Our research aimed to develop a new method for the synthesis of trazodone and its derivatives. In the known methods of the synthesis of trazodone and its derivatives, organic and toxic solvents are used, and the synthesis time varies from several to several dozen hours. Our research shows that trazodone and its derivatives can be successfully obtained in the presence of potassium carbonate as a reaction medium in the microwave field in a few minutes. As a result of the research work, 17 derivatives of trazodone were obtained, including compounds that exhibit the characteristics of 5-HT1A receptor ligands. Molecular modeling studies were performed to understand the differences in the activity toward 5-HT1A and 5-HT2A receptors between ligand 10a (2-(6-(4-(3-chlorophenyl)piperazin-1-yl)hexyl)-triazolopyridin-3(2H)-one) (5-HT1AKi = 16 nM) and trazodone. The docking results indicate the lack of the binding of ligand 10a to 5-HT2AR, which is consistent with the in vitro studies. On the other hand, the docking results for the 5-HT1A receptor indicate two possible binding modes. Crystallographic studies support the hypothesis of an extended conformation.Trazodone, a well-known antidepressant drug widely used throughout the world, works as a 5-hydroxytryptamine (5-HT As a result, 5-HT1A, 5-HT2, and other receptors  play an important role in these diseases of the central nervous system triazolopyridin-3(2H)-one (1) using two methods (6a/b) with hydrazine in the first stage (yield 14%) in dimethylformamide (DMF) for 120 s. Bearing in mind the low efficiency, the reaction was also carried out under conventional conditions by heating the substrates in ethanol for 25 h pyridin-3(2 methods . The fir-apyridin1 in a one-step reaction involves the use of semicarbazide in 2-ethoxyethanol (yield 43–48%). All reactions were carried out under microwave radiation, which is a new way of obtaining 1,2,4-triazolo pyridin-3(2H)-one (1) and which is yet to be described in the literature.The second method for the synthesis of N-alkylation of the previously obtained 1,2,4-triazolopyridin-3(2H)-one (1) with dihalogenopropane (2a/b)  .2CO3 and PTC catalysts (TBAB). 3a/b.The reactions were carried out under microwave radiation in the presence of K2a on 2b caused a slight 17% drop in yield -one (3a/b) reacted with 1-(3-chlorophenyl)piperazine hydrochloride (4) triazolopyridin-3(2ride (4) .H)-one (3b) using 10% by weight DMF and TBAB as a PTC catalyst, which allowed obtaining a product with 98% efficiency in 1 min . The reactions were carried out under microwave radiation. During the experiment, we observed that the addition of a small amount (<10% weight) of DMF or ACN was beneficial for the duration of the process, but the reaction also took place under completely solvent-free conditions -one (3a), the amount of ACN in the range of 10–40% did not significantly affect the efficiency -1,2,4-triazolopyridin-3-(25) was obtained in the reaction of 3-chloroarylpiperazine (4) with 1-bromo-3-chloropropane (2a) -4-(3-chloropropyl)piperazine (ane (2a)  under mi5) were obtained by reacting with ACN in a Samsung microwave reactor, where the product was obtained with a yield of 88% within 40 s. (5) can be obtained with a 60% yield within 7 h pyridin-3(2H)-one (1) -4- (3-chlorophenyl)piperazine (-one (1) . The synThe highest efficiency (92%) in the synthesis of trazodone with method II was obtained in the reaction for 80 s using about 15 wt.% ACN , entry 4H)-one (1) with 1-bromo-3-chloropropane (2a) for 50 s, followed by the addition of 1-(3-chlorophenyl)piperazine (4) for another 90 s. The expected product was obtained with a yield of 31%. The synthesis was also performed in the CEM Discover SP reactor (100 W), carrying out the process for 30 s in the first stage and for 60 s in the second, which allowed obtaining trazodone with a yield of 71%.Trazodone was also obtained in a “one-pot” variant. The process was carried under microwave radiation by firstly heating 1,2,4-triazolopyridin-3(2H)-one (1), 1-bromo-3-chloropropane (2a), and 1-(3-chlorophenyl)piperazine (4), were treated with microwave radiation, but in this case trazodone was not observed in the post-reaction mixture.We also tested the variant in which all of the reactants, 1,2,4-triazolo pyridin-3. The reactions were carried out under similar conditions as the previous ones, i.e., potassium carbonate, TBAB, and a small amount of ACN. All of the syntheses were carried out in the SAMSUNG device . The obtained products were converted into hydrochlorides.The synthesis of trazodone with method I also works very well in the synthesis of its derivatives , Table 5G device . Additio10a–k) with a modified aryl substituent were obtained by the condensation reaction of 2-(3-chloropropyl)-1,2,4-triazolopyridin-3-(2H)-one (4a) with appropriate arylpiperazines 7. As already mentioned in the introduction, and bearing in mind the high activity with 5-HT1A receptors in ligands with the hexyl linker that we previously synthesized pyridin-3-(2H)-one (1), 0.25 cm3 (2.6 mol) of 1-bromo-3-chloropropane (2a), 32 mg (0.1 mmol) of TBAB, and 414 mg (3 mmol) of