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To obtain more active and selective anti-platelet candidate drugs, we tried to introduce a methyl group at the 5-position and 6-position of the parent benzene ring first time, respectively or simultaneously. The idea could inspect compound with tetra-substituted or penta-substituted characteristics rather than retained classical 1,3,4-position triple substitutions characteristic whether it continues to have anti-platelet activity in vitro. The biological evaluation revealed that most of compounds with this novel structure were more potent than the positive control drug Picotamide. At the concentration of 1.3 μmol/L, using Arachidonic acid as an inducer, it was found that the anti-platelet activity in vitro of five compounds 1a, 1b, 1c, 2f, and 3d was higher than that of Picotamide and the series 1 compounds were generally higher than that of the series 2 and 3. And with ADP as an inducer, the activity in vitro of nine compounds 2a, 2b, 2d, 2f, 2g, 2h, 3a, 3b, and 3c was more elevated than that of Picotamide and the compounds of series 2 and 3 were all evidently even more active than that of series 1. The proportion of newly designed target compounds with active is higher than that of previously developed series of compounds. Based on the in vitro activity results, a preliminary analysis of the structure–activity relationship was deduced. Meanwhile, cytotoxic effects in vitro of 11 target compounds 1b, 1c, 2f, 2a, 2b, 3a, 3b, 3c, 2d, 2g, and 2h on L-929 cells were analyzed, but the data analysis shows that at two concentrations, target compounds have higher effect on L-929 cells than that of control drug Picotamide. The reason or mechanism for obtaining higher in vitro activity and higher cytotoxicity of the target compound under tetra- or penta- substitutions requires further relevant research work before conclusion can be drawn.

Cardiovascular diseases are the most frequent cause of morbidity and mortality worldwide. In order to discover novel compounds with anti-platelet aggregation activities, a series of novel 4-methoxy-1,3-phthalamidesamides (1a–1i) and a series of novel 4-methoxy-1,3-benzenedisulfon-amides (2a–2i) were synthesized and their anti-platelet aggregation activities were evaluated by the turbidimetric method in response to the following agonists: adenosine diphosphate (ADP), arachidonic acid (AA), and Collagen. Those compounds that have better in vitro activities were subjected to cell toxicity tests via cell counting kit-8 (CCK-8) assay. The inhibition rates of anti-platelet in vitro of five compounds 1g (39.45%), 2d (38.87%), 2g (38.55%), 2h (44.56%), and 2i (43.93%) were higher than that of two reference drugs picotamide (36.12%) and aspirin (38.45%) when ADP was selected as an inducer. The inhibition rates of seven compounds 1c (43.63%), 1d (40.02%), 1g (47.42%), 1i (40.45%), 2c (40.11%), 2d (40.45%), and 2i (49.05%) were higher than that of picotamide (34.89%) and aspirin (39.43%) when AA was selected as inducer. And the inhibition rates of five compounds 1d (47.22%), 1i (45.01%), 2d (38.74%), 2e (42.21%), and 2f (39.94%) were higher than picotamide (38.45%) and aspirin (37.08%) when collagen was selected as inducer. Moreover, the effect of cell toxicity exhibited that none of the compounds had obvious cell toxicity against L-929 cells. Therefore, 4-methoxy-1,3-phthalamidesamides (1a–1i) and 4-methoxy-1,3-benzenedisulfon-amides (2a–2i) have the potential to become a novel kind of anti-platelet drugs and deserve further study.

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.

A series of 4-methoxyisophthalamides (1d–1w) were designed and synthesized and their chemical structures were confirmed by IR, MS, 1H-NMR, and 13C-NMR. The in vitro on anti-platelet aggregation activities of these compounds were assessed by using Born method. Compounds with higher activities were selected to continue research via Cell Counting Kit-8 (CCK-8) assays of their cytotoxicities. Biological screening results revealed four compounds 1h, 1i, 1q, and 1v exhibited higher activities than the control drugs on against the platelet aggregation induced by adenosine triphosphate (ADP). Moreover, compounds 1p and 1q exhibited higher in vitro activities than picotamide induced by collagen at the concentration of 1.3 μM. Compound 1p also possessed anti-platelet aggregation activity superior to the control drug picotamide induced by arachidonic acid (AA) at the concentration of 1.3 μM. At the same time, the result of cytotoxicities exhibited that none of the compounds have significant cytotoxicities. Therefore, 4-methoxyisophthalamides are potential to become novel anti-platelet drugs with high activities and minimum toxicities.

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.