Synthesis and Antioxidant Properties of Pyrazine-Thiazole Bi-heteroaryl Compounds

doi:10.6023/cjoc202011013

Abstract

In order to find novel pyrazine- and thiazole-based derivatives with potent antioxidant properties, eight pyrazine-thiazole bi-heteroaryl compounds were designed and prepared via active group splicing method between pyrazine-N- oxides and thiazoles. They were structurally characterized by ¹H NMR, ¹³C NMR, IR, and HPLC-MS. Antioxidant abilities of the obtained compounds were evaluated by inhibiting radicals induced oxidation of DNA and quenching radicals. The results showed that eight compounds can effectively inhibit radicals induced oxidation of DNA and quench radicals, which revealed that the compounds have strong radical scavenging properties and reduction ability, and can be potential antioxidants. The effective measurement factor (n) values of these compounds ranged from 1.48 to 2.12 in 2,2-azobis(2-amidinopropanehydro- chloride) (AAPH) induced oxidation of DNA. The absorbance percentages of eight compounds to the blank thiobarbituric acid reactive substance (TBARS percentage) were 54.3%~76.1% and 55.4%~68.3% in inhibiting HO• and glutathione radical (GS•) induced oxidation of DNA, respectively. Eight compounds can scavenge 2,2-azinobis(3-ethylbenzothiazoline-6-sul- fonate) cationic radical (ABTS•) and 2,2-diphenyl-1-picrylhydrazyl radical (DPPH•). In addition, it was found that the antioxidant activity of pyrazine-thiazole bi-heteroaryl compounds was significantly higher than that of pyrazine-oxazole bi-heteroaryl compound.

Key words: pyrazine-thiazole, oxidative cross-dehydrogenative coupling, antioxidant, DNA, free radical

Cite this article

Xiaoping Zhang, Guiyong Jin, Zhifei Chen, Qingfu Wang, Sensen Zhao, Zhiyong Wu, Shuai Wan, Gaolei Xi, Xu Zhao. Synthesis and Antioxidant Properties of Pyrazine-Thiazole Bi-heteroaryl Compounds[J]. Chinese Journal of Organic Chemistry, 2021, 41(6): 2445-2453.