K2CO3 0.075 cm3 of acetonitrile were placed in a PTFE vessel, after which the mixture was subjected to microwave radiation. The progress of the reaction was monitored by TLC (eluent chloroform–methanol 9:1). After 2 min, 5 cm3 of water was added and the resulting product was filtered off on a Büchner funnel. Y = 81%.Firstly, 135 mg (1 mmol) of 1,2,4-triazolo  pyridin-3-(2H)-one (3a)/2.56 g (10 mmol) of 2-(3-bromopropyl)-1,2,4-triazolopyridin-3-(2H)-one (3b), 2.33 g (10 mmol) of 1-(3-chlorophenyl) piperazine hydrochloride (4), 320 mg (1 mmol) of TBAB, 4.14 g (30 mmol) of K2CO3, and the appropriate amount of acetonitrile /DMF /water (50 cm3), were placed in a conical flask, after which the mixture was subjected to microwave radiation. The progress of the reaction was monitored by TLC (eluent chloroform–methanol 9:1). The reaction times are summarized in 3 water was added and the resulting product was filtered off on a Büchner funnel. The reaction yields are summarized in Firstly, 2.11 g (10 mmol) of 2-(3-chloropropyl)-1,2,4-triazolopyridin-3-(2H)-one (3a), 186 mg (8 mmol) of 1-(3-chlorophenyl)piperazine hydrochloride (4), 25.8 mg (0.8 mmol) of TBAB, 331 mg (2.4 mmol) of K2CO3, and 0.28 cm3 of ACN were placed in a PTFE vessel, after which the mixture was subjected to microwave radiation under pressure of 1, 5, or 10 bar. The reaction yields are summarized in Firstly, 168 mg (8 mmol) of 2-(3-chloropropyl)-1,2,4-triazolopyridin-3- of 1-bromo-3-chloropropane (2a), 2.33 g (10 mmol) of 1-(3-chlorophenyl)piperazine hydrochloride (4), 320 mg (10 mmol) of TBAB, 4.14 g (30 mmol) of K2CO3, and 3 cm3 of acetonitrile/DMF were placed in a conical flask, after which the mixture was subjected to microwave radiation. The progress of the reaction was monitored by TLC (eluent chloroform–methanol 9:1). After the reaction, 50 cm3 of water was added and the resulting product was filtered off. After drying, obtained 5 was dissolved in acetone and a solution of 2M HCl in dioxane was added until acidic . The precipitated hydrochloride was filtered off on a Büchner funnel; Rf = 0.83. The reaction yields are summarized in Firstly, 2.50 cm3  of 1-bromo-3-chloropropane (2a) 233 mg (1 mmol) of 1-(3-chlorophenyl) piperazine hydrochloride (4), 32 mg (1 mmol) of TBAB, 414 mg of K2CO3 (3 mmol), and 0.3 cm3 of acetonitrile were added in a PTFE vessel, after which the mixture was subjected to microwave radiation. The progress of the reaction was monitored by TLC (eluent chloroform–methanol 9:1). After drying, obtained 5 was dissolved in acetone and a solution of 2M HCl in dioxane was added until acidic . The precipitated hydrochloride was filtered off on a Büchner funnel.Firstly, 0.25 cm5), 1.35 g (10 mmol) of 1,2,4-triazolopyridin-3-(2H)-one (1), 322 mg (1 mmol) of TBAB, 4.14 g (30 mmol) of K2CO3, and a corresponding amount of acetonitrile  were placed in a conical flask, after which the mixture was subjected to microwave radiation. The progress of the reaction was monitored by TLC (eluent chloroform–methanol 9:1). The reaction times are summarized in 3 of water was added and the resulting product was filtered off on a Büchner funnel. The reaction yields are summarized in f = 0.75.Firstly, 2.76 g (10 mmol) of 1-(3-chloropropyl)-4-(3-chlorophenyl)piperazine hydrochloride (5), 135 mg (1 mmol) of 1,2,4-triazolo  pyridin-3-(2H)-one (1), 32 mg (0.1 mmol) of TBAB, 414 mg (3 mmol) of K2CO3, and 0.2 cm3 of acetonitrile were placed in a PTFE vessel, after which the mixture was subjected to microwave radiation. The progress of the reaction was monitored by TLC (eluent chloroform–methanol 9:1). After the reaction, water was added and the resulting product was filtered off. After drying to solution 1-(3-chloropropyl)-4-(3-chloropheyl)piperazine (5) in acetone, a solution of HCl in dioxane was added until acidic. The precipitated hydrochloride was filtered off on a Büchner funnel.Firstly, 276 mg (1 mmol) of 1-(3-chloropropyl)-4-(3-chlorophenyl)piperazine hydrochloride (H)-one (1), 2.5 cm3 (26 mmol) of 1-bromo-3-chloropropane (2a), 322 mg (1 mmol) of TBAB, 8.28 g (60 mmol) of K2CO3, and 5 cm3 of acetonitrile were placed in a conical flask. The reactions were carried out under microwave radiation  for 50 s. After this time, 2.3 g (10 mmol) of 1-(3-chlorophenyl)piperazine hydrochloride (4) and 5 cm3 of acetonitrile were added to the reaction mixture. Reactions were carried out in the presence of microwave radiation for another 90 s. The progress of the reaction was monitored by TLC (eluent chloroform–methanol 9:1). After the reaction, 50 cm3 of water was added and the resulting product was filtered off on a Büchner funnel. Yield  31%, yield  71%.Firstly, 1.35 g (10 mmol) of 1,2,4-triazolopyridin-3-(2H)-one (1), 4.6 cm3 (30 mmol) of 1,6-dibromohexane, 0.322 g (1 mmol) of TBAB, 4.14 g (30 mmol) of K2CO3, and 2.5 cm3 of acetonitrile were placed in a conical flask, after which the mixture was subjected to microwave radiation for 60 s. The progress of the reaction was monitored by TLC (eluent chloroform–methanol 9:1). After the reaction, 15 cm3 of water was added to the mixture and extracted with methylene chloride. The product was purified by column chromatography (eluent chloroform–methanol 9:1).Firstly, 1.35 g (10 mmol) of 1,2,4-triazolo  pyridin-3-(22-(3-bromohexyl)-1,2,4-triazolopyridin-3-(2H)-one (8): 1H NMR  δ 7.78 , 7.15–7.07 , 6.51 , 4.02 , 3.42 , 1.89 , 1.55–1.48 , 1.46–1.39 . 