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Communication

Synthesis of Novel Thiazoles Based on (+)-Usnic Acid

by
Aleksandr S. Filimonov
*,
Olga A. Luzina
and
Nariman F. Salakhutdinov
N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 9, Lavrentieva Ave., 630090 Novosibirsk, Russia
*
Author to whom correspondence should be addressed.
Molbank 2024, 2024(4), M1894; https://doi.org/10.3390/M1894
Submission received: 12 August 2024 / Revised: 30 September 2024 / Accepted: 2 October 2024 / Published: 3 October 2024

Abstract

:
A series of usnic acid derivatives containing a thiazole ring with an amide substituent were synthesized. The convenient method for synthesis of these compounds is a reaction of 14-bromousnic acid with N-acylthioureas. Acylation of aminothiazole does not lead to the targeted compound.

1. Introduction

(+)-Usnic acid 1 (Figure 1) is an accessible metabolite of lichens. Its biological activity is very diverse and is of interest for pharmaceuticals. Its wide distribution in various types of lichens, the simplicity of the isolation procedure from plant materials, and the high optical purity of the extracted compound draw the attention of researchers as a basis for the development of new pharmacological agents [1]. Usnic acid derivatives containing thiazole fragments in ring A exhibit a wide range of biological activities; in particular, those containing an aminothiazole substituent (compound 2) exhibit antimycobacterial properties [2], and hydrazonothiazoles (compounds 3 and 4) exhibit antiviral activity [3] and enhance the cytostatic efficiency in anticancer therapy [4] (Figure 1).
However, the hydrazone structural fragment of compounds 3 and 4 is an undesirable structural element, since it belongs to common pan-assay interference compounds (PAINS) [5]. PAINS are chemical compounds that often give false positive results in high-throughput screens [6]. PAINS tend to react nonspecifically with numerous biological targets rather than specifically affecting one desired target.
The goal of this work was the synthesis of an analog of compounds 3 and 4 containing thiazole and aryl(hetaryl) substituents connected not by a hydrazone but by an amide linker. Such a functional group is poorly reactive and resistant to hydrolysis. In addition, the presence of an electronegative nitrogen atom, as well as an oxygen atom, capable of forming hydrogen bonds, determines the use of the amide structural motif for the creation of protein-targeted drugs. Amides commonly occur in drugs, and have both basic and acidic possibilities. However, their basic pKa values are very low, and their acidic pKa values are very high, and, unless affected by substitution, they are always unionized at physiological pH [7]. Amides are commonly used in biologically active compounds, with a broad variety of biotechnological, agricultural, and medical applications. Amides and their derivatives are associated with a broad range of biological activities, including anticonvulsant, antitubercular, antimicrobial, analgesic and anti-inflammatory, insecticidal, antitumor, fibrinolytic, and antiplatelet aggregator activities [8,9,10,11,12,13,14]. Amide bonds are well known in biological and natural pathways. Amides are one of the most essential functionalities of anticonvulsant drugs in chemical building blocks [15].