Export EndNote|Reference Manager|ProCite|BibTeX|RefWorks

share this article

Fig. & Tab. 8

References 24

[1]	(a) Abu-Hashem, A. A.; El-Shazly, M. Med. Chem. 2018, 14,356.
	(b) Zaki, R. M.; Kamal El-Dean, A. M.; Radwan, S. M.; Abdul-Malik, M. A. Curr. Org. Synth. 2018, 6,863.
	(c) Shankar, B.; Jalapathi, P.; Valeru, A.; Kumar, A. K.; Saikrishna, B.; Kudle, K. R. Med. Chem. Res. 2017, 26,1835.
[2]	(a) Srinivasa, S. B.; Poojary, B.; Brahmavara, U.; Das, A. J.; Middha, S. K. ChemistrySelect 2018, 44.12478.
	(b) Sinha, S.; Doble, M.; Manju, S. L. Eur. J. Med. Chem. 2018, 158,34.
	(c) Rajendran, N. D.; Stephen, A. D.; Jelsch, C.; Escudero-Adan, E. C. Croat. Chem. Acta 2018, 2,221.
	(d) Leleu-Chavain, N.; Baudelet, D.; Heloire, V. M.; Rocha, D. E.; Renault, N.; Barczyk, A.; Djouina, M.; Body-Malapel, M.; Carato, P.; Millet, R. Eur. J. Med. Chem. 2019, 165,347.
[3]	(a) Kusstatscher, P.; Cernava, T.; Liebminger, S.; Berg, G. Sci. Rep. 2017, 7,13253.
	(b) Zitko, J.; Dolezal, M.; Svobodova, M.; Vejsova, M.; Kunes, J.; Kucera, R.; Jilek, P. Bioorg. Med. Chem. 2011, 19,1471.
[4]	(a) Reddy, N. B.; Zyryanov, G. V.; Reddy, G. M.; Balakrishna, A.; Padmaja, A.; Padmavathi, V.; Reddy, C. S.; Garcia, J. R.; Sravya, G. J. Heterocycl. Chem. 2019, 2,589.
	(b) Masood, M. M.; Irfan, M.; Alam, S.; Hasan, P.; Queen, A.; Shahid, S.; Zahid, M.; Azam, A.; Abid, M. Russ. Lett. Drug. Des. Discovery 2019, 2,160.
	(c) Panchani, N. M.; Joshi, H. S. Russ. Lett. Drug. Des. Discovery 2019, 3,284.
	(d) Edrees, M. M.; Abu-Melha, S.; Saad, A. M.; Kheder, N. A.; Gomha, S. M.; Muhammad, Z. A. Molecules 2018, 11,2970.
[5]	Gabr, I. M.; El-Asmy, H. A.; Emmam, M. S.; Mostafa, S. I. Transition Metal. Chem. 2009, 34,409.
[6]	(a) Sharma, A.; Gudala, S.; Ambati, S. R.; Mahapatra, S. P.; Raza, A.; Aruna, L. V.; Payra, S.; Jha, A.; Kumar, A.; Penta, S. Chemistry- Select 2018, 39,11012.
	(b) Bhatt, P.; Kumar, M.; Jha, A. Mol. Diversity 2018, 4,827.
	(c) Biswas, N. M.; Shard, A.; Patel, S.; Sengupta, P. Drug Dev. Res. 2018, 8,391.
	(d) Zhang, Z. H.; Wu, H. M.; Deng, S. N.; Chai, R. X.; Mwenda, M. C.; Peng, Y. Y.; Cai, D.; Chen, Y. Chem. Pap. 2019, 2,355.
[7]	Kucerova-Chlupacova, M.; Dosedel, M.; Kunes, J.; Soltesova- Prnova, M.; Majekova, M.; Stefek, M. Monatsh. Chem. 2018, 149,921.
[8]	(a) Uremis, N.; Uremis, M. M.; Tolun, F. I.; Ceylan, M.; Doganer, A.; Kurt, A. H. J. Anticancer. Res. 2017, 11,6381.
	(b) Parasotas, I.; Anusevicius, K.; Vaickelioniene, R.; Jonuskiene, I.; Stasevych, M.; Zvarych, V.; Komarovska-Porokhnyavets, O.; Novikov, V.; Belyakov, S.; Mickevicius, V. ARKIVOC 2018, 3,240.
	(c) Djukic, M.; Fesatidou, M.; Xenikakis, I.; Geronikaki, A.; Angelova, V. T.; Savic, V.; Pasic, M.; Krilovic, B.; Djukic, D.; Gobeljic, B. Chem.-Biol. Interact. 2018, 286,119.
[9]	(a) Sebastian, S. H. R.; Al-Alshaikh, M. A.; El-Emam, A. A.; Panicker, C. Y.; Zitko, J.; Dolezal, M.; VanAlsenoy, C. J. Mol. Struct. 2016, 1119 188.
	(b) Wu, H. M.; Zhou, K.; Wu, T.; Cao, Y. G. Chem. Biol. Drug Des. 2016, 88,411.
[10]	(a) Wang, Y. Y.; Wu, C. L.; Zhang, Q. J.; Shan, Y.; Gu, W.; Wang, S. F. Bioorg. Chem. 2019, 84,468.
	(b) George, R. F.; Samir, E. M.; Abdelhamed, M. N.; Abdel-Aziz, H. A.; Abbas, S. E. S. Bioorg. Chem. 2019, 83,186.
	(c) Prajapati, N. P.; Patel, K. D.; Vekariya, R. H.; Patel, H. D.; Rajani, D. P. J. Mol. Struct. 2019, 1179 401.
[11]	(a) Khake, S. M.; Soni, V.; Gonnade, R. G.; Punji, B.; Dalton Trans. 2014, 43,16084.
	(b) Dowlut, M.; Mallik, D.; Organ, M. G. Chem.-Eur. J. 2010, 16,4279.
[12]	(a) Pandey, D. K.; Khake, S. M.; Gonnade, R. G.; Punji, B. RSC Adv. 2015, 5,81502.
	(b) Khake, S. M.; Jagtap, R. A.; Dangat, Y. B.; Gonnade, R. G.; Vanka, K.; Punji, B. Organometallics 2016, 35,875.
[13]	Wu, Z. Y.; Chang, C. C.; Tang, X. T.; Liu, S.; Xi, G. L.; Zhao, M. Q.; Liu, P. F. ChemistrySelect 2018, 3,13038.
[14]	Zhang, X. P.; Chen, Z. F.; Han, L. Fine Chem. 2020, 37:1461.
[15]	Xiao, C.; Song, Z. G.; Liu, Z. Q. Eur. J. Med. Chem. 2010, 45:2559.
[16]	Stojanoić, S.; Brede, O. Phys. Chem. Chem. Phys. 2002, 4,757.
[17]	Xi, G. L.; Liu, Z. Q. J. Agric. Food Chem. 2015, 63,3516.
[18]	(a) Xi, G. L.; Liu, Z. Q. Tetrahedron 2014, 70,8397.
	(b) Xi, G. L.; Liu, Z. Q. Tetrahedron 2015, 71,9602.
[19]	He, J. H.; Li, J. Z.; Liu, Z. Q. Med. Chem. Res. 2013, 22,2847.
[20]	Nabi, G.; Liu, Z. Q. Med. Chem. Res. 2012, 21,3015.
[21]	Zhao, C.; Liu, Z. Q. Biochimie 2013, 95,842.
[22]	Wang, R.; Liu, Z. Q. Med. Chem. Res. 2013, 22,1563.
[23]	Li, G. X.; Liu, Z. Q.; Luo, X. Y. Eur. J. Med. Chem. 2010, 45,1821.
[24]	Xi, G. L.; Liu, Z. Q. Eur. J. Med. Chem. 2013, 68,385.

