Synthesis and SAR Studies of Praziquantel Derivatives with Activity against Schistosoma japonicum
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Biological Activities
Compound | R | X | Y | Z | Killing activity a | |||
---|---|---|---|---|---|---|---|---|
Conc (μM) b | 24 h | 48 h | 72 h | |||||
Vehicle | n.e | n.e | n.e | |||||
PZQ | 10 | 25.0%D | 25.0%D | 37.5%D | ||||
25 | 25.0%D | 25.0%D | 62.5%D | |||||
50 | 25.0%D | 37.5%D | 62.5%D | |||||
100 | 37.5%D | 50.0%D | 87.5%D | |||||
1 d, e | None | O | CH=CH | None | 100 | n.e. | n.e. | n.e. |
2 d, e | | O | CH=CH | O | 100 | sluggish | 25.0% | 75.0% |
3 e | | O | CH=CH | O | 10 | n.e. | n.e. | sluggish |
25 | n.e. | n.e. | 10.0%D | |||||
50 | n.e. | sluggish | 75.0%D | |||||
100 | sluggish | sluggish | 87.5%D | |||||
4 e | | O | CH=CH | O | 10 | sluggish | sluggish | 37.5%D |
25 | sluggish | sluggish | 50.0%D | |||||
50 | sluggish | sluggish | 100%D | |||||
100 | 12.5%D | 12.5%D | 75.0%D | |||||
5 d, e | CH3 | O | CH=CH | O | 100 | n.e. | n.e. | n.e. |
6 d, e | | O | CH=CH | O | 100 | n.e. | n.e. | 20.0%D |
7 c, e | ClCH2 | O | CH=CH | O | 1 | n.e. | n.e. | n.e. |
3 | n.e. | 25.0%D | 25.0%D | |||||
5 | 70.0%D | 90.0%D | 100%D | |||||
8 | 100%D | 100%D | 100%D | |||||
10 | 100%D | 100%D | 100%D | |||||
25 | 100%D | 100%D | 100%D | |||||
50 | 100%D | 100%D | 100%D | |||||
100 | 100%D | 100%D | 100%D | |||||
8 d, e | | O | CH=CH | O | 100 | n.e. | n.e. | n.e. |
9 e | | O | CH=CH | O | 10 | n.e. | n.e. | 55.6%D |
25 | sluggish | 25.0%D | 87.5%D | |||||
50 | 18.2%D | 36.4%D | 45.5%D | |||||
100 | 45.5%D | 45.5%D | 81.8%D | |||||
10 d, e | | O | CH=CH | O | 100 | n.e. | n.e. | sluggish |
11 e | | O | CH=CH | O | 10 | n.e. | n.e. | 62.5%D |
25 | n.e. | n.e. | 62.5%D | |||||
50 | 25.0%D | 37.5%D | 87.5%D | |||||
100 | 14.3%D | 28.6%D | 87.5%D | |||||
12 d, e | | O | CH=CH | O | 100 | n.e. | n.e. | n.e. |
13 d | | O | CH=CH | H2 | 100 | n.e. | n.e. | n.e. |
14 d, e | | O | CH=CH | H2 | 100 | n.e. | n.e. | n.e. |
15 d | | O | CH=CH | H2 | 100 | n.e. | n.e. | n.e. |
16 d, e | None | H2 | CH=CH | None | 100 | n.e. | n.e. | n.e. |
17 d | | H2 | CH=CH | O | 100 | n.e. | n.e. | n.e. |
18 | | H2 | CH=CH | O | 10 | sluggish | sluggish | sluggish |
25 | sluggish | 18.2%D | 18.2%D | |||||
50 | 10.0%D | 20.0%D | 50.0%D | |||||
100 | 25.0%D | 25.0%D | 75.0%D | |||||
19 | | H2 | CH=CH | O | 10 | n.e. | n.e. | n.e. |
25 | n.e. | 14.3%D | 57.1%D | |||||
50 | sluggih | 33.3%D | 66.7%D | |||||
100 | sluggish | sluggish | 85.7%D | |||||
20 d, e | | H2 | CH=CH | O | 100 | n.e. | n.e. | n.e. |
21 d | | H2 | CH=CH | O | 100 | n.e. | n.e. | n.e. |
22 | ClCH2 | H2 | CH=CH | O | 10 | n.e. | sluggish | 50.0%D |