2. Results and Discussion

The usnic acid derivative with an aminothiazole fragment 6 (Scheme 1), which was obtained according to the method described in work [2], is a convenient starting material for the synthesis of usnic acid derivatives, with a thiazole ring with amide linker 5. However, the acylation reaction of usnic acid derivative 6 with benzoyl chloride in the presence of triethylamine did not lead to the production of the target derivative 5. As a result of this reaction, the mixture of initial reagents was isolated (Scheme 1). This may be due to the fact that the amino group of derivative 6 was deactivated. The electron pair of the amino group is conjugated to the 4-phenylthizole π-system.
Since this approach did not lead to the desired result, a series of compounds 5ae with a variation in the type of substituent at the carbonyl atom of the amide fragment were prepared, starting from 14-bromousnic acid 7 and the corresponding acylthiourea. For this purpose, at the first step, a series of monoacylated thioureas 8ae was synthesized (Scheme 2). The synthesis was carried out starting from freshly prepared acyl chlorides, which were introduced into the reaction with sodium thiocyanate, followed by formation of acylisothiocyanate. This fact is consistent with the hard and soft Lewis acids and bases theory: the carbon atom of the acyl group is a hard acid and the nitrogen atom of the thiocyanate anion is a hard base. The resulting intermediate is then reacted with aqueous ammonia. The last step involves the attack of the ammonia nitrogen atom on the carbon atom of the isothiocyanate group. As a result of this reaction, compounds 8ae were isolated with 28–40% yields. Bromousnic acid 7 was synthesized by the reaction of usnic acid with two equivalents of bromine in dioxane [3,4]. The resulting acylthioureas 8ae were reacted with the usnic acid derivative 7 in methanol, as a result of which the target compounds 5ae were isolated with a yield of 80–92% (Scheme 2). Structure of compounds 5a-e had been confirmed using 1H and 13C NMR and mass spectroscopy (see Supplementary Materials).

3. Materials and Methods

The analytical and spectral studies were conducted at the Chemical Service Center for the collective use of the Siberian Branch of the Russian Academy of Science.
The 1H and 13C-NMR spectra for solutions of the compound in CDCl3 or DMSO-d6 were recorded on a Bruker AV-400 spectrometer (Bruker Corporation, Karlsruhe, Germany; operating frequencies 400.13 MHz for 1H and 100.61, for 13C). The residual signals of the solvent were used as references (δH 2.50, δC 39.52 for DMSO-d6, δH 7.24, δC 76.90 for CDCl3). The mass spectra (ionizing-electron energy 70 eV) were recorded on a DFS Thermo Scientific high-resolution mass spectrometer (Thermo Fisher Scientific, Waltham, MA, USA). Electron impact ionization was used in the measurement of mass spectra. Thin-layer chromatography was performed on TLC Silica gel 60F254 (Merck KGaA, Darmstadt, Germany). Synthetic starting materials and reagents were acquired from Reachem (Moscow, Russia). (+)-Usnic acid was obtained from Zhejiang Yixin Pharmaceutical Co., Ltd., (Lanxi, China). All chemicals were used as described unless otherwise noted.
The atom numbers in the compound provided for the assignment of signals in the NMR spectra correspond to the traditional numeration for usnic acid.
The synthesis of the bromo-substituted derivatives for 7 was performed by reaction of usnic acid with bromine in dioxane [3].

