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N, N’-disubstitutedphenyl-4-ethoxyl benzene-1, 3-disulfonamides: design, synthesis, and evaluation of anti-platelet aggregation activity

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Abstract

According to the bio-isosterism theory, a series of N, N’-disubstitutedphenyl-4-ethoxylbenzene-1, 3-disulfonamides (5a-p) were designed and synthesized by two steps of reactions including chlorosulfonation and ammonolysis. The structures of all compounds have been confirmed by IR, 1H-NMR, 13C-NMR, and ESI-MS spectra. The in vitro anti-platelet aggregation activities were evaluated by Born’s test induced by adenosine diphosphate (ADP) and arachidonic acid (AA), respectively. The biological evaluation results revealed that compound 5h had the lowest IC50 value (0.32 μM) and the highest inhibition rate (40.9 %) that of three positive control agents clopidogrel (0.41 μM, 23.5 %), aspirin (0.53 μM, 28.9 %), and picotamide (0.76 μM, 32.7 %). Afterwards, compounds with higher activities were selected to further study in vitro cytotoxicity via cell counting kit-8 (CCK-8) assay. The cytotoxicity results indicated that compound 5h had simultaneously the lowest cytotoxicity, while other compounds had no significant relationship between the anti-platelet activities and cytotoxicities. Based on above in vitro anti-platelet activity data, the SAR (Structure Activity Relationship) of the target compounds was preliminarily summarized. In general, N, N’-disubstitutedphenyl-4-ethoxylbenzene-1, 3-disulfonamides have the potential of further study and very likely become safer and more effective anti-platelet agents.

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Abbreviations

ADP:

Adenosine diphosphate

AA:

Arachidonic acid

SAR:

Structure activity relationship

COX-I:

Cyclooxygenase-I

TXA2 :

Thromboxane A2

PGI2 :

Prostaglandin I2

TLC:

Thin layer chromatography

CCK-8:

Cell Counting Kit-8

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Acknowledgements

The authors grate to the National Science Foundation of China (11341014) & the Committee of Science and Technology of Tianjin of China (15JCZDJC33100) for the financial supports and Shenyang Pharmaceutical University of China for running platelet aggregation assays.

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Authors and Affiliations

  1. Tianjin Key Laboratory of Organic Solar Cells and Photochemical Conversion, Tianjin University of Technology, 300384, Tianjin, P. R. China

    Xin Chen & Xiujie Liu

  2. School of Chemistry and Chemical Engineering, Tianjin University of Technology, 300384, Tianjin, P. R. China

    Xin Chen, Xiujie Liu, kai Qiu, Xiang Xu, Caiwen Li & Yan Wang

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  1. Xin Chen
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  2. Xiujie Liu
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  3. kai Qiu
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  4. Xiang Xu
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Correspondence to Xiujie Liu.

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Chen, X., Liu, X., Qiu, k. et al. N, N’-disubstitutedphenyl-4-ethoxyl benzene-1, 3-disulfonamides: design, synthesis, and evaluation of anti-platelet aggregation activity. Med Chem Res 28, 1388–1401 (2019). https://doi.org/10.1007/s00044-019-02379-5

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