation of 4'-hydroxy-1'-(2-hydroxyphenyl)-3'-(4-fluorobenzoyl)-2H-spiro[naphtho[1,2-i]furan-3,2'-pyrrole]-2,5'(1'H)-Dione (2e).

[0064] 1.0 mmol of 1-naphthol was added to a solution of 1.0 mmol of pyrroledione (1e) in 5 ml of anhydrous toluene. The reaction mixture was refluxed for 1-2 hours (until the violet color of the starting compound 1e disappeared), and the formed precipitate was filtered off. Yield 71%, mp 222-224°C (decomp.).

[0065] Connection (2e) C 28 H 16 FNO6.

[0066] Found, %: C 69.86; H 3.35; N 2.91.

[0067] Calculated, %: C 69.85; H 3.35; N 2.90.

[0068] Compound (2e) is a yellow crystalline solid, readily soluble in acetone, DMSO, and 1,4-dioxane; sparingly soluble in dichloromethane, acetonitrile, toluene, and chloroform; insoluble in alkanes and water. Stable when stored under normal conditions.

[0069] IR spectrum taken as a paste in vaseline oil: 3262, 1817, 1713, 1685 cm -1 .

[0070] NMR spectrum 1 H (400 MHz, DMSO-d6, δ, ppm): 6.65-6.72 m (1H аром ), 6.74 d.d (1H аром , J 8.3, 1.0 Hz), 6.97-7.07 m (2H аром ), 7.26-7.35 m (2N аром ), 7.54-7.69 m (4N аром ), 7.84-7.92 m (3H аром ), 7.92-7.97 m (1N аром ), 9.85 us.s (1H, OH фенол ). The hydrogen atom of the enol hydroxyl group is not visible due to strong broadening. NMR spectrum 13C (100 MHz, DMSO-d6, δ, ppm): 69.8 (C 5 спиро ), 115.2 d (2С, J21.6 Hz), 116.5, 117.0, 117.4, 118.6, 119.0, 120.5, 121.2, 121.3, 123.8, 127.0, 127.6, 128.2, 128.4, 130.0, 131.8 d (2С, J 10 Hz), 133.5 d (J 3.1 Hz), 134.5, 150.0, 153.8, 153.8, 166.1 d (C apом F, J 252 Hz), 165.4, 173.3, 186.8 (COAr).

[0071] Example 7. Preparation of 3'-benzoyl-4'-hydroxy-1'-(2-hydroxy-5-chlorophenyl)-2H-spiro[naphtho[1,2-b]furan-3,2 , -pyrrole]-2,5'(1'H)-dione (2g).

[0072] 1.0 mmol of 1-naphthol was added to a solution of 1.0 mmol of pyrroledione (1g) in 5 ml of anhydrous toluene. The reaction mixture was refluxed for 1-2 hours (until the violet color of the starting compound 1g disappeared), and the formed precipitate was filtered off. Yield 77%, mp 234-235°C (decomp.).

[0073] Connection (2g) C 28 H 16 ClO6.

[0074] Found, %: C 67.51; H 3.21; N2.83.

[0075] Calculated, %: C 67.55; H 3.24; N 2.81.

[0076] Compound (2g) is a light yellow crystalline substance, readily soluble in acetone, DMSO, 1,4-dioxane, sparingly soluble in dichloromethane, acetonitrile, toluene, chloroform, and insoluble in alkanes and water. Stable when stored under normal conditions.

[0077] IR spectrum taken as a paste in vaseline oil: 3181, 1790, 1730, 1671 cm -1 .

[0078] NMR spectrum 1 H (400 MHz, DMSO-d6, δ, ppm): 6.74 d (1H apом , J 8.8 Hz), 7.02-7.20 m (2H аром ), 7.47 t (2N аром , J 7.3 Hz), 7.54-7.71 m (5N аром ), 7.79 d (2N аром , J 7.3 Hz), 7.91 d (1H аром , J 7.8 Hz), 7.98 d (1H ap0M , J 7.8 Hz), 10.30 br.s (1H, OH фенол ). The hydrogen atom of the enol hydroxyl group is not visible due to strong broadening. NMR spectrum 13 C (100 MHz, DMSO-d6, δ, ppm): 69.6(C 5 спиро), 116.7, 117.8, 117.9, 118.6, 120.6, 121.3, 121.6, 122.5, 123.9, 127.1, 127.6, 128.1(2С), 128.3, 128.3, 128.8(2С), 129.7, 133.0, 134.5, 136.8, 150.1, 152.9, 153.4, 165.8, 173.0, 188.4(COAr).

[0079] Example 8. Preparation of 3-(benzoyl)-1'-(5-bromo-2-hydroxyphenyl)-4'-hydroxy-2H-spiro[naphtho[1,2-b]furan-3,2'-pyrrole]-2,5'(1'H)-dione (2z).

[0080] 1.0 mmol of 1-naphthol was added to a solution of 1.0 mmol of pyrroledione (1h) in 5 ml of anhydrous toluene. The reaction mixture was refluxed for 1-2 hours (until the violet color of the starting compound 1h disappeared), and the formed precipitate was filtered off. Yield 94%, mp 232-234°C (decomp.).

