Design, synthesis and biological evaluation of 4-methoxy diaryl isophthalates as antiplatelet agents
- 326 Downloads
A series of 4-methoxy diphenyl isophthalates, which are the isosturctural analogs of picotamide, were designed and synthesized using the concept of isosterism. The structures of these new analogs were characterized by all means of spectroscopy, including 1H NMR, 13C NMR, and MS spectra. In vitro antiplatelet aggregation activities of these compounds were investigated by using Born’s test method. Among the 19 compounds tested for both ADP and collagen inducers, six of them (P216–P219 and P220–P221) were found to exhibit higher activity in vitro antiplatelet aggregation than Picotamide. In particular, the compound P220 bearing a nitrooxyl group showed the highest acitivity 72.1% (induced by collagen) and 72.5% (induced by ADP), with IC50 values of 0.30 μM/L induced by ADP (1.3 μM/L) and LD50 > 2500 mg/kg, could have dual mechanism of action. Evaluation of cytotoxic activity of the compounds against L929 cell line revealed that none of the compounds have significant cytotoxicity. Through the careful analysis of in vitro activity data, the SAR of these compounds was preliminarily deduced. The results of this study showed that 4-methoxy diaryl isophthalates derivatives are potential to become an antiplatelet aggregation agents.
Keywords4-Methoxy diphenyl isophthalates Antiplatelet aggregation SAR, Organic synthesis
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.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no competing interests.
- Celestini A, Violi F (2007) A review of picotamide in the reduction of cardiovascular events in diabetic patients. Vasc Health Risk Manage 3(1):93–98Google Scholar
- Ellis JL, Augustyniak ME, Cochran ED, Earl RA, Garvey DS, Gordon LJ, Janero DR, Khanapure SP, Letts LG, Melim TJ, Murty MG, Schwalb DJ, Shumway MJ, Selig WM, Trocha AM, Young DV, Zemtseva IS (2005) NMI-1182, a gastro-protective cyclo-oxygenase-inhibiting nitric oxide donor. Inflamm Pharmacol 12(5–6):521–534CrossRefGoogle Scholar
- Li GA, Wang X, Meng X, Lin YB, Li X, Liu XJ (2015) Design, synthesis of novel N,N’-bis-(halogenophenyl)-4-methoxybenzene-1,3-disulfonamides and evaluation of their anti-platelet aggregation activity. Acta Pharm Sin 50(2):185–190Google Scholar
- Liu XJ, He X, Shi CL, Meng J, Shao YL, Si HQ, Hu T (2011) Synthesis and in vitro activities on anti-platelet aggregation of N,N‛-di(2-substituted-phenyl)-4-methoxyisophthalamides and benzene-1,3-disulfonamides. Chin Chem Lett 22(10):1139–1142Google Scholar
- Meng J, Liu XJ, Shi CL (2011) Synthesis and anti-platelet aggregation activities of bis(4-substituted-phenyl)-4-methoxyisophthalates. J Chin Pharm Univ 21(3):195–198Google Scholar
- Sartori E, Camy F, Teulon JM, Caussade F, Virone-Oddos A, Cloarec A (1993) ChemInform abstract: synthesis and activities of new arylsulfonamido thromboxane A2 receptor antagonists. Cheminform 24(52):625–632Google Scholar
- Xiong JW, Xiao H, Zhang ZX (2007) An experimental research on different detection conditions between MTT and CCK-8. Acta Laser Biol Sin 16(5):559–562Google Scholar
- Xu SY, Bian RL, Chen X (1991) Pharmacological experimental methods, 2rd ed. People’s medical Publishing House, Beijing, p 1438–1442Google Scholar
- Zhao DY, Jie M, Wang TT, Deng N, Liu XJ (2012) Synthesis and in vitro activities on anti-platelet aggregation of bis-phenyl-4-methoxyisophthalate compounds. J Chin Pharm Univ 43(1):21–24Google Scholar