13C NMR  δ 148.57 (Ar), 141.47 (Ar), 129.75 (Ar), 123.77 (Ar), 115.38 (Ar), 110.48 (Ar), 45.77 (CAliph), 33.69 (CAliph), 32.56 (CAliph), 28.62 (CAliph), 27.71 (CAliph), 25.75 (CAliph). HPLC 91% (tR = 7.31), Rf = 0,96, yield = 79%, oil.H)-one (3a)/745 mg (2.5 mmol) of 2-(3-bromohexyl)-1,2,4-triazolopyridin-3-(2H)-one (8), 2.5 mmol of the corresponding arylpiperazine hydrochloride (9a–m), 80 g (0.25 mmol) of TBAB, 1.04 g (7.5 mmol) of K2CO3, and 0.75 cm3 of acetonitrile were placed in a conical flask, after which the mixture was subjected to microwave radiation . The progress of the reaction was monitored by TLC (eluent chloroform–methanol 9:1). After the reaction, water was added and the resulting product was filtered off on a Büchner funnel. After drying, the obtained 10a–k were dissolved in acetone and a solution of 2M HCl in dioxane was added until acidic . The precipitated hydrochloride was filtered off on a Büchner funnel.Firstly, 529 mg (2.5 mmol) of 2-(3-chloropropyl)-1,2,4-triazolopyridin-3-piperazin-1-yl]propyl]-triazolopyridin-3-one hydrochloride (10a): 1H NMR  δ 7.76 , 7.17 , 7.02 , 6.54 , 4.18 , 3.67 , 3.37 , 3.17 , 3.06 , 2.60 .13C NMR  δ 149.07 (Ar), 148.89 (Ar), 142.14 (Ar), 134.44 (Ar), 130.61 (Ar), 128.09 (Ar), 127.82 (Ar), 126.45 (Ar), 123.92 (Ar), 119.52 (Ar), 115.58 (Ar), 111.10 (Ar), 55.54 (Ctriaz), 52.66 , 48.15 , 43.45 (Cpip), 23.55 . Fourier-transform (FT)-IR 3000 , 2954, 2850 , 1704 , 1650 , 1500, 1450 , 1350 , 750 . HPLC 97% (tR = 4.33), m/z = 406,19, Rf = 0.87, yield = 25%, melting point (mp) = 225–230 °C.2-[3-[4-(2-fluorophenyl)piperazin-1-yl]propyl]-triazolopyridin-3-one hydrochloride (10b): 1H NMR  δ 7.76 , 7.26 , 7.12 , 6.54 , 4.18 , 4.03–3.91 , 3.62 , 3.58–3.49 , 3.46–3.30 , 3.26–3.16 , 2.66–2.53 . 13C NMR ) δ 155.88 (Ar), 152.63 (Ar), 147.58 (Ar), 140.62 (Ar), 137.71(Ar) 130.04 (Ar), 122.79 (Ar), 119.02 (Ar), 115.72 (Ar), 115.45 (Ar), 114.47 (Ar), 110.31 (Ar), 52.42 (Ctriaz), 50.35 , 46.41 , 42.01 (Cpip), 22.38 . FT-IR 3000 , 2946, 2852 , 1711 , 1639 , 1574, 1451 , 1355 , 1108 . HPLC 99% (tR = 3.38), m/z = 356.21; Rf = 0.70, yield = 30%, mp = 146–150 °C.2-[3-(4-pyrimidin-2-ylpiperazin-1-yl)propyl]-triazolopyridin-3-one hydrochloride (10c): 1H NMR  δ 7.76 , 7.26–7.07 , 7.02 , 6.57–6.50 , 4.18 , 3.67 , 3.37 , 3.25–3.15 , 3.06 , 2.59 . 13C NMR  δ 148.85 (Ar), 148.67 (Ar), 141.93 (Ar), 130.41 (Ar), 127.89  126.23 (Ar), 119.32 (Ar), 115.37 (Ar), 110.90 (Ar), 55.32(Ctriaz), 52.46 , 47.94 , 43.24 (Cpip), 23.34 . FT-IR 2990 , 2946, 2850 , 1706 , 1636 , 1601, 1459 , 1355 . HPLC 99% (tR = 4.32), m/z = 340.46; Rf = 0.68, yield = 34%, mp = 235–240 °C.2-[3-[4-(2-ethoxyphenyl)piperazin-1-yl]propyl]-triazolopyridin-3-one hydrochloride (10d): 1H NMR  δ 7.76 , 7.18–6.95 , 6.89 , 6.54 , 4.17 , 4.08 , 3.65–3.53 , 3.16 , 2.60 , 1.64 , 1.59 . 13C NMR  δ 151.66 (Ar), 148.87 (Ar), 142.17 , 130.62 (Ar), 123.92 , 121.47 (Ar), 115.59 , 113.05 (Ar), 111.11 (Ar), 64.37 (Coxy), 55.39 (Ctriaz), 51.37 , 48.08 , 43.41 (Cpip), 23.53 , FT-IR 3001 , 2941, 2858 , 1708 , 1611 , 1531, 1458 , 1349 , 1260, 1021 . HPLC 98% (tR = 3.73), m/z = 382.27; Rf = 0.66, yield = 33%, mp = 104–111 °C.2-[6-[4-(3-chlorophenyl)piperazin-1-yl]hexyl]-triazolopyridin-3-one hydrochloride (10e): 1H NMR  δ 7.76 , 7.61 , 7.49 , 7.39 , 7.31 , 7.15–7.05 , 6.51 , 4.45 , 4.02 , 3.83 , 3.73–3.63 , 3.11 , 2.00–1.81 , 1.46 . 13C NMR  δ 148.62(Ar), 146.74 (Ar), 141.56 (Ar), 135.80 (Ar), 131.06 (Ar), 129.92 (Ar), 125.69 (Ar), 123.72 (Ar), 119.31 (Ar), 116.98 (Ar), 115.37 (Ar), 110.65 (Ar), 57.28 (Ctriaz), 50.21 , 48.35 , 45.33 (Cpip), 28.32 , 26.06 , 25.67 , 23.39 . FT-IR 2981 , 2935, 2851 , 1703 , 1639 , 1593, 1451 , 1354 , 734 . HPLC 97% (tR = 4.23), m/z = 414.30, Rf = 0.66, yield = 47% (Samsung), yield = 58 (CEM Discover SP reactor), mp = 178–183 °C.2-[6-[4-(2-chlorophenyl)piperazin-1-yl]hexyl]-triazolopyridin-3-one hydrochloride (10f): 1H NMR  δ 8.44 , 8.33–8.17 , 7.93–7.82 , 7.63 , 7.08 , 6.75 , 3.84 , 3.58 , 3.04 , 1.84 , 1.52 . 13C NMR  δ 161.06 (Ar), 158.58 (Ar), 136.22 (Ar), 132.01 (Ar), 130.58 (Ar), 130.23 (C Ar), 129.15 (Ar), 120.70 (Ar), 118.62 (Ar), 118.54(Ar), 111.66 (Ar), 104.35 (Ar), 55.87 (Ctriaz), 50.74 , 42.71 , 41.81 (Cpip), 27.98 , 27.82 , 27.61 , 26.22 . FT-IR 3008 , 2942, 2856 , 1738 , 1616 , 1538, 1456 , 1349 , 738 . HPLC 92% (tR = 4.86), m/z = 452.19; Rf = 0.67, yield = 45%, mp = 145–148 °C.2-[6-[4-(4-chlorophenyl)piperazin-1-yl]hexyl]-triazolopyridin-3-one hydrochloride (10g): 1H NMR  δ 7.85 , 7.77 , 7.51 , 7.13–7.09 , 6.52 , 4.78 , 4.21 , 4.04 , 3.75–3.56 , 3.15 , 2.03–1.81 , 1.45 . 13C NMR  δ 148.89 (Ar), 148.39 (Ar), 141.35 (Ar), 130.85 (Ar), 129.27 , 124.30 (Ar) 124.00 (Ar), 117.93 , 115.44 (Ar), 111.30 (Ar), 55.69 (Ctriaz), 50.79 , 45.64 , 45.26 (Cpip), 28.44 , 25.96 , 25.87 , 23.29 . FT-IR 3034 , 2934, 2860 , 1708 , 1637 , 1539, 1482 , 1354 , 755 . HPLC 98% (tR = 1.63); Rf = 0.50, yield = 44%, mp = 163–167 °C.2-[6-[4-piperazin-1-yl]hexyl]-triazolopyridin-3-one hydrochloride (10h): 1H NMR  δ 7.84 , 7.45 , 7.23 , 7.00 , 6.66–6.58 , 4.67 , 3.89 , 3.60–3.47 , 3.16 , 1.75 , 1.32 . 