[0081] Connection (2z) C 28 H 16 BrNO6.

[0082] Found, %: C 62.03; H 2.99; N 2.60.

[0083] Calculated, %: From 62.01; H 2.97; N 2.58.

[0084] Compound (2z) is a light yellow crystalline substance, readily soluble in acetone, DMSO, 1,4-dioxane, sparingly soluble in dichloromethane, acetonitrile, toluene, chloroform, and insoluble in alkanes and water. Stable when stored under normal conditions.

[0085] IR spectrum taken as a paste in vaseline oil: 3347, 1793, 1715, 1671 cm -1 .

[0086] NMR spectrum 1 H (400 MHz, DMSO-d6, δ, ppm): 6.69 d (1H apом , J 8.8 Hz), 7.20 d.d (1H аром , J 8.8, 2.4 Hz), 7.24 d (1H аром , J 2.4 Hz), 7.43-7.51 m (2H аром ), 7.56-7.69 m (5N аром ), 7.74-7.84 m (2N аром ), 7.87-7.95 m (lH ap0M ), 7.95-8.02 m (1N аром ), 10.33 us (1H, OH фенол ). The hydrogen atom of the enol hydroxyl group is not visible due to strong broadening. NMR spectrum 13 C (100 MHz, DMSO-d6, δ, ppm): 70.3 (C 5 спиро), 109.3, 117.3, 118.5, 118.9, 119.2, 121.2, 121.9, 123.6, 124.5, 127.7, 128.2, 128.7 (2С), 128.9, 129.4 (1С), 131.8, 133.1, 133.6, 135.1, 137.4, 150.7, 153.9, 154.0, 166.4, 173.6, 189.1 (COAr).

[0087] Example 9. Preparation of 3'-benzoyl-4'-hydroxy-1'-(2-hydroxy-5-methylphenyl)-2H-spiro[naphtho[1,2-b]furan-3,2'-pyrrole]-2,5'(1'H)-dione (2i).

[0088] 1.0 mmol of 1-naphthol was added to a solution of 1.0 mmol of pyrroledione (1i) in 5 ml of anhydrous toluene. The reaction mixture was refluxed for 1-2 hours (until the violet color of the starting compound 1i disappeared), and the formed precipitate was filtered off. Yield 64%, mp 236-237°C (decomp.).

[0089] Connection (2i) C 29 H 19 NO6.

[0090] Found, %: C 72.96; H 4.03; N 2.95.

[0091] Calculated, %: C 72.95; H 4.01; N 2.93.

[0092] Compound (2i) is a yellow crystalline substance, readily soluble in acetone, DMSO, 1,4-dioxane, sparingly soluble in dichloromethane, acetonitrile, toluene, chloroform, and insoluble in alkanes and water. Stable when stored under normal conditions.

[0093] IR spectrum taken as a paste in vaseline oil: 3166, 1796, 1715, 1671 cm -1 .

[0094] NMR spectrum 1 H (400 MHz, DMSO-d6, δ, ppm): 2.06 s (3H, Me), 6.63 d (1H аром , J 7.8 Hz), 6.80-6.87 m (2H аром ), 7.44-7.51 m (2N аром ), 7.55-7.67 m (5N аром ), 7.76-7.80 M (2N аром ), 7.88-7.92 M (Ball), 7.94-7.98 M (1H аром ), 9.60 us.s (1H, OH фенол ). The hydrogen atom of the enol hydroxyl group is not visible due to strong broadening. NMR spectrum 13 C (100 MHz, DMSO-d6, δ, ppm): 20.2 (Me), 70.5 (C 5 спиро), 116.9, 117.6, 118.2, 119.2, 121.1, 121.5, 122.0, 124.3, 127.6, 128.1, 128.3, 128.7(2С), 128.8, 129.1, 129.4(2С), 131.2, 133.6, 135.1, 137.4, 150.6, 152.0, 154.1, 166.0, 174.0, 189.0 (COAr).

[0095] Example 10. Preparation of 3'-benzoyl-4'-hydroxy-1'-(2-hydroxyphenyl)-2H-spiro[naphtho[2,1-b]furan-1,2'-pyrrole]-2,5'(1'H)-dione (3a).

[0096] 1.0 mmol of 2-naphthol was added to a solution of 1.0 mmol of pyrroledione (1a) in 5 ml of anhydrous toluene. The reaction mixture was refluxed for 1-2 hours (until the violet color of the starting compound 1a disappeared), and the formed precipitate was filtered off. Yield 68%, mp 252-254°C (decomp.).

[0097] Connection (Z3a) C 28 H 17 NO6.

[0098] Found, %: C 72.57; H 3.71; N 3.00.

[0099] Calculated, %: C 72.57; H 3.70; N 3.02.

[0100] Compound (3a) is a yellow crystalline solid, readily soluble in acetone, DMSO, and 1,4-dioxane; sparingly soluble in dichloromethane, acetonitrile, toluene, and chloroform; insoluble in alkanes and water. Stable when stored under normal conditions.

