English version Ukrainian version
Last issue Archive Editorial board Instructions to authors Contact us

This site supported by


Ukr. Bioorg. Acta 2020, Vol. 15, N2, 3-12.

 Features of the synthesis and biological evaluation of

Olga V. Shablykina, Viktoriia S. Moskvina*, Volodymyr P. Khilya

V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, 1 Murmanska St., Kyiv, 02094, Ukraine.
tel.: +380-44-239-3342; e-mail: v.moskvina@gmail.com

Flavonoids and their derivatives have historically been a source of therapeutic agents. Every year, more and more data is published on new flavonoid compounds (both isolated from natural sources and synthesized) and their innumerable physiological and pharmacological activities. This review presents synthetic routes towards 3-(carboxyphenyl)chromones and their biological activity as published in both journal and patent literature. We have focused specifically on the 3-(carboxyphenyl)chromones, since there is a lot of data on the methods of synthesis and biological activity of 2(3)-substituted and 2,3-disubstituted chromones, but literature data on isoflavones containing a carboxyl, ester, or amide group in ring B is scarce and fragmentary. The presented generalization of synthetic strategies and biological activity of 3-(carboxyphenyl)chromone derivatives demonstrates that this class of compounds can be targeted for the discovery of new drugs and can be readily prepared owing to recent advances in synthetic organic and medicinal chemistry.

chromones, isoflavones, biological activity, synthesis

Full text: (PDF, in English)