13C NMR  δ 149.77 (Ar), 148.38 (Ar), 141.35 (Ar), 132.11 (Ar), 131.10 (Ar), 130.84 (Ar), 124.29 (Ar), 121.22 (Ar), 117.44 (Ar), 116.29 (Ar), 115.44 (Ar), 111.30 (Ar), 55.73 (Ctriaz), 50.54 (Cpip), 45.71–44.67 , 42.66 , 32.66 (Cpip), 28.44 , 25.68 , 23.34 , 22.55. FT-IR 3016 , 2949, 2860 , 1738 , 1642 , 1542 , 1365 , 757 . HPLC 95% (tR = 4.79), m/z = 448.20; Rf = 0.54, yield = 45%, mp = 116–120 °C.2-[6-[4-(2-fluorophenyl)piperazin-1-yl]hexyl]-triazolopyridin-3-one hydrochloride (10i): 1H NMR  δ 7.85 , 7.20–7.03 , 6.62 , 3.90 , 3.55 , 3.46 , 3.24–3.15 , 3.08 , 1.78–1.69 , 1.35–1.29 . 13C NMR  δ 154.21–153.60 (Ar), 148.39 (Ar), 141.35 (Ar), 138.74 (Ar), 130.84 (Ar), 125.46 (Ar), 124.31 (Ar), 120.01 (Ar), 116.71 (Ar), 116.51 (v), 115.45 (Ar), 111.30 (Ar), 55.79 (Ctriaz), 51.22 , 47.41 , 45.26 (Cpip), 28.44 , 26.05 , 25.89 , 23.29 . FT-IR 3021 , 2936, 2850 , 1713 , 1635 , 1541, 1500 , 1355 , 1141 . HPLC 94% (tR = 1.46), Rf = 0.51, yield = 45%, mp = 183–187 °C.2-[6-[4-(2-methoxyphenyl)piperazin-1-yl]hexyl]-triazolopyridin-3-one hydrochloride (10j): 1H NMR  δ 8.26 , 7.77 , 7.55–7.42 , 7.08 , 6.50 , 5.16 , 4.46 , 4.13–3.95 , 3.66–3.52 , 3.14 , 2.02–1.76 , 1.45 . 13C NMR  δ 152.27 (Ar), 148.39 (Ar), 141.36 (Ar), 139.75 (Ar), 130.85 (Ar), 124.30 (Ar), 124.00 (Ar), 121.30 (Ar), 118.72 (Ar), 115.45 (Ar), 112.41 (Ar), 111.31 (Ar), 55.84 (Coxy), 51.45 (Ctriaz), 47.32 (Cpip), 45.75 (Cpip), 45.27 , 32.18 (Cpip), 28.44 , 26.56 , 26.16 , 25.79 , 23.30 . FT-IR 3016 , 2942, 2860 , 1708 , 1640 , 1540, 1448 , 1366 , 1261, 1020 . HPLC 95% (tR = 3.66), Rf = 0.45, yield = 32%, mp = 140–141 °C.2-[6-[4-(3-methoxyphenyl)piperazin-1-yl]hexyl]-triazolopyridin-3-one hydrochloride (10k): 1H NMR  δ 7.77 , 7.49 , 7.42 , 7.11 , 7.01 , 6.51 , 4.78 , 4.29 , 4.03 , 3.86 , 3.66 , 3.15 , 1.91 , 1.48 . 13C NMR  δ 150.21 (Ar), 140.44 , 139.99 (Ar), 129.15 (Ar), 120.10 , 121.16 (Ar), 119.89 (Ar), 114.42 (Ar), 112.11 (Ar), 111.11 (Ar), 55.44 (Coxy), 50.42 (Ctriaz), 47.39 (Cpip), 45.85 , 32.21 (Cpip), 28.41 , 27.14 , 28.12 , 25.67 , 23.31 . FT-IR 2982 , 2938, 2861 , 1640 , 1615 , 1541, 1491 , 1356 , 1271, 1027 . HPLC 100% (tR = 3.88), Rf = 0.54, yield = 30%, mp = 137–138 °C.2-[6-[4-(4-methoxyphenyl)piperazin-1-yl]hexyl]-triazolopyridin-3-one hydrochloride: (10l) 1H NMR  δ 7.86 , 7.76 , 7.10 , 7.00 , 6.51 , 4.80 , 4.45–4.26 , 4.04 , 3.84 , 3.62 , 3.13 , 1.91 , 1.73 . 13C NMR  δ 154.37 (Ar), 148.39 (Ar), 143.82 (Ar), 141.36 (Ar), 130.85 (Ar), 124.30 (Ar), 118.65 (Ar), 115.45  114.88 , 111.31 (Ar), 56.98 (Coxy), 55.70 (Ctriaz), 51.03 , 47.31 , 45.27 (Cpip), 28.44 , 26.50–25.58 , 23.31 , 13.96 . FT-IR 3002 , 2939, 2840 , 1708 , 1640 , 1541, 1509 , 1374 , 1260, 1025 . HPLC 92% (tR = 1.40), Rf = 0.65, yield = 27%, mp = 144–146 °C.2-[6-[4-(2-ethoxyphenyl)piperazin-1-yl]hexyl]-triazolopyridin-3-one hydrochloride (10m): 1H NMR  δ 8.20–8.15 , 7.77 , 7.43 , 7.08 , 6.51 , 4.96 , 4.45 , 4.33 , 4.02 , 3.61 , 3.13 , 1.89 , 1.64 , 1.44 . 13C NMR  δ 155.67 (Ar), 147.23 (Ar), 144.81 (Ar), 139.45 (Ar), 137.84 (Ar), 120.12 (Ar), 120.01 (Ar), 116.42 , 112.98 , 110.31 (Ar), 58.91 (Coxy), 55.74 (Ctriaz), 50.04 , 48.21 , 44.18 (Cpip), 29.60 , 26.12 , 21.13 , 13.90 , 13.40 . FT-IR 2990 , 2936; 2860 , 1701 , 1636 , 1541, 1491 , 1356 , 1251, 1040 . HPLC 97% (tR = 1.63), Rf = 0.46, yield = 31%, mp = 143–145 °C.2-[6-[4-(2-pyridyl)piperazin-1-yl]hexyl]-triazolopyridin-3-one hydrochloride (10n): 1H NMR  δ 8.14 , 7.83 , 7.22 , 7.15 , 6.88 , 6.67–6.57 , 4.40 , 3.88 , 3.58 , 3.37 , 3.22 , 3.08 , 1.75 , 1.28 . 13C NMR  δ 148.38 (Ar), 141.35 (Ar), 130.85 , 124.30 , 115.44 (Ar), 114.27 , 114.16 (Ar), 111.31 (Ar), 55.80 (Ctriaz), 50.29 (Cpip), 45.27 (Cpip), 43.34 (Cpip), 42.34 (Cpip), 28.44 , 26.02 , 25.88 , 23.28 . FT-IR 2970 , 2936, 2861 , 1701 , 1633 , 1536, 1495 , 1365 . HPLC 98% (tR = 2.32), m/z = 381.27, Rf = 0.48, yield = 70%, mp = 175–178 °C.2-[6-(4-pyrimidin-2-ylpiperazin-1-yl)hexyl]-triazolopyridin-3-one hydrochloride (10o): 1H NMR  δ 8.61 , 8.29 , 7.76 , 7.10 , 6.99 , 6.54–6.50 , 4.28–4.21 , 4.01 , 3.70 , 3.07–3.00 , 1.95–1.81 , 1.45–1.38 . 13C NMR  δ 157.67 (Ar), 148.81 (Ar), 141.73 (Ar), 130.08 (Ar), 123.96 (Ar), 115.59 (Ar), 111.38 (Ar), 110.82 (Ar), 109.87 (Ar), 57.58 (Ctriaz), 51.54 , 45.57 , 41.78 (Cpip), 29.56 , 28.11 , 26.16 , 23.54 . FT-IR 3023 , 2937, 2857 , 1700 , 1616 , 1540 , 1350 . HPLC 90%, (tR = 1.42), Rf = 0.35, yield = 45% (Samsung), yield = 61% (CEM Discover SP reactor), mp = 146–148 °C.2-[6-(4-phenylpiperazin-1-yl)hexyl]-triazolopyridin-3-one hydrochloride (10p): 1H NMR  δ 7.84 , 7.25 , 7.00 , 6.86 , 6.61 , 3.77 , 3.64–3.35 , 3.16 , 3.06 , 1.74 , 1.32 . FT-IR 2987 , 2937, 2861 , 1693 , 1639 , 1541, 1491 , 1375 . HPLC 90% (tR = 3.69), m/z = 380.27, Rf = 0.58, yield = 55%, mp = 133–137 °C. 2-[6-[4-(2-phenylphenyl)piperazin-1-yl]hexyl]-triazolopyridin-3-one hydrochloride (10r): 1H NMR  δ 7.76 , 7.52 , 7.42 , 7.37–7.29 , 7.24–7.22 , 7.21–7.13 , 7.09 , 6.54–6.46 , 3.99 , 3.53 , 3.35 , 3.10 , 2.86 , 2.69 , 1.81 , 1.39 . 