[0101] IR spectrum taken as a paste in vaseline oil: 3165, 1820, 1705, 1665 cm -1 .

[0102] NMR spectrum 1 H (400 MHz, DMSO-d6, δ, ppm): 6.57 t (1H apом , J 7.6 Hz), 6.70 d.d (1H арром , J 8.3, 1.0 Hz), 6.82 d.d (1H аром , J 7.8, 1.5 Hz), 6.95-7.04 m (1H аром ), 7.37-7.49 m (4N аром ), 7.52-7.59 m (1N аром ), 7.63 t.d (1H apом , J 7.6, 1.0 Hz), 7.72-7.78 m (2H ар ohm), 7.88 d (W а rum, J 8.3 Hz), 8.00 d (1H аром , J 8.8 Hz), 7.97 d (1H аром , J 8.8 Hz), 9.81 br.s (1H, OH фенол ). The hydrogen atom of the enol hydroxyl group is not visible due to strong broadening. NMR spectrum 13C (100 MHz, DMSO-d6, δ, ppm): 69.4 (C 5 спирор ), 111.4, 113.9, 116.3, 118.1, 118.6, 121.1, 122.2, 124.9, 127.8, 127.9, 128.2(2С), 128.8(2С), 128.9, 129.0, 129.6, 130.3, 132.7, 133.0, 136.6, 152.7, 153.6, 153.7, 164.9, 173.1, 188.2 (COAr).

[0103] Example 11. Preparation of 4'-hydroxy-1'-(2-hydroxyphenyl)-3'-(4-chlorobenzoyl)-2H-spiro[naphtho[2,1-b]furan-1,2'-pyrrole]-2,5'(1'H)-Dione (3b).

[0104] 1.0 mmol of 2-naphthol was added to a solution of 1.0 mmol of pyrroledione (1b) in 5 ml of anhydrous toluene. The reaction mixture was refluxed for 1-2 hours (until the violet color of the starting compound 1b disappeared), and the formed precipitate was filtered off. Yield 72%, mp 261-262°C (decomp.).

[0105] Connection (3b) C 28 H 16 ClNO6.

[0106] Found, %: C 67.59; H 3.26; N 2.83.

[0107] Calculated, %: C 67.55; H 3.24; N 2.81.

[0108] Compound (36) is a yellow crystalline substance, readily soluble in acetone, DMSO, 1,4-dioxane, sparingly soluble in dichloromethane, acetonitrile, toluene, chloroform, insoluble in alkanes and water. Stable when stored under normal conditions.

[0109] IR spectrum taken as a paste in vaseline oil: 3313, 1814, 1708, 1678 cm -1 .

[0110] NMR spectrum 1 H (400 MHz, DMSO-d6, δ, ppm): 6.57 t (1H аром , J 7.6 Hz), 6.69 d.d (1H аром , J 8.1, 1.2 Hz), 6.80 d.d (1H аром , J 8.1, 1.2 Hz), 6.95-7.03 m (1H аром ), 7.37-7.47 m (2N аром ), 7.52 d (2N аром , J 8.3 Hz), 7.57-7.64 m (1H apом ), 7.73-7.79 m (2N аром ), 7.88 d (1H аром , J 8.3 Hz), 7.94-8.02 m (2H аром ), 9.81 units (1H, OH фенол ). The hydrogen atom of the enol hydroxyl group is not visible due to strong broadening. NMR spectrum 13 C (100 MHz, DMSO-d6, δ, ppm): 69.3 (C 5 спиро), 111.4, 113.9, 116.3, 117.6, 118.6, 121.1, 122.2, 124.9, 127.8, 127.9, 128.3(2С), 128.9, 129.0, 129.6, 130.3, 130.6(2С), 132.7, 135.3, 137.9, 152.7, 153.7, 154.3, 164.8, 173.1, 186.9 (COAr).

[0111] Example 12. Preparation of 3'-(4-bromobenzoyl)-4'-hydroxy-1'-(2-hydroxyphenyl)-2H-spiro[naphtho[2,1 -b]furan-1,2'-pyrrole]-2,5'(1'H)-Dione (3c).

[0112] 1.0 mmol of 2-naphthol was added to a solution of 1.0 mmol of pyrroledione (1c) in 5 ml of anhydrous toluene. The reaction mixture was refluxed for 1-2 hours (until the violet color of the starting compound 1c disappeared), and the formed precipitate was filtered off. Yield 68%, mp 257-260°C (decomp.).

[0113] Connection (3v) C 28 H 16 BrNO6.

[0114] Found, %: C 62.04; H 2.95; N 2.56.

[0115] Calculated, %: From 62.01; H 2.97; N 2.58.

[0116] Compound (3b) is a yellow crystalline solid, readily soluble in acetone, DMSO, and 1,4-dioxane; sparingly soluble in dichloromethane, acetonitrile, toluene, and chloroform; insoluble in alkanes and water. Stable when stored under normal conditions.

[0117] IR spectrum taken as a paste in vaseline oil: 3311, 1814, 1706, 1667 cm -1 .