Entry	Catalyst	Solvent	Time/h	T/℃	Yield/%
1	FeCl₃	Toluene	6	Reflux	31
2	FeCl₃	CH₃CN	6	Reflux	37
3	FeCl₃	CHCl₃	6	Reflux	47
4	FeCl₃	ClCH₂CH₂Cl	6	Reflux	61
5	FeCl₃	ClCH₂CH₂Cl	8	Reflux	64
6	FeCl₃	ClCH₂CH₂Cl	10	Reflux	62
7	FeCl₃	ClCH₂CH₂Cl	8	60	39
8	FeCl₃	ClCH₂CH₂Cl	8	25	Trace
9	^tBuOLi/TBAB^[13]	Xylene	24	Reflux	46
10	InCl₃	ClCH₂CH₂Cl	8	Reflux	31
11	BiCl₃	ClCH₂CH₂Cl	8	Reflux	34
12	LaCl₃	ClCH₂CH₂Cl	8	Reflux	25
13	CeCl₃	ClCH₂CH₂Cl	8	Reflux	37
14	YbCl₃	ClCH₂CH₂Cl	8	Reflux	33
15	ScCl₃	ClCH₂CH₂Cl	8	Reflux	26
16	CuCl₂	ClCH₂CH₂Cl	8	Reflux	21
17	AgCl	ClCH₂CH₂Cl	8	Reflux	12

Entry	Catalyst	Solvent	Time/h	T/℃	Yield/%
1	FeCl₃	Toluene	6	Reflux	31
2	FeCl₃	CH₃CN	6	Reflux	37
3	FeCl₃	CHCl₃	6	Reflux	47
4	FeCl₃	ClCH₂CH₂Cl	6	Reflux	61
5	FeCl₃	ClCH₂CH₂Cl	8	Reflux	64
6	FeCl₃	ClCH₂CH₂Cl	10	Reflux	62
7	FeCl₃	ClCH₂CH₂Cl	8	60	39
8	FeCl₃	ClCH₂CH₂Cl	8	25	Trace
9	^tBuOLi/TBAB^[13]	Xylene	24	Reflux	46
10	InCl₃	ClCH₂CH₂Cl	8	Reflux	31
11	BiCl₃	ClCH₂CH₂Cl	8	Reflux	34
12	LaCl₃	ClCH₂CH₂Cl	8	Reflux	25
13	CeCl₃	ClCH₂CH₂Cl	8	Reflux	37
14	YbCl₃	ClCH₂CH₂Cl	8	Reflux	33
15	ScCl₃	ClCH₂CH₂Cl	8	Reflux	26
16	CuCl₂	ClCH₂CH₂Cl	8	Reflux	21
17	AgCl	ClCH₂CH₂Cl	8	Reflux	12

Compd.	t_inh(min)=(n/R_i)c_compound+constant	n
3a	t_inh=0.53(±0.03)c(3a)–1.34(±0.07)	1.78(±0.08)
3b	t_inh=0.54(±0.03)c(3b)+0.59(±0.03)	1.81(±0.09)
3c	t_inh=0.57(±0.03)c(3c)–0.73(±0.04)	1.92(±0.10)
3d	t_inh=0.63(±0.03)c(3d)+0.68(±0.03)	2.12(±0.11)
3e	t_inh=0.54(±0.03)c(3e)–1.72(±0.09)	1.81(±0.09)
3f	t_inh=0.55(±0.03)c(3f)+0.96(±0.05)	1.85(±0.09)
3g	t_inh=0.61(±0.03)c(3g)–1.66(±0.08)	2.05(±0.10)
3h	t_inh=0.63(±0.03)c(3h)–0.99(±0.05)	2.12(±0.11)

Compd.	t_inh(min)=(n/R_i)c_compound+constant	n
3a	t_inh=0.53(±0.03)c(3a)–1.34(±0.07)	1.78(±0.08)
3b	t_inh=0.54(±0.03)c(3b)+0.59(±0.03)	1.81(±0.09)
3c	t_inh=0.57(±0.03)c(3c)–0.73(±0.04)	1.92(±0.10)
3d	t_inh=0.63(±0.03)c(3d)+0.68(±0.03)	2.12(±0.11)
3e	t_inh=0.54(±0.03)c(3e)–1.72(±0.09)	1.81(±0.09)
3f	t_inh=0.55(±0.03)c(3f)+0.96(±0.05)	1.85(±0.09)
3g	t_inh=0.61(±0.03)c(3g)–1.66(±0.08)	2.05(±0.10)
3h	t_inh=0.63(±0.03)c(3h)–0.99(±0.05)	2.12(±0.11)

吡嗪-噻唑联芳类化合物的合成及抗氧化性能研究