13C NMR  δ 148.71 (Ar), 148.37 (Ar), 141.34 (Ar), 140.59 (Ar), 134.47 (Ar), 131.74 (Ar), 130.84 (Ar), 129.03 , 128.73 , 127.55 (Ar), 124.29 (Ar), 123.96 (Ar), 119.01 , 115.44 (Ar), 111.30 (Ar), 55.75 (Ctriaz), 51.25 (Cpip), 47.76 , 45.25 , 28.42 , 26.01 , 25.84 , 23.25 . FT-IR 3023 , 2937, 2858 , 1702 , 1637 , 1541, 1500 , 1351 . HPLC 95% (tR = 4.99), m/z = 456.94, Rf = 0.65, yield = 61% (Samsung), yield = 66% (CEM Discover SP reactor), oil.1A receptor, which is an important hold of drugs used in the diseases of the central nervous system. All ligands, as well as substrates for them, were obtained by means of the new synthesis method in the presence of potassium carbonate as a reaction medium under microwave radiation. The in vitro studies showed that, in the obtained group of ligands, there are selective ligands for the 5-H1A receptor . Among the ligands obtained, those having a hexyl chain, as compared with a propyl chain, have a higher incremental activity. It is very interesting that the elongation in the trazodone of the alkyl chain by three carbon atoms changes the activity profile from the 5-HT2A ligand  to 5-HT1A . This change in the activity was evaluated in the molecular modeling procedure and additionally supported with crystallographic studies. A very interesting pharmacological profile is shown by the compound 10r, which has the properties of a dual 5-HT1A/7 ligand . Bearing in mind all of the above, we are continuing the research on the activity of these ligands . Currently, we are conducting in vivo studies, the aim of which is to confirm their antidepressant activity.As part of the research, 17 new trazodone derivatives were obtained, which were tested for their activity toward the 5-HTSome of the results concerning the synthesis of trazodone are presented in “Method for the preparation trazodone” PCT/PL2018/000024, 6 March 2018.


Antimicrobial activity was tested on standard strains representing different groups of microorganisms. The tested compounds were found to inhibit microbial growth. Concentrations of 0.01–1250 µmol/L were found to influence cell proliferation, demonstrating antiproliferative and stimulation of proliferation against two cell lines: the L929 cell line (mouse fibroblast cell line) and the EA.hy926 cell line .The hydrazine and hydrazide derivatives of benzo-γ-pyrones with fluorine substituents remain an unexplored group of chemical compounds. This preliminary study reports the synthesis, structural assessment, initial microbiological screening and biological testing of the synthesized compounds on cell lines using the XTT-assay. A series of 10 novel hydrazine and hydrazide derivatives of 3-formylchromone were synthesized and their structures determined. Structural assessment consisted of elemental analysis, IR,  Due to the increasing problem of drug resistance, the search for novel and efficient antimicrobial and antiproliferative agents is a worldwide concern. Benzopyrones occur widely in Nature, and benzopyrone derivatives have been reported in algae , fungi ,3 and pl3-Formylchromone is a benzopyrone derivative characterized by high chemical reactivity, especially when nitrogen nucleophilic groups are present. Its structure includes three electron-deficient sites  where attack by strong nucleophilic agents results in the production of various types of compounds . Howevera, intrinsic potency, membrane permeability, metabolic pathways and pharmacokinetic properties -hydrazide  was dissolved in ethyl acetate (30 mL). The temperature was raised to reflux temperature and mixture was stirred until dissolved. After 5 min, a suitable amount  of anhydrous CuCl2 was added. The substances were mixed and heated under reflux for 48 h. The obtained precipitate was filtered and air-dried. The resulting substance was recrystallized from 50:50 acetone/ethanol.4-Fluorobenzoic acid [1--hydrazonomethyl]-chromen-4-one (1). Yellow solid. Yield: 68%. m.p. 226–227 °C. Anal. calcd. for C16H10F2N2O2: C, 64.00; H, 3.36; N, 9.33. Found: C, 63.95; H, 2.93; N, 9.36%. FT IR  νmax: 3271.86 (NH2), 1628.54 (C=O), 1582.35 (CH=N), 1290.34 (C-O). 1H-NMR δ: 10.60 , 8.97 , 8.30 , 8.14–8.15 , 7.84–7.87 , 7.73–7.74 , 7.54–7.57 , 7.34–7.37 , 7.16–7.20 , 6.53–6.57 . 13C-NMR δ: 175.4 (C=O), 160.6 (Ar-CF), 159.0 (Cq), 156.2 (CH), 154.0 (Ar-CF), 146.5 (CH), 144.9 (Ar-Cq), 134.8 (=CH-), 132.9 (CH), 126.3 (Cq), 125.7 (CH), 123.8 (CH), 119.4 (Cq), 116.4 (Ar-CH), 104.4 (Ar-CH), 101.2 (Ar-CH). HRMS (ESI) m/z calcd. for C16H11F2N2O2 (M + H)+: 301.0789, found 301.0792.3-[(4-Trifluoromethylphenyl)-hydrazonomethyl]-chromen-4-one (3). Yellow solid. Yield: 76%. m.p. 215–216 °C. Anal. calcd. for C17H11F3N2O2: C, 61.45; H, 3.34; N, 8.43. Found: C, 61.02; H, 2.88; N, 8.43%. FT IR  νmax: 3271.86 (NH2), 1628.54 (C=O), 1582.35 (CH=N), 1290.34 (C-O). 1H-NMR δ: 10.91 , 8.89 , 8.15–8.16 , 8.09  7.85–7.88, , 7.73–7.74 , 7.55–7.57 , 7.20–7.22 . 