[0118] NMR spectrum 1 H (400 MHz, DMSO-d6, δ, ppm): 6.53-6.60 m (1H аром ), 6.69 D.D (1N аром , J 8.3, 1.0 Hz), 6.80 d.d (1H аром , J 7.8, 1.5 Hz), 6.95-7.03 m (1N аром ), 7.38-7.46 m (2N аром ), 7.61 t.d (1N аром , J 7.8, 1.0 Hz), 7.64-7.71 m (4H аром ), 7.88 d (1N аром , J 8.3 Hz), 7.97 d.d (2H аром , J 8.6, 4.6 Hz), 9.80 us.s (1H, OH фенол ). The hydrogen atom of the enol hydroxyl group is not visible due to strong broadening. NMR spectrum 13 C (100 MHz, DMSO-d6, δ, ppm): 69.3 (C 5 спиро), 111.4, 113.9, 116.3, 117.5, 118.6, 121.1, 122.2, 124.9, 126.9, 127.8, 127.9, 128.9, 129.0, 129.6, 130.3, 130.7(2C), 131.3(2С), 132.7, 135.6, 152.7, 153.7, 154.4, 164.9, 173.1, 187.0 (COAr).

[0119] Example 13. Preparation of 4'-hydroxy-1'-(2-hydroxyphenyl)-3'-(4-methylbenzoyl)-2H-spiro[naphtho[2,1-b]furan-1,2'-pyrrole]-2,5'(1'H)-dione (3 g).

[0120] 1.0 mmol of 2-naphthol was added to a solution of 1.0 mmol of pyrroledione (1 g) in 5 ml of anhydrous toluene. The reaction mixture was refluxed for 1-2 hours (until the violet color of the starting compound (1 g) disappeared), and the formed precipitate was filtered off. Yield 75%, mp 258-259°C (decomp.).

[0121] Compound (3g) C 29 H 19 NO6.

[0122] Found, %: C 72.91; H 3.99; N 2.94.

[0123] Calculated, %: C 72.95; H 4.01; N 2.93.

[0124] Compound (3g) is a yellow crystalline substance, readily soluble in acetone, DMSO, and 1,4-dioxane; sparingly soluble in dichloromethane, acetonitrile, toluene, and chloroform; insoluble in alkanes and water. Stable when stored under normal conditions.

[0125] IR spectrum taken as a paste in vaseline oil: 3184, 1814, 1705, 16566 cm -1 .

[0126] NMR spectrum 1 H (400 MHz, DMSO-d6, δ, ppm): 2.32 s (3H, Me), 6.54-6.61 m (1H аром ), 6.70 d.d (1N аром , J 8.3, 1.0 Hz), 6.82 d.d (1H аром , J 7.8, 1.5 Hz), 6.96-7.02 m (1Harom), 7.24 d (2H аром , J 7.8 Hz), 7.40 t (1N аром , J 7.6 Hz), 7.44 d (1H аром , J 8.8 Hz), 7.58-7.64 m (1H аром ), 7.66 d (2N аром , J 8.3 Hz), 7.87 d (1H аром , J 8.3 Hz), 7.99 d (1H аром , J 8.8 Hz), 7.96 d (1H аром , J 9.3 Hz), 9.80 us.s (1H, OH фенол ), 12.48 us (1H, OH енол ). NMR spectrum 13C (100 MHz, DMSO-d6, δ, ppm): 21.6 (Me), 70.1 (C 5 спиро ), 112.0, 114.5, 116.9, 119.0, 119.2, 121.8, 122.8, 125.4, 128.4, 128.4, 129.3(2С), 129.5, 129.6(2С), 129.6, 130.2, 130.9, 133.2, 134.5, 144.2, 153.3, 153.5, 154.3, 165.6, 173.7, 188.3 (COAr).

[0127] Example 14. Preparation of 4'-hydroxy1'(2-hydroxyphenyl)-3'-(4-methoxybenzoyl)-2H-spiro[naphtho[2,1-b]furan-1,2'-pyrrole]-2,5'(1'H)-dione (3d).

[0128] 1.0 mmol of 2-naphthol was added to a solution of 1.0 mmol of pyrroledione (1e) in 5 ml of anhydrous toluene. The reaction mixture was refluxed for 1-2 hours (until the violet color of the starting compound 1e disappeared), and the formed precipitate was filtered off. Yield 88%, mp 255-257°C (decomp.).

[0129] Connection (3d) C 29 H 19 NO7.

[0130] Found, %: C 70.64; H 3.85; N 2.86.

[0131] Calculated, %: C 70.59; H 3.88; N 2.84.

[0132] Compound (3d) is a yellow crystalline substance, readily soluble in acetone, DMSO, and 1,4-dioxane; sparingly soluble in dichloromethane, acetonitrile, toluene, and chloroform; insoluble in alkanes and water. Stable when stored under normal conditions.

[0133] IR spectrum taken as a paste in vaseline oil: 3433, 1789, 1716, 1673 cm -1 .