The Synthesis of Compounds 5ae

(A)
A total of 1 mmol of carboxylic acid was placed in a flask with a solution of oxalyl chloride in methylene chloride (2 mmol in 2 mL). A few drops of DMF were added to the mixture and left to be stirred at room temperature for one hour. Afterwards, the solvent was removed using a rotary evaporator. The resulting mixture was dissolved in 10 mL of acetone, and the solution was heated to 50 °C. Sodium thiocyanate (1 mmol) was added to the solution. After 15 min, the solution was cooled, and the precipitate that formed (sodium chloride) was filtered off. The resulting solution was evaporated on a rotary evaporator. An aqueous solution of ammonia (120 µL, 30% in water) was added to the resulting mixture and left to be stirred for 30 min. The precipitate that formed was filtered off, washed with water, and dried in air.
(B)
A total of 1 mmol of bromousnic acid 7 was dissolved in 35 mL of methanol. The corresponding acylthiourea 8ae (1 mmol) was added to the solution. The solution was stirred for 1 h. Then, the solution was diluted with water, and the precipitate that formed was filtered, washed with water and dried in air.
(R)-N-(4-(8-acetyl-1,3,7-trihydroxy-2,9a-dimethyl-9-oxo-9,9a-dihydrodibenzo[b,d] furan-4-yl)thiazol-2-yl)benzamide (5a).
Yellow amorphous powder. Yield: 95%. 1H NMR (CDCl3, δ): 1.76 (3H, s, H-15), 2.10 (3H, s, H-10), 2.67 (3H, s, H-12), 5.96 (1H, s, H-4), 7.48 (3H, m, H-20 and H-14), 7.60 (1H, m, H-21), 7.35 (1H, d, J = 7.35, H-14), 9.92 (1H, s, NH), 10.30 (1H, s, OH-9), 12.27 (1H, bs, OH-7), 18.82 (1H, s, OH-3). 13C NMR (CDCl3, δ): 8.18 (C-10), 27.74 (C-15), 32.03 (C-12), 59.29 (C-9b), 96.85 (C-9a), 97.41 (C-4), 103.51 (C-6), 105.11 (C-2), 108.91 (C-8), 109.16 (C-14), 127.25 (C-19), 128.83 (C-20), 130.96 (C-18), 133.02 (C-21), 142.47 (C-13), 151.42 and 151.52 (C-7 and C-9), 156.1 and 156.29 (C-5a and C-16), 164.14 (C-17), 180.39 (C-4a), 191.54 (C-3), 197.94 (C-11), 201.33 (C-11). IR (cm−1): 3500, 3140, 1681, 1627, 1544, 1456, 1301, 1180. HRMS: m/z 504.0991 [M]+ (calcd for (C26H20O7N232S)+: 504.0986).
(R)-N-(4-(8-acetyl-1,3,7-trihydroxy-2,9a-dimethyl-9-oxo-9,9a-dihydrodibenzo[b,d] furan-4-yl)thiazol-2-yl)-4-bromobenzamide (5b).
Yellow amorphous powder. Yield: 92%. 1H NMR (CDCl3, δ): 1.75 (3H, s, H-15), 1.96 (3H, s, H-10), 2.64 (3H, s, H-12), 5.95 (1H, s, H-4), 7.43 (1H, s, H-14), 7.50 (2H, AB-syst, 12.43 (1H, bs, OH-7), 18.81 (1H, s, OH-3). 13C NMR (CDCl3, δ): 8.25 (C-10), 27.80 (C-15), 32.09 (C-12), 59.27 (C-9b), 96.88 (C-9a), 97.58 (C-4), 103.86 (C-6), 105.18 (C-2), 108.81 (C-8), 109.41 (C-14), 128.04 (C-21), 128.89 (C-19), 129.74 (C-18), 132.01 (C-20), 142.33 (C-13), 151.49 and 151.61 (C-7 and C-9), 155.82 and 156.30 (C-5a and C-16), 163.35 (C-17), 180.32 (C-4a), 191.59 (C-3), 197.92 (C-11), 201.42 (C-11). IR (cm−1): 3594, 3147, 1681, 1627, 1556, 1456, 1303, 1180. HRMS: m/z 582.0092 [M]+ (calcd for (C26H19O7N279Br32S)+: 582.0091).