1. Edwards, A. M.; Howell, J. B. L. The chromones: history, chemistry and clinical development. A tribute to the work of Dr R. E. C. Altounyan. Clin Exp Allergy. Clin. Exp. Allergy 2000, 30, 756-774.
2. Wilk, W.; Waldmann, H.; Kaiser, M. Gamma-pyrone natural products - a privileged compound class provided by nature. Bioorg. Med. Chem. 2009, 17, 2304-2309.
3. Khadem, S.; Marles, R. J. Chromone and Flavonoid Alkaloids: Occurrence and Bioactivity. Molecules 2012, 17, 191-206.
4. Silva, C. F. M.; Batista, V. F.; Pinto, D. C. G. A.; Silva, A. M. S. Challenges with chromone as a privileged scaffold in drug discovery. Exp. Opinion Drug Disc. 2018, 13, 795-798.
5. Reis, J.; Gaspar, A.; Milhazes, N.; Borges, F. Chromone as a Privileged Scaffold in Drug Discovery: Recent Advances. J. Med. Chem. 2017, 60, 7941-7957.
6. Gaspar, A.; Matos, M. J.; Garrido, J.; Uriarte, Eu.; Borges, F. Cromone: A Valid Scaffold in Medicinal Chemistry. Chem. Rev. 2014, 114, 4960-4992.
7. Keri, R. S.; Budagumpi, S.; Pai, R. K.; Balakrishna, R. G. Chromones as a privileged scaffold in drug discovery: a review.Eur. J. Med. Chem. 2014, 78, 340-374.
8. Santos, C. M. M.; Silva, V. L. M.; Silva, A. M. S. Synthesis of Chromone-Related Pyrazole Compounds. Molecules 2017, 22, 1665-1711.
9. Malets, Y. S.; Moskvina, V. S.; Grygorenko, O. O.; Brovarets, V. S. Synthesis of azachromones and azachromanones. Chem. Heterocycl. Comp. 2019, 55, 1007-1012.
10. Dictionary of Flavonoids, Buckingham, J.; Munasinghe, V. R. N., Eds., CRC Press, Taylor & Francis Group: Boca Raton, FL, USA, 2015.
11. Flavonoids. Chemistry, Biochemistry and Applications; Andersen, O. M.; Markham, K. R., Eds., CRC Press, Taylor & Francis Group: Boca Raton, FL, USA, 2005.
12. WO Patent No WO2011/099978 A1. Chromone inhibitors of S-nitrosoglutathione reductase / Sun, X.; Qiu, J.; Wasley, J. Patent appl. No PCT/US2010/024035 12.02.2010. Publ. 18.08.2011.
13. Biswas, K.; Peterkin, T. A. N.; Bryan, M. C.; Arik, L.; Lehto, S. G.; Sun, H.; Hsieh, F. Y.; Xu, C.; Fremeau, R. T.; Allen, J. R. Discovery of Potent, Orally Bioavailable Phthalazinone Bradykinin B1 Receptor Antagonists. J. Med. Chem. 2011, 54, 7232-7246.
14. CN Patent No CN105541777 A. Isoflavone amide type derivative, preparation method and medical application thereof / Xiang, H.; Xu, P.; Wang, W.; Qian, Z.; Chen, M.; You, Q. Patent appl. No CN201610064415.4A 29.01.2016. Publ. 04.05.2016 (in Chinese).
15. WO Patent No WO2011/100433 A1. Novel S-nitrosoglutathione reductase inhibitors / Sun, X.; Qiu, J. Patent appl. No PCT/US2011/024353 10.02.2011. Publ. 18.08.2011.
16. US Patent No 2009/0124672 A1. Aldh-2 inhibitors in the treatment of psychiatric disorders / Diamond, I.; Overstreet, D. Patent appl. No 12/266288 06.11.2008. Publ. 14.05.2009.
17. WO Patent No WO2009/094028 A1. Aldh-2 inhibitors in the treatment of addiction / Bilokin, Y.; Elzein, E.; Zablocki, J.; Organ, M.; Perry, T.; Kobayashi, T.; Abelman, M.; Kalla, R.; Fan, P.; Diamond, I.; Jiang, R.; Arolfo, M. P.; Li, X.; Yao, L.; Jiang, Z.; Keung, W. M.; Tao, G. Patent appl. No PCT/US2008/051862 24.01.2008. Publ. 30.07.2009.
18. Bryan, M. C.; Biswas, K.; Peterkin, T. A. N.; Rzasa, R. M.; Arik, L.; Lehto, S. G.; Sun, H.; Hsieh, F. Y.; Xu, C.; Fremeau, R. T.; Allen, J. R. Chromenones as potent bradykinin B1 antagonists. Bioorg. Med. Chem. Lett. 2012, 22, 619-622.
19. Qiu, R.; Luo, G.; Cai, X.; Liu, L.; Chen, M.; Chen, D.; You, Q.; Xiang, H. Structure-guided design and synthesis of isoflavone analogs of GW4064 with potent lipid accumulation inhibitory activities. Bioorg. Med. Chem. Lett. 2018, 28, 3726-3730.