[0134] NMR spectrum 1 H (400 MHz, DMSO-d 6 , δ, ppm): 3.80 s (3H, OMe), 6.53-

[0135] 6.61 M (1N аром ), 6.69 D.D. (Sharom, J 8.1, 1.2 Hz), 6.81 d.d. (1H аром , J 7.8, 1.5 Hz),

[0136] 6.93-7.02 m (3N аром ), 7.36-7.47 m (2N аром ), 7.56-7.63 m (1H а rum), 7.73-7.79 m (2H аром ), 7.87 d (1H аром , J 8.3 Hz), 7.96 d.d (2H аром , J 8.3, 4.9 Hz), 9.78 us.s (1H, OH фенол ), 12.75 br.s (1H, ONenol). NMR spectrum 13 С (100 MHz, DMSO-d6, δ, ppm): 55.4(ОМе), 69.5 (С 5 спиро), 111.4, P3.5(2S), 114.0, 116.3, 118.6, 118.7, 121.2, 122.3, 124.8, 127.8(2S), 128.9, 129.0, 129.1, 129.5, 130.2, 131.3(2С), 132.6, 152.3, 152.7, 153.7, 163.3, 165.0, 173.1, 186.5 (COAr).

[0137] Example 15. Preparation of 4'-hydroxy-1'-(2-hydroxyphenyl)-3'-(4-fluorobenzoyl)-2H-spiro[naphtho[2,1-b]furan-1,2'-pyrrole]-2,5'(1'H)-Dione (3e).

[0138] 1.0 mmol of 2-naphthol was added to a solution of 1.0 mmol of pyrroledione (1e) in 5 ml of anhydrous toluene. The reaction mixture was refluxed for 1-2 hours (until the violet color of the starting compound 1e disappeared), and the formed precipitate was filtered off. Yield 68%, mp 255-258°C (decomp.).

[0139] Connection (3e) C 28 H 16 FNO6.

[0140] Found, %: C 69.87; H 3.35; N 2.92.

[0141] Calculated, %: C 69.85; H 3.35; N 2.90.

[0142] Compound (3e) is a yellow crystalline solid, readily soluble in acetone, DMSO, and 1,4-dioxane; sparingly soluble in dichloromethane, acetonitrile, toluene, and chloroform; insoluble in alkanes and water. Stable when stored under normal conditions.

[0143] IR spectrum taken as a paste in vaseline oil: 3177, 1820, 1715, 1665 cm -1 .

[0144] NMR spectrum 1 H (400 MHz, DMSO-d6, δ, ppm): 6.57 t (1H аром , J 7.6 Hz), 6.70 d (1H аром , J 7.8 Hz), 6.77-6.85 m (1N аром ), 6.94-7.03 m (1N аром ), 7.27 t (2N аром , J 8.8 Hz), 7.36-7.48 m (2H apoм ), 7.61 t (1H аром , J 7.6 Hz), 7.78-7.92 m (3H аром ), 7.93-8.05 m (2N аром ), 9.80 us.s (1H, OH фенол ). The hydrogen atom of the enol hydroxyl group is not visible due to strong broadening. NMR spectrum 13 C (100 MHz, DMSO-d6.5, ppm): 69.4 (C 5 спиро), 111.4, 113.9, 115.2 d (2С, J 22.3 Hz), 116.3, 117.8, 118.6, 121.1, 122.3, 124.8, 127.8, 127.9, 129.0, 129.0, 129.6, 130.3, 131.8 d (2С, J 9.2 Hz), 132.6, 133.2 d (J 3.1 Hz), 152.7, 153.7, 153.8, 164.8 d(С аромF ,J 252 Hz), 164.9, 173.1, 186.6 (COAr).

[0145] Example 16. Preparation of 3'-benzoyl-4'-hydroxy-1'-(2-hydroxy-5-chlorophenyl)-2H-spiro[naphtho[2,1-b]furan-1,2'-pyrrole]-2,5 , (1'H)-dione (3g).

[0146] 1.0 mmol of 2-naphthol was added to a solution of 1.0 mmol of pyrroledione (1g) in 5 ml of anhydrous toluene. The reaction mixture was refluxed for 1-2 hours (until the violet color of the starting compound 1g disappeared), and the formed precipitate was filtered off. Yield 85%, mp 266-268°C (decomp.).

[0147] Connection (3g) C 28 H 16 ClNO6.

[0148] Found, %: C 67.56; H 3.24; N 2.81.

[0149] Calculated, %: C 67.55; H 3.24; N 2.81.

[0150] Compound (3g) is a light yellow crystalline substance, readily soluble in acetone, DMSO, and 1,4-dioxane; sparingly soluble in dichloromethane, acetonitrile, toluene, and chloroform; insoluble in alkanes and water. Stable when stored under normal conditions.

[0151] IR spectrum taken as a paste in vaseline oil: 3183, 1782, 1719, 1682 cm -1 .