(R)-N-(4-(8-acetyl-1,3,7-trihydroxy-2,9a-dimethyl-9-oxo-9,9a-dihydrodibenzo[b,d] furan-4-yl)thiazol-2-yl)-5-methylfuran-2-carboxamide (5c).
Yellow amorphous powder. Yield: 89%. 1H NMR (CDCl3, δ): 1.54–2.10 (9H, bs, H-10 and H-15 and H-22), 2.65 (3H, s, H-12), 6.00 (1H, s, H-4), 6.07 (1H, bs, H-20), 7.09 (1H, bs, H-19), 7.35 (1H, s, H-14), 10.17 (1H, s, OH-9), 13.13 (1H, bs, OH-7), 18.83 (1H, s, OH-3). 13C NMR (CDCl3, δ): 7.69 (C-10), 13.19 (C 22), 27.80(C-15), 32.09 (C-12), 59.43 (C-9b), 97.17 (C-9a), 97.46 (C-4), 103.99 (C-6), 105.28 (C-2), 109.07 (C-8 and C-20), 109.47 (C-14), 118.73 (C-19), 141.92 (C-18), 143.73 (C-13), 151.30 and 151.61 (C-7 and C-9), 154.6 (C-21), 155.85 (C-5a), 156.06 and 156.29 (C-16 and C-17), 180.79 (C-4a), 191.70 (C-3), 198.24 (C-11), 201.30 (C-11). IR (cm−1): 3500, 3139, 1680, 1623, 1542, 1456, 1303, 1176. HRMS: m/z 508.0931 [M]+ (calcd for (C25H20O8N232S)+: 508.0935).
(R)-N-(4-(8-acetyl-1,3,7-trihydroxy-2,9a-dimethyl-9-oxo-9,9a-dihydrodibenzo[b,d] furan-4-yl)thiazol-2-yl)-5-bromofuran-2-carboxamide (5d).
Yellow amorphous powder. Yield: 82%. 1H NMR (DMSO-d6, δ): 1.70 (3H, s, H-15), 2.06 (3H, s, H-10), 2.59 (3H, s, H-12), 6.17 (1H, s, H-4), 6.92 (1H, AB-syst, J = 3.58, H-20), 7.58 (2H, m, H-14 and H-19), 10.30 (1H, s, OH-9), 12.54 (1H, s, NH), 12.86 (1H, s, OH-7), 18.81 (1H, bs, OH-3). 13C NMR (DMSO-d6, δ): 8.51 (C-10), 27.69 (C-15), 31.79 (C-12), 59.18 (C-9b), 96.16 (C-9a), 97.46 (C-4), 103.61 (C-6), 105.19 (C-2), 109.07 (C-8), 109.20 (C-20), 114.97 (C-14), 119.53 (C-19), 127.53 (C-21), 141.78 (C-13), 147.23 (C-18), 150.76 and 151.43 (C-7 and C-9), 154.46 (C-16), 156.21 and 156.68 (C-5a and C-16), 180.46 (C-4a), 191.44 (C-3), 198.15 (C-11), 201.14 (C-11). IR (cm−1): 3521, 3137, 1679, 1621, 1554, 1469, 1305, 1182. HRMS: m/z 571.9877 [M]+ (calcd for (C24H17O8N279Br32S)+: 571.9877).
(R)-N-(4-(8-acetyl-1,3,7-trihydroxy-2,9a-dimethyl-9-oxo-9,9a-dihydrodibenzo[b,d] furan-4-yl)thiazol-2-yl)-5-bromothiophen-2-carboxamide (5e).
Yellow amorphous powder. Yield: 90%. 1H NMR (CDCl3, δ): 1.74 (3H, s, H-15), 1.94 (3H, s, H-10), 2.66 (3H, s, H-12), 5.98 (1H, s, H-4), 6.96 (1H, bs, H-20), 7.33 (1H, bs, H-19), 7.43 (1H, s, H-14), 10.15 (1H, s, NH), 10.29 (1H, s, OH-9), 12.47 (1H, bs, OH-7), 18.83 (1H, s, OH-3). 13C NMR (CDCl3, δ): 8.27 (C-10), 27.78 (C-15), 32.04 (C-12), 59.32 (C-9b), 96.92 (C-9a), 97.61 (C-4), 104.05 (C-6), 105.23 (C-2), 108.85 (C-8), 109.61 (C-14), 121.45 (C-21), 129.76 (C-20), 131.18 (C-19), 137.18 (C-18), 142.41 (C-13), 151.64 and 151.71 (C-7 and C-9), 155.86 (C-17), 155.88 (C-5a), 157.57 (C-16), 180.42 (C-4a), 191.61 (C-3), 197.95 (C-11), 201.42 (C-11). IR (cm−1): 3500, 3139, 1682, 1624, 1548, 1454, 1301, 1176. HRMS: m/z 587.9654 [M]+ (calcd for (C24H17O7N279Br32S2)+: 587.9655).