13C-NMR δ: 199.4 (-CF3), 175.4 (C=O), 160.4 (Ar-Cq), 160.2 (Ar-Cq), 159.8 (Ar-CH), 159.4 (Cq), 156.2 (CH), 153.5 (Ar-CH), 134.9 (=CH-), 131.2 (CH), 126.6 (Cq), 125.7 (CH), 123.7 (CH), 119.6 (Cq), 119.1 (CH), 112.2 (Ar-CH). HRMS (ESI) m/z calcd. for C17H12F3N2O2 (M + H)+: 333.0851, found 333.0858.3-[-hydrazonomethyl]-chromen-4-one (4). Light yellow solid. Yield: 60%. m.p. 253–254 °C. Anal. calcd. for C18H10F6N2O2: C, 51.01; H, 2.52; N. 7.00. Found: C, 51.84; H, 1.98; N, 7.07%. FT IR  νmax: 3260.17 (NH2), 1640.84 (C=O), 1579.82 (CH=N), 1285.36 (C-O). 1H-NMR δ: 11.11 , 9.03 , 8.14–8.16 , 8.10 , 7.85–7.88 , 7.73–7.75 , 7.59 , 7.55–7.56 , 7.35 . 13C-NMR δ: 198.7 (-CF3), 192.6 (-CF3), 175.0 (C=O), 166.0 (Ar-Cq), 154.5 (CH), 138.8, 135.0 (=CH-), 131.8 (CH), 126.4 (Cq), 125.7 (CH), 123.8 (CH), 119.5 (Cq), 119.2 (CH), 112.1 (CH), 104.8, (Ar-CH), 100.9 (Ar-CH). HRMS (ESI) m/z calcd. for C18H11F6N2O2 (M + H)+: 401.0725, found 401.0730.4-Fluorobenzoic acid [1-(4-oxo-4H-chromen-3-yl)-meth-(E)-ylidene]-hydrazide (5). Yellow solid. Yield: 65%. m.p. 201–202 °C. Anal. calcd. for C17H11FN2O3: C, 65.81; H, 3.57; N, 9.03. Found: C, 65.45; H, 3.51; N, 8.87%. FT IR  νmax: 1642.11 (C=O), 1562.88 (CH=N), 1290.94 (C-O). 1H-NMR δ: 11.96 , 8.85 , 8.65 , 8.15–8.16 , 8.02–8.04 , 7.87–7.90 , 7.74–7.76 , 7.56–7.59 , 7.37–7.34 . 13C-NMR δ: 175.5 (C=O), 165.5 (Ar-CF), 163.9 (C=O), 162.4 (Cq), 156.3 (CH), 155.0 (Ar-CH), 141.0 (Ar-CH), 135.2 (=CH-), 130.9 (CH), 130.1 (CH), 126.6 (Cq), 125.7 (CH), 123.8 (CH), 119.2 (Cq), 118.8 (CH), 116.0 (Ar-CH), 115.9 (Ar-CH). HRMS (ESI) m/z calcd. for C17H12FN2O3 (M + H)+: 311.0840, found 311.0832.3-[-hydrazonomethyl]-chromen-4-one (6). White solid. Yield: 72%. m.p. 241–242 °C. Anal. calcd. for C16H8F4N2O2: C, 57.15; H, 2.40; N, 8.33. Found: C, 56.94 H, 2.12; N, 8.07%. FT IR  νmax: 3243.32 (NH2), 1641.28 (C=O), 1517.95 (CH=N), 1226.21 (C-O). 1H-NMR δ: 10.58 , 8.63 , 8.31 , 8.14–8.15 , 7.85–7.88 , 7.71–7.73 , 7.54–7.57 , 7.24–7.29 . 13C-NMR δ: 175.4 (C=O), 156.3 (CH), 153.4 (Ar-CF), 135.0 (Ar-CF), 134.8 (=CH-), 126.4 (Cq), 125.7 (CH), 123.8 (CH), 119.4 (Cq), 119.1 (CH), 96.3 (Ar-CH). HRMS (ESI) m/z calcd. for C16H9F4N2O2 (M + H)+: 337.0600, found 337.0604.3-[(5-Fluoro-2-methylphenyl)-hydrazonomethyl]-chromen-4-one (7). White solid. Yield: 80%. m.p. 224–225 °C. Anal. calcd. for C17H13FN2O2: C, 68.91; H, 4.42; N, 9.45. Found: C, 69.01; H, 4.19; N, 9.12%. IR  νmax: 3312.09 (NH2), 1639.40 (C=O), 1537.14 (CH=N), 1281.08 (C-O). 1H-NMR δ: 9.88 , 8.93 , 8.34 , 8.15–8.16 , 7.84–7.86 , 7.72–7.74 , 7.54–7.56 , 7.23–7.25 , 7.04–7.07 , 6.47–6.50 , 2.19 . 13C-NMR δ: 175.5 (C=O), 161.6 (Ar-CF), 156.3 (Cq), 153.5 (Ar-Cq), 145.0 (Ar-Cq), 134.8 (=CH-), 131.8 (CH), 131.6 (CH), 126.2 (Cq), 125.7 (CH), 123.8 (CH), 119.9 (Cq), 119.1 (CH), 116.9 (Ar-CH), 105.1 (Ar-CH), 95.4 (Ar-CH), 17.3 (-CH3). HRMS (ESI) m/z calcd. for C17H14FN2O2 (M + H)+: 297.1047, found 297.1039.3-[-hydrazonomethyl]-chromen-4-one (8). Dark yellow solid. Yield: 64%. m.p. 211–212 °C. Anal. calcd. for C16H9F3N2O2: C, 60.38; H, 2.85; N, 8.80. Found: C, 60.65; H, 2.52; N, 8.59%. FT IR  νmax: 3247.92 (NH2), 1644.23 (C=O), 1536.56 (CH=N), 1223.66 (C-O). 1H-NMR δ: 9.77 , 8.58 , 8.12–8.14 , 8.10 , 7.83–7.86 , 7.69–7.70 , 7.53–7.55 , 7.19–7.24 . 13C-NMR δ: 175.4 (C=O), 164.0 (Ar-CF), 156.1 (Ar-CF), 135.7 (=CH-), 127.2 (Cq), 125.8 (Cq), 125.2 (CH), 120.5 (Cq), 119.4 (CH). HRMS (ESI) m/z calcd. for C16H10F3N2O2 (M + H)+: 319.0694, found 319.0707.3-(Pentafluorophenyl-hydrazonomethyl)-chromen-4-one (9). Yellow solid. Yield: 70%. m.p. 245–246 °C. Anal. calcd. for C16H7F5N2O2: C, 54.25; H, 1.99; N, 7.91. Found: C, 54.43; H, 2.05; N, 7.85%. FT IR  νmax: 3271.30 (NH2), 1620.34 (C=O), 1524.56 (CH=N), 1272.51 (C-O). 1H-NMR δ: 10.41 , 8.61 , 8.28 , 8.13–8.15 , 7.84–7.87 , 7.70–7.72 , 7.54–7.56 . 13C-NMR δ: 175.4 (C=O), 156.3 (CH), 153.3 (Ar-CH), 135.0 (=CH-), 134.8 (CH), 126.4 (Cq), 125.7 (CH), 123.8 (CH), 119.3 (Cq), 119.2 (CH). HRMS (ESI) m/z calcd. for C16H8F5N2O2 (M + H)+: 355.0506, found 355.0513.3-[(2-Trifluoromethylphenyl)-hydrazonomethyl]-chromen-4-one (10). Yellow solid. Yield: 75%. m.p. 233–235 °C. Anal. calcd. for C17H11F3N2O2: C, 61.45; H, 3.34, N, 8.43. Found: C 61.23; H, 3.15; N, 8.55%. FT IR  νmax: 3319.96 (NH2), 1641.56 (C=O), 1584.02 (CH=N), 1274.36 (C-O). 1H-NMR δ: 9.98 , 8.88 , 8.51 , 8.15–8.17 , 7.84–7.86 , 7.83–7.82 , 7.72–7.74 , 7.53–7.57 , 6.95–6.96 . 13C-NMR δ: 188.8 (-CF3), 175.5 (C=O), 159.6 (Ar-Cq), 156.2 (CH), 153.8 (Ar-Cq), 142.8 (CH), 137.8 (Ar-CH), 134.9 (=CH-), 133.8 (CH), 126.3 (Cq), 125.7 (CH), 124.0 (CH), 122.5 (Cq), 119.3 (Cq), 119.1 (CH), 115.7 (Ar-CH), 111.9 (Ar-CH). HRMS (ESI) m/z calcd. for C17H12F3N2O2 (M + H)+: 333.0851, found 333.0858.Complex of 4-Fluorobenzoic acid [1-(4-oxo-4H-chromen-3-yl)-meth-(E)-ylidene]-hydrazide with Cu (II) (11). Green solid. Yield: 65%. m.p. > 300 °C. Anal. calcd. for C17H11ClCuFN2O3: C, 49.88; H, 2.69; N, 6.85. Found: C, 50.07; H, 3.07, N: 6.32%. FT IR  νmax: 1636.91 (C=O), 1573.46 (CH=N), 1239.25 (C-O), 614.26 (Cu-N). HRMS (ESI) m/z calcd. for C17H12ClCuFN2O3 (M + H)+: 410.9973, found 411.0966.