[0152] NMR spectrum 1 H (400 MHz, DMSO-d6, δ, ppm): 6.70 d (1H аром , J 8.8 Hz), 6.87 d (1H аром , J 2.4 Hz), 7.04 d.d (1H aом , J 8.8, 2.4 Hz), 7.37-7.52 m (4H аром ), 7.52-7.59 m (W аром ), 7.63 t (1N аром , J 7.6 Hz), 7.75 d (2H аром , J 7.3 Hz), 7.89 d (1H аром , J 8.3 Hz), 8.00 d.d (2H аром , J 8.6, 4.2 Hz), 10.25 us.s (1H, OH фенол ). The hydrogen atom of the enol hydroxyl group is not visible due to strong broadening. NMR spectrum 13 C (100 MHz, DMSO-d6, δ, ppm): 69.3 (C 5 спиро), 111.4, 113.6, 117.6, 118.3, 121.3, 122.2, 122.3, 124.9, 127.7, 128.0, 128.2(2С), 128.8, 128.8(2С), 129.1, 129.3, 130.2, 132.8, 133.0, 136.5, 152.8, 152.8, 153.5, 165.2, 173.0, 188.2 (COAr).

[0153] Example 17. Preparation of 3'-(benzoyl)1'(5-bromo-2-hydroxyphenyl)-4'-hydroxy-2H-spiro[naphtho[2,1-b]furan-1,2'-pyrrole]-2,5'(1'H)-dione (3z).

[0154] 1.0 mmol of 2-naphthol was added to a solution of 1.0 mmol of pyrroledione (1h) in 5 ml of anhydrous toluene. The reaction mixture was refluxed for 1-2 hours (until the violet color of the starting compound 1h disappeared), and the formed precipitate was filtered off. Yield 74%, mp 281-285°C (decomp.).

[0155] Connection (3z) C 28 N 16 B rNO6.

[0156] Found, %: C 62.08; H 2.99; N 2.57.

[0157] Calculated, %: From 62.01; H 2.97; N 2.58.

[0158] Compound (3z) is a light yellow crystalline substance, readily soluble in acetone, DMSO, 1,4-dioxane, sparingly soluble in dichloromethane, acetonitrile, toluene, chloroform, and insoluble in alkanes and water. Stable when stored under normal conditions.

[0159] IR spectrum taken as a paste in vaseline oil: 3330, 1781, 1719, 1679 cm -1 .

[0160] NMR spectrum 1 H (400 MHz, DMSO-d6, δ, ppm): 6.65 d (1H аром , J 8.8 Hz), 6.99 d (1H аром , J 2.4 Hz), 7.15 d.d (1H аром , J 8.8, 2.4 Hz), 7.38-7.51 m (4H аром ), 7.52-7.59 m (1H аром ), 7.60-7.66 m (1H apом ), 7.72-7.80 m (2N аром ), 7.89 d (1H apом , J 8.3 Hz), 8.00 d.d (2H аром , J 8.6, 3.7 Hz), 10.27 br.s (1H, OH фенол ). The hydrogen atom of the enol hydroxyl group is not visible due to strong broadening. NMR spectrum 13 C (100 MHz, DMSO-d6, δ, ppm): 69.3 (C 5 спиро), 108.4, 111.4, 113.5, 118.1, 118.3, 122.2, 122.7, 124.9, 128.0, 128.2(2С), 128.8, 128.8(2С), 129.1, 130.2, 130.6, 132.2, 132.8, 133.0, 136.5, 152.8, 153.3, 153.4, 165.2, 173.0, 188.2 (COAr).

[0161] Example 18. Preparation of 3'-benzoyl-4'-hydroxy-1'-(2-hydroxy-5-methylphenyl)-2H-spiro[naphtho[2,1-b]furan-1,2'-pyrrole]-2,5'(1'H)-Dione (3i).

[0162] 1.0 mmol of 2-naphthol was added to a solution of 1.0 mmol of pyrroledione (1i) in 5 ml of anhydrous toluene. The reaction mixture was refluxed for 1-2 hours (until the violet color of the starting compound 1i disappeared), and the formed precipitate was filtered off. Yield 78%, mp 268-269°C (decomp.).

[0163] Connection (3i) C29H 19 NO6.

[0164] Found, %: C 72.97.76; H 4.04; N 2.92.

[0165] Calculated, %: C 72.95; H 4.01; N 2.93.

[0166] Compound (3i) is a yellow crystalline substance, readily soluble in acetone, DMSO, 1,4-dioxane, sparingly soluble in dichloromethane, acetonitrile, toluene, chloroform, and insoluble in alkanes and water. Stable when stored under normal conditions.

[0167] IR spectrum taken as a paste in vaseline oil: 3159, 1783, 1717, 1673 cm -1 .