Supplementary Materials

Figures S1, S5, S9, S13 and S17: 1H NMR spectra of compounds 5ae; Figures S2, S6, S10, S14 and S18: 13C NMR spectra of compounds 5ae. Figures S3, S7, S11, S15 and S19: IR spectra of compound 5ae; Figures S4, S8, S12, S16 and S20: mass spectra of compound 5ae.

Author Contributions

Conceptualization, A.S.F. and O.A.L.; Data curation, O.A.L.; Investigation, A.S.F., O.A.L.; Supervision, N.F.S.; Writing—original draft, A.S.F.; Writing—review and editing, O.A.L. All authors have read and agreed to the published version of the manuscript.

Funding

This work was funded by a grant from the Ministry of Science and Higher Education of the Russian Federation (agreement no. 122040400033-9).

Data Availability Statement

The data presented in this study are available on request from the corresponding authors.

Acknowledgments

The authors would like to acknowledge the Multi-Access Chemical Research Center SB RAS for their assistance with the spectral and analytical measurements.

Conflicts of Interest

The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

References

  1. Luzina, O.A.; Salakhutdinov, N.F. Usnic acid and its derivatives for pharmaceutical use: A patent review (2000–2017). Expert Opin. Ther. Pat. 2018, 28, 477–491. [Google Scholar] [CrossRef] [PubMed]
  2. Bekker, O.B.; Sokolov, D.N.; Luzina, O.A.; Komarova, N.I.; Gatilov, Y.V.; Andreevskaya, S.N.; Smirnova, T.G.; Maslov, D.A.; Chernousova, L.N.; Salakhutdinov, N.F.; et al. Synthesis and activity of (+)-usnic acid and (-)-usnic acid derivatives containing 1,3-thiazole cycle against Mycobacterium tuberculosis. Med. Chem. Res. 2015, 24, 2926–2938. [Google Scholar] [CrossRef]
  3. Yarovaya, O.I.; Filimonov, A.S.; Baev, D.S.; Borisevich, S.S.; Chirkova, V.Y.; Zaykovskaya, A.V.; Mordvinova, E.D.; Belenkaya, S.V.; Shcherbakov, D.N.; Luzina, O.A.; et al. Usnic acid based thiazole-hydrazones as multi-targeting inhibitors of a wide spectrum of SARS-CoV-2 viruses. New J. Chem. 2023, 47, 19865–19879. [Google Scholar] [CrossRef]
  4. Zakharenko, A.L.; Luzina, O.A.; Sokolov, D.N.; Kaledin, V.I.; Nikolin, V.P.; Popova, N.A.; Patel, J.; Zakharova, O.D.; Chepanova, A.A.; Zafar, A.; et al. Novel tyrosyl-DNA phosphodiesterase 1 inhibitors enhance the therapeutic impact of topotecan on in vivo tumor models. Eur. J. Med. Chem. 2019, 161, 581–593. [Google Scholar] [CrossRef] [PubMed]
  5. Baell, J.; Walters, M.A. Chemistry: Chemical con artists foil drug discovery. Nature 2014, 513, 481–483. [Google Scholar] [CrossRef] [PubMed]
  6. Baell, J.B.; Holloway, G.A. New substructure filters for removal of pan assay interference compounds (PAINS) from screening libraries and for their exclusion in bioassays. J. Med. Chem. 2010, 53, 2719–2740. [Google Scholar] [CrossRef] [PubMed]
  7. Comer, J.E.A. Ionization Constants and Ionization Profiles. Compr. Med. Chem. II 2007, 5, 357–397. [Google Scholar] [CrossRef]