α and ω scan. The measurements were carried out at low temperature for 1, 8 and 10 whereas at room temperature for 3 and 5. The X-ray data were corrected for absorption [1, 3, 5, 8 and 10 have been deposited with the Cambridge Crystallographic Data Centre (CCDC nos.1851685–1851689). These data can be obtained free of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html .Single crystal X-ray data were collected on a micro-focus SuperNova diffractometer  with an Atlas detector using MoKsorption . All strsorption  and refisorption . The crysorption  and MERCsorption  were useCandida albicans ATCC 10231, Enterococcus faecalis ATCC 29212, Klebsiella pneumoniae ATCC 700603, Pseudomonas aeruginosa NCTC 6749, Proteus vulgaris CCM 1799, Staphylococcus epidermidis ATCC 12228, Shigella flexneri ATCC 12022, Streptococcus pneumoniae ATCC 49619, Streptococcus pyogenes ATCC 19615, Corynebacterium jeikeium K411, Escherichia coli ATCC 25922, Staphylococcus aureus NCTC 4135, Streptococcus dysgalactiae subsp. equisimilis ATCC 12394, Neisseria meningitidis DSM 25942, Listeria monocytogenes PCM 2191.The microbial reference strains representing different families of bacteria and fungi, pathogenic for man and animals, were used. The 15 strains were derived from international microbial collections held by the Department of Pharmaceutical Microbiology and Microbiological Diagnostics of the Medical University of Lodz: Corynebacterium jeikeium) Triptic Soy Agar (TSA) with the addition of sheep blood, yeast extract and Tween-80. The susceptibility of the strains to chemical compounds was measured analogously to the adopted method of diffusion and disc preparation of antibiotics for compounds introduced into treatment [The strains were stored at −80 °C, frozen in a 1:1 mixture of Brain Heart Infusion (BHI) broth and glycerol. The reference strains, depending on the growth requirements, were grown on a solid medium—nutrient agar, nutrient agar with 5% addition of lambs defibrinated blood or (in the case of reatment . After r2. Cells were plated and grown to 80% confluence before the initiation of the assay.The mouse fibroblast cell line L929 (Sigma-Aldrich) was grown in MEM   containing 10% of Fetal Bovine Serum (Biowest), 1 mmol/L sodium pyruvate , 0.5 mmol/L non-essential amino acids (Sigma-Aldrich) and 100 units/mL penicillin with 100 mg/mL streptomycin  in an incubator at 37 °C with 5% CO2 to 80% confluence before the initiation of the assay.The EA.hy926 cell line  was used to evaluate the cytotoxicity of novel compounds. Cells were grown in Dulbecco’s Modified Eagle’s Medium (DMEM) which contains 10% of Fetal Bovine Serum (Biowest), 2 mmol/L glutamine (Sigma-Aldrich) and 100 units/mL penicillin with 100 mg/mL streptomycin . Cells were plated and grown in an incubator at 37 °C with 5% COThe XTT assay was used to evaluate cell metabolic activity ,43. In v4 cells per well. They were cultured for 24 h in the incubator (37 °C and 5% CO2). After that time, the medium was removed. Then the 100 µL of medium containing investigated compounds (in the range of concentration 0.01–1250 µmol/L) or only culture medium (blank control) were added. Cisplatin was used as a reference compound. Cells were further incubated for 24 h. At the third day, the old medium were removed and cells were washed with PBS. 100 µL of culture medium with the additional 50 µL of the XTT/PMS solution were added to each well. Plates were incubated in the dark for 3 h at 37 °C. Then, the plates were swayed and an aliquot of 100 µL from each well was transferred into the corresponding well of a new plate. Finally, the absorbance was measured by using the microplate reader  at a wavelength of 450 nm. The cell viability was expressed as a percentage of the control values (blanks).L929 and EA.hy926 cells were seeded into 96-well plates at a density of 1 × 10t-test and the Shapiro-Wilk test. The significance levels were set at p < 0.05 for the t-test and p > 0.05 for the Shapiro-Wilk test.All statistical analyses were performed using Statistica  software . The dat1, 4, 7, 9, 10, 11 were found to exhibit antimicrobial potential. Tested compounds were able to inhibit specific microbial growth during the experiment. A good number of synthesized compounds exhibited comparable or higher antiproliferative activities than the control drug cisplatin. 5 and 11 were found to possess IC50 values below 1 µmol/L on EA.hy926 cell line. This supports the hypothesis that hydrazide derivatives of 3-formylchromone constitute a class of potential antiproliferative agents.The presented method for synthesizing hydrazine or hydrazide derivatives of 3-formylchromone with fluorine substituents resulted in the creation of novel ligands which can be used to synthesize the respective complexes with metal ions. Eight hydrazine and two hydrazide derivatives of chromone with fluorine substituents were obtained as a result of chemical condensation of 3-formylchromone with respective hydrazines or hydrazide. X-ray single-crystal studies confirmed that in all structures, the hydrazine moiety is oriented similarly with respect to the chromone ring. The bond lengths and angles were found to be in good agreement to each other. The crystal packing appeared to be dominated by N-H···O interactions, with hydrogen-bonded dimers being the preferred structural motif. The reaction of the ligand with copper (II) chloride resulted in neutral mononuclear complex. All compounds described in this paper were initially tested for antimicrobial properties, and