[0168] NMR spectrum 1 H (400 MHz, DMSO-d6, δ, ppm): 1.95 s (3H, Me), 6.58 d (1H аром , J 8.3 Hz), 6.62-6.67 m (1H аром ), 6.80 d.d (1H аром , J 8.3, 2.0 Hz), 7.37-7.48 m (4H аром ), 7.52-7.59 m (1H аром ), 7.62 t.d (1H аром , J 7.8, 1.0 Hz), 7.71-7.78 m (2H аром ), 7.87 d (1H аром , J 8.3 Hz), 8.00 d (1H аром , J 8.3 Hz), 7.96 d (1H аром , J 8.8 Hz), 9.52 br.s (1H, OH фенол ). The hydrogen atom of the enol hydroxyl group is not visible due to strong broadening. NMR spectrum 13 C (100 MHz, DMSO-d6, δ, ppm): 19.6 (Me), 69.5 (C 5спиро ), 111.4, 114.0, 116.1, 118.1, 120.8, 122.4, 124.9, 127.2, 127.7, 128.0, 128.2(2С), 128.8(2С), 129.0, 129.0, 130.1, 130.3, 132.6, 133.0, 136.6, 151.4, 152.7, 153.6, 164.9, 173.2, 188.2 (COAr).

[0169] Example 19. Preparation of 3'-benzoyl-4',8-dihydroxy1'(2-hydroxyphenyl)-2H-spiro[naphtho[1,2-b]furan-3,2'-pyrrole]-2,5'(1'H)-dione (3k).

[0170] 1.0 mmol of 2,7-dihydroxynaphthalene was added to a solution of 1.0 mmol of pyrroledione (1a) in 5 ml of anhydrous toluene. The reaction mixture was refluxed for 1-2 hours (until the violet color of the starting compound 1a disappeared), and the formed precipitate was filtered off. Yield 61%, mp 259-260°C (decomp.).

[0171] Connection (3k) C 28 H 17 NO7.

[0172] Found, %: C 70.13; H 3.58; N 2.94.

[0173] Calculated, %: C 70.15; H 3.57; N 2.92.

[0174] Compound (3k) is a light yellow crystalline substance, readily soluble in acetone, DMSO, and 1,4-dioxane; sparingly soluble in dichloromethane, acetonitrile, toluene, and chloroform; insoluble in alkanes and water. Stable when stored under normal conditions.

[0175] IR spectrum taken as a paste in vaseline oil: 3407, 3358, 1785, 1690, 1666 cm -1 .

[0176] NMR spectrum 1 H (400 MHz, DMSO-d6, δ, ppm): 6.52-6.60 m (1H), 6.73 d.d (1H, J 8.2, 1.2 Hz), 6.77 d.d (1H, J 7.9, 1.5 Hz), 6.91 d.d (1H, J 8.9, 2.4 Hz), 7.00 m (1H), 7.14 d (1H, J 8.7 Hz), 7.27 d (1H, J 2.3 Hz), 7.42-7.49 m (2H), 7.57 t.t (1H, J 7.5, 1.2 Hz), 7.70 d (1H, J 9.0 Hz), 7.76-7.84 m (3H), 9.86 br.s (1H, HE фенол ), 10.24 units (1H, OH фенол ), 12.81 units (1H, OH енол ). The hydrogen atom of the enol hydroxyl group is not visible due to strong broadening. NMR spectrum 13 C (100 MHz, DMSO-d6, δ, ppm): 69.4 (C 5 спиро), 103.6, 107.6, 111.8, 116.3, 117.5, 117.9, 118.5, 121.1, 124.9, 127.9, 128.1 (2С), 128.9 (2С), 129.5, 130.8 (2С), 132.2, 133.0, 136.6, 153.1, 153.3, 153.8, 157.0, 165.0, 173.0, 188.3 (COPh).

[0177] Example 20. Pharmacological study of 3'-aroyl-4'-hydroxy-1'-(2-hydroxyaryl)-2H-spiro[naphtho[1,2-b]furan-3,2'-pyrrole]-2,5'(1'H)-diones (2a-z), 3'-aroyl-4'-hydroxy-1'-(2-hydroxyaryl)-2H-spiro[naphtho[2,1-b]furan-1,2'-pyrrole]-2,5'(1'H)-diones (3a-z) and 3'-benzoyl-4',8-dihydroxy-1'-(2-hydroxyphenyl)-2H-spiro[naphtho[1,2-b]furan-3,2'-pyrrole]-2,5'(1'H)-dione for antimicrobial activity (3k).

[0178] The antimicrobial properties of chemicals were studied on 3 collection opportunistic strains of microorganisms: Staphylococcus aureus (ATCC 25923), Escherichia coli (ATCC 25922), Candida albicans (РКПГУ 1353 / 1277).

[0179] The antimicrobial activity was determined by the method of two-fold serial dilutions in accordance with the guidelines for studying the antimicrobial activity of drugs [Khabriev R.U. Guide to the experimental (preclinical) study of new pharmacological substances. - M.: I-vo Meditsina, 2005. - 832 p.]. Initial dilutions of microorganisms were prepared in a physiological solution from a daily agar culture according to the optical turbidity standard (OTS) of 5 IU using a densitometer. After a series of dilutions, the final cell concentration in the experiment was 2.5×10 5cells / ml. Two parallel rows of two-fold serial dilutions of chemical compounds in RPB broth were prepared in the wells of a sterile 96-well flat-bottomed microplate. Each well contained 150 μl of a specified concentration of the test substance and 150 μl of the culture inoculum. The last rows contained the nutrient medium and the culture in equal volumes (control). The maximum tested concentration corresponded to 1000.0 μg / ml, the minimum - 1.0 μg / ml. The microplate was placed in an Epoch spectrophotometer thermostat, and the optical density (OD) was measured at a wavelength of 540 nm. After 24 hours and 7 days, the OD of the culture fluid was again recorded.