  8. Siddiqui, N.; Alam, M.; Ahsan, W. Synthesis, anticonvulsant and toxicity evaluation of 2-(1H-indol-3-yl) acetyl-N-(substituted phenyl) hydrazine carbothioamides and their related heterocyclic derivatives. Acta Pharm. 2008, 58, 445–454. [Google Scholar] [CrossRef] [PubMed]
  9. Hegab, M.I.; Abdel-Fattah, A.S.; Yousef, N.M.; Nour, H.F.; Mostafa, A.M.; Ellithey, M. Synthesis, X-ray Structure, and Pharmacological Activity of Some 6, 6-Disubstituted Chromeno [4,3-b]- and Chromeno-[3, 4-c]- quinolines. Arch. Pharm. 2007, 340, 396–403. [Google Scholar] [CrossRef] [PubMed]
  10. Sana, A.; Khan, S.W.; Zaidi, J.H.; Ambreen, N.; Khan, K.M.; Perveen, S. Syntheses and antimicrobial activities of amide derivatives of 4-[(2-isopropyl-5-methylcyclohexyl) oxo]-4-oxobutanoic acid. Nat. Sci. 2011, 3, 855–861. [Google Scholar] [CrossRef]
  11. Graybill, T.L.; Ross, M.J.; Gauvin, B.R.; Gregory, J.S.; Harris, A.L.; Ator, M.A.; Rinker, J.M.; Dolle, R.E. Synthesis and evaluation of azapeptide-derived inhibitors of serine and cysteine proteases. Bioorg. Med. Chem. Lett. 1992, 2, 1375–1380. [Google Scholar] [CrossRef]
  12. Bi, Y.; Xu, J.; Sun, F.; Wu, X.; Ye, W.; Sun, Y.; Huang, W. Synthesis and biological activity of 28-amide derivatives of 23-hydroxy betulinicacid as antitumor agent candidates. Med. Chem. 2013, 9, 920–925. [Google Scholar] [CrossRef] [PubMed]
  13. Midura-Nowaczek, K.R.; Lepietuszko, I.; Bruzgo, I.; Markowska, A. Biological activity of amide derivatives of lysine. Acta Pol. Pharm. 2008, 65, 377–381. [Google Scholar] [PubMed]
  14. Hu, L.H.; Chen, Z.L.; Xie, Y.Y. Synthesis and biological activity of amide derivatives of ginkgolide A. J. Asian Nat. Prod. Res. 2001, 3, 219–227. [Google Scholar] [CrossRef] [PubMed]
  15. Kamal, M.; Jawaid, T.; Dar, U.A.; Shah, S.A. Amide as a Potential Pharmacophore for Drug Designing of Novel Anticonvulsant Compounds. In Chemistry of Biologically Potent Natural Products and Synthetic Compounds; Wiley-Scrivener Publishing: Beverly, MA, USA, 2021; pp. 319–342. [Google Scholar] [CrossRef]
Figure 1. Usnic acid and thiazoles based on it.
Figure 1. Usnic acid and thiazoles based on it.
Molbank 2024 m1894 g001
Scheme 1. Aminothiazole 6 acylation.
Scheme 1. Aminothiazole 6 acylation.
Molbank 2024 m1894 sch001
Scheme 2. Synthesis of thiazoles 5a-e.
Scheme 2. Synthesis of thiazoles 5a-e.
Molbank 2024 m1894 sch002
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MDPI and ACS Style

Filimonov, A.S.; Luzina, O.A.; Salakhutdinov, N.F. Synthesis of Novel Thiazoles Based on (+)-Usnic Acid. Molbank 2024, 2024, M1894. https://doi.org/10.3390/M1894

AMA Style

Filimonov AS, Luzina OA, Salakhutdinov NF. Synthesis of Novel Thiazoles Based on (+)-Usnic Acid. Molbank. 2024; 2024(4):M1894. https://doi.org/10.3390/M1894

Chicago/Turabian Style

Filimonov, Aleksandr S., Olga A. Luzina, and Nariman F. Salakhutdinov. 2024. "Synthesis of Novel Thiazoles Based on (+)-Usnic Acid" Molbank 2024, no. 4: M1894. https://doi.org/10.3390/M1894

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