25 | 87.5%D | 100%D | 100%D | |||||
50 | 100%D | 100%D | 100%D | |||||
100 | 100%D | 100%D | 100%D | |||||
23 e | | O | S | O | 10 | sluggish | 75.0%D | 75.0%D |
25 | sluggish | 87.5%D | 87.5%D | |||||
50 | 25.0% | 75.0%D | 87.5%D | |||||
100 | 28.6%D | 71.4%D | 71.4%D | |||||
24 d | None | O | S | None | 100 | n.e. | n.e. | n.e. |
25 d | | O | S | O | 100 | n.e. | 12.5%D | 37.5%D |
26 d | | O | S | O | 100 | n.e. | sluggish | sluggish |
27 d | | O | S | O | 100 | n.e. | n.e. | sluggish |
28 d | | O | S | O | 100 | n.e. | n.e. | n.e. |
29 d | | O | S | O | 100 | sluggish | sluggish | sluggish |
30 e | | O | S | O | 10 | n.e. | n.e. | n.e. |
25 | n.e. | sluggish | sluggish | |||||
50 | n.e. | 14.3%D | 14.3%D | |||||
100 | sluggish | 37.5%D | 75.0%D | |||||
31 d, e | | O | S | O | 100 | n.e. | n.e. | n.e. |
32 d, e | | O | S | O | 100 | n.e. | n.e. | n.e. |
33 c | ClCH2 | O | S | O | 1 | n.e. | n.e. | n.e. |
3 | n.e. | n.e. | n.e. | |||||
5 | sluggish | 25%D | 37.5%D | |||||
8 | 75%D | 87.5%D | 87.5%D | |||||
10 | 100%D | 100%D | 100%D | |||||
25 | 100%D | 100%D | 100%D | |||||
50 | 100%D | 100%D | 100%D | |||||
100 | 100%D | 100%D | 100%D |
3. Experimental
3.1. Chemistry
3.1.1. Procedure for the Preparation of Compound 1
3.1.2. Procedure for the Preparation of Compound 8
3.1.3. General Procedure for the Preparation of Derivatives 2–7 and 9–12
3.1.4. General Procedure for the Preparation of Derivatives 13–15
3.1.5. Procedure for the Preparation of Compound 16
3.1.6. General Procedure for the Preparation of Derivatives 17–22
3.1.7. The Procedure for the Preparation of Compound 24
3.1.8. General Procedure for the Preparation of Compound 25–33
3.2. Killing Activity of Compounds 1–33 on S. Japonicum Adult Worms in Vitro [36]
4. Conclusions
Acknowledgments
Conflicts of Interest
References
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Wang, W.-L.; Song, L.-J.; Chen, X.; Yin, X.-R.; Fan, W.-H.; Wang, G.-P.; Yu, C.-X.; Feng, B. Synthesis and SAR Studies of Praziquantel Derivatives with Activity against Schistosoma japonicum. Molecules 2013, 18, 9163-9178. https://doi.org/10.3390/molecules18089163
Wang W-L, Song L-J, Chen X, Yin X-R, Fan W-H, Wang G-P, Yu C-X, Feng B. Synthesis and SAR Studies of Praziquantel Derivatives with Activity against Schistosoma japonicum. Molecules. 2013; 18(8):9163-9178. https://doi.org/10.3390/molecules18089163
Chicago/Turabian StyleWang, Wen-Long, Li-Jun Song, Xia Chen, Xu-Ren Yin, Wen-Hua Fan, Gu-Ping Wang, Chuan-Xin Yu, and Bainian Feng. 2013. "Synthesis and SAR Studies of Praziquantel Derivatives with Activity against Schistosoma japonicum" Molecules 18, no. 8: 9163-9178. https://doi.org/10.3390/molecules18089163