[0180] The results were evaluated using the Gen 5 software of the Epoch microplate reader. The last well of the row with growth inhibition and OD values ​​equal to the control well corresponds to the minimum inhibitory concentration of the compound.

[0181] The studies conducted showed (see Table 1) that compounds (2a-z, 3a-g, e-z, j) exhibit selective antimicrobial activity against the gram-positive bacteria Staphylococcus aureus. Most compounds exhibit inhibitory activity at a concentration of 62.5 μg / ml, while bactericidal activity is observed at a concentration of 125 μg / ml.

[0182]

[0183] Example 21. Study of growth-regulating activity of 3'-aroyl-4'-hydroxy-1'-(2-hydroxyaryl)-2H-spiro[naphtho[1,2-b]furan-3,2'-pyrrole]-2,5'(1'H)-diones (2a-d,g,i), 3'-aroyl-4'-hydroxy-1'-(2-hydroxyaryl)-2H-spiro[naphtho[2,1-b]furan-1,2'-pyrrole]-2,5'(1'H)-diones (3a,b,d,f,i) and 3'-benzoyl-4',8-dihydroxy-1'-(2-hydroxyphenyl)-2H-spiro[naphtho[1,2-b]furan-3,2'-pyrrole]-2,5'(1'H)-dione (3k).

[0184] Growth-regulating activity was studied using Chlorella vulgaris microalgae cultures. Compound activity was measured by comparing the algal cell concentration in the test cultures with that of a negative control (DMSO). Cell concentration was assessed spectrophotometrically. Growth medium supplemented with glucose served as a positive control.

[0185] Microalgae cells (strain IMBR-19, obtained from A.O. Kovalevsky Institute of Biology of the Southern Seas, Russian Academy of Sciences, Sevastopol, Russia) were grown in BG-11 medium [E. Touloupakis, G. Tartari, G.C. Zittelli, G. Torzillo / Growth and photo synthetic performance of Cmamydopodium fusi-forme cells cultivated in BG11 and Bristol media / / J. Appl. Phycol. - 2020. - Vol. 32. - №1. - 145-152. DOI: 10.1007 / s10811-019-01900-у] under aseptic conditions. The only exception was the use of DMSO solutions of the studied compounds, which were not sterilized after dilution.

[0186] BG-11 medium, C. vulgaris seed culture, and DMSO solutions of the test compounds were added to 96-well plates to a final volume of 300 µl per well. The initial cell density was 5 × 10 4 cells / well, and the final DMSO concentration in all wells was 1% (v / v). An equivalent volume of DMSO without the test compounds was added to the negative control wells, and BG-11 medium supplemented with 2 g / L glucose and DMSO was added to the positive control wells. For each concentration of each substance, testing was performed in two wells. Control samples were tested in 6 wells each. To reduce edge effects, sterile distilled water was added to all edge and corner wells of the plates. The plates were covered with a sterile lid, which ensured sufficient gas exchange.

[0187] The cultures were incubated for five days in a humidified chamber at 28°C with orbital shaking at 150 rpm. Illumination was carried out on a 12-h light: 12-h dark cycle at an intensity of 100 μmol m-2 With -1 The cells were illuminated using evenly spaced white LEDs placed beneath the plates. The lighting system was equipped with a cooling mechanism to prevent the plates from heating up. After incubation, the contents of each well were thoroughly mixed using a multichannel pipette to obtain a homogeneous cell suspension.

[0188] Cell concentration was estimated by optical density at 750 nm (OD750) using a microplate spectrophotometer [M. Chioccioli, B. Hankamer, I. L. Ross / Flow cytometry pulse width data enables rapid and sensitive estimation of biomass dry weight in the microalgae Chlamydomonas reinhardtii and Chlorella vulgaris II PloS One - 2014. - Vol.9. -№5. - e97269. DOI: 10.1371 / journal.pone.0097269]. To identify substances with growth-promoting activity, a threshold optical density value was set that had to be exceeded. It was equal to the average OD750 of the negative control plus three standard deviations.

[0189] Most of the tested compounds inhibit the growth of C. vulgaris (see Table 2). The increase in optical density in the presence of compound 26 at a concentration of 0.1 μmol / L is statistically insignificant, as it does not exceed the mean value of the negative control plus three standard deviations.

[0190]

[0191] The claimed 3'-aroyl-4'-hydroxy1'(2-hydroxyaryl)-2H-spiro[naphthofuran-pyrrole]-2,5'(1'H)-diones, which have not been previously described in the literature and exhibit antimicrobial and growth-regulating activity, can find application as starting materials for the synthesis of heterocyclic systems and in pharmacology as potential drugs with antimicrobial properties.

Images