20. CN Patent No CN108264506 A. Novel isoflavone derivative, preparation method and medical usage / Chen, D.; Chen, M.; Hu, W.; Li, H.; Liu, M.; Qiu, R.; Tao, R.; Xiang, H.; Yang, Q.; You, Q.; Zhang, J.; Zheng, F. Patent appl. No CN201810061682.5A 17.01.2018. Publ. 10.07.2018 (in Chinese).
21. WO Patent No WO2006/099193 A2. Chromen-4-one inhibitors of anti-apoptotic bcl-2 family members and the uses thereof / Wang, S.; Ding, K.; Tang, G.; Wang, R.; Yang, C. Y. Nikolovska-Coleska, Z. Patent appl. No PCT/US2006/008690 13.03.2006. Publ. 11.01.2007.
22. Wu, C.; Tu, Y. B.; Li, Z., Li, Y. F. Highly selective carbamate-based butyrylcholinesterase inhibitors derived from a naturally occurring pyranoisoflavone. Bioorg. Chem. 2019, 88, 102949.
23. Tang, B., Frasinyuk, M. S., Chikwana, V. M., Mahalingan, K. K., Morgan, C. A., Segvich, D. M., Bondarenko, S. P.; Mrug, G. P.; Wyrebek, P.; Watt, D. S.; DePaoli-Roach, A. A.; Roach, P. J.; Hurley, T. D. Discovery and Development of Small-Molecule Inhibitors of Glycogen Synthase. J. Med. Chem. 2020, 63, 3538-3551.
24. US Patent No 4814346 A. Benzopyrans and use thereof in treating vascular diseases / Albert, A. I.; Zilliken. Patent appl. No 116737 04.11.1987. Publ. 21.03.1989.
25. Buarque, C. D.; Militao, G. C. G.; Lima, D. J. B.; Costa-Lotufo, L. V.; Pessoa, C., De Moraes, M. O.; Cunha-Junior, E. F.; Torres-Santos, E. C.; Netto, C. D.; Costa, P. R. R. Pterocarpanquinones, aza-pterocarpanquinone and derivatives: synthesis, antineoplasic activity on human malignant cell lines and antileishmanial activity on Leishmania amazonensis. Bioorg. Med. Chem. 2011, 19, 6885-6891.
26. Sepulveda-Boza, S.; Walizei, G. H.; Rezende, M. C.; Vasquez, Y.; Mascayano, C.; Mej?as, L. The preparation of new isoflavones. Synth. Commun. 2001, 31, 1933-1940.
27. Bass, R. J. Synthesis of chromones by cyclization of 2-hydroxyphenyl ketones with boron trifluoride-diethyl ether and methanesulphonyl chloride. J. Chem. Soc., Chem. Commun. 1976, 78-79.
28. Ding, K.; Wang, S. Efficient synthesis of isoflavone analogues via a Suzuki coupling reaction. Tetrahedron Lett. 2005, 46, 3707-3709.
29. Huang, Z.; Lim, L. H.; Chen, Z.; Li, Y.; Zhou, F.; Su, H.; Zhou, J. S. Arene CH-O hydrogen bonding: a stereocontrolling tool in palladium-catalyzed arylation and vinylation of ketones. Angew. Chem. Int. Ed. 2013, 52, 4906-4911.
30. Alcaide, B.; Almendros, P.; Busto, E.; Herrera, F.; Lazaro-Milla, C.; Luna, A. Photopromoted Entry to Benzothiophenes, Benzoselenophenes, 3H?Indoles, Isocoumarins, Benzosultams, and (Thio)flavones by Gold?Catalyzed Arylative Heterocyclization of Alkynes. Adv. Synth. Catal. 2017, 359, 2640-2652.
31. Buarque, C. D.; Pinho, V. D.; Vaz, B. G.; Eberlin, M. N.; Da Silva, A. J. M.; Costa, P. R. R.Palladium-catalyzed oxyarylation of olefins using silver carbonate as the base. Probing the mechanism by electrospray ionization mass spectrometry. J. Organomet. Chem. 2010, 695, 2062-2067.
32. Leao, R. A. C.; Pinho, V. D.; Coelho, A. S.; Buarque, C. D.; Moraes, P. F.; Alonso, D. A.; Najera, C.; Costa, P. R. R. Microwave?Promoted Palladium?Catalysed Oxyarylation of Dihydronaphthalene and Chromenes by o?Iodophenols and Its Acetates. Eur. J. Org. Chem. 2011, 2011, 3313-3316.
33. Gong, J.; Xie, F.; Ren, W.; Chen, H.; Hu, Y. Domino reactions of 2-methyl chromones containing an electron withdrawing group with chromone-fused dienes. Org. Biomol. Chem. 2012, 10, 486-489.
34. Ferreira, J. A.; Nel, J. W.; Brandt, E. V.; Bezuidenhoudt, B. C. B.; Ferreira, D. Oligomeric isoflavonoids. Part 3. Daljanelins A-D, the first pterocarpan- and isoflavanoid-neoflavonoid analogues. J. Chem. Soc., Perkin Trans. 1 1995, 33, 1049-1056.