H)-one compounds (DHPMs) possess extensive biological activities and are mainly prepared via Biginelli reaction and N-alkylation. In the present study, selective alkylation of N1 was investigated by using tetrabutylammonium hydroxide. In vitro cytotoxicity study on all synthesized compounds demonstrated that introduction of the aryl chain in the R3 as well as the low electron-donating group in the R1 of DHPMs contributed to the anti-proliferative potency. A larger value of the partition coefficient (Log P) and suitable polar surface area (PSA) values were both found to be important in order to maintain the antitumor activity. The results from in vivo study indicated the great potential of compound 3d to serve as a lead compound for novel anti-tumor drugs to treat glioma. Pharmacophore study regarding the structure-activity relations of DHPMs were also conducted. Our results here could provide a guide for the design of novel bioactive 3,4-dihydropyrimidin-2(1H)-one compounds. 3,4-dihydropyrimidin-2(1 Noncommunicable diseases (NCDs) are a major threat to global health, causing a significant amount of death every year. Second only to cardiovascular disease, cancer is becoming a global burden which lead to an estimation of 8.7 million deaths in 2015 . UnfortuThe interests of using DHPMs in medicinal chemistry is dramatically growing  due to t1 is usually an aryl group, such as phenyl or pyridyl, while R2 is an ester or amide group and R3 is an alkyl group, such as methyl or ethyl. General method for the synthesis of DHPMs starts with firstly obtaining the basic scaffold via Biginelli reaction followed by N alkylation. Mohammadi and Behbahani reviewed the synthesis of DHPMs and improved procedures for the preparation of DHPMs under solvent-free conditions or with the presence of solvent undec-7-ene (DBU) and tetramethylguanidine (TMG). Interestingly, when tetrabutylammonium hydroxide was selected as the base, the yield was similar to that of cesium carbonate (Cs2CO3), while no dialkyl products was found  measured for the distinct compounds investigated were comprised in 50 in the micromolar range against U87 and U251 cell lines. These results evidenced that although compounds 1d , 1h , 3d , and 3g  did not display stronger cytotoxic activity on the U87 and U251 cell lines compared to positive control, they can still possess certain cytotoxic activity in micromolar range. In the present study, it was verified that the alkyl chain or aryl chain in the R3, and low electron-donating ability or low electron-withdrawing ability in the R1 displayed obvious effect. As expected, all of the four compounds especially 3d displaying high Log P (5.01) values and suitable PSA (58.64).The values of 50% inhibitory concentration , or compound 3d (100 mg/kg), or compound 3g (100 mg/kg). The results of representative studies were summarized in 3d or 3g were able to significantly inhibit tumor growth, with inhibition ratios (IR) of 54.9% and 34.3%, respectively. The compound 3d produced a similar antitumor activity compared with BIIB021 (IR 59.7%). This study had shown that the aryl chain in the R3, and 4-biphenyl low electron-donating group in the R1 had a moderate growth inhibitory effected on xenograft tumor model. The compound 3d also had suitable Log P and PSA values. Although the compounds were less active when compared to the positive control, compound 3d had the potential to serve as lead compound and be further optimized to improve activity.We further investigated the efficacy of compounds 2 position and X position. Hydrophobic center is the DHPMs parent ring, R1 position and R3 position.According to previous studies, thirteen substituted DHPMs with good anticancer activities were selected to generate pharmacophores and guide the design of novel DHPMs derivatives . Galahad254 plates. Melting points were measured on an XT3A micro-melting point apparatus and are uncorrected . 1H NMR and 13C NMR spectra were recorded with a Bruker AV-400 instrument or a Bruker AV-300 . Chemical shifts were reported as δ values (ppm) from internal reference tetramethylsilane (TMS). All coupling constants were reported in hertz (Hz), and proton multiplicities were labeled as br (broad), s (singlet), d (doublet), dd (doublet of doublets), t (triplet), q (quartet), and m (multiplet). HR-MS were performed on a Waters Vion IMS Q-tof .All reagents were obtained from commercial suppliers and were used without any further purification unless otherwise stated. Column chromatography was performed using an SRL silica gel (200–300 mesh). Thin layer chromatography was performed using Merck silica gel GF2SO4 and the solvent was removed under reduced pressure. Column chromatographic purification using a methanol in dichloromethane gradient (dichloromethane: methanol = 60:1–5:1) yielded compounds 1a–8e.Tetrabutylammonium hydrogen sulfate (TBAS 0.1 eq) was added to a solution of ethyl 4-(4-bromophenyl)-6-methyl-2-oxo-1, 2, 3, 4-tetrahydropyrimidine-5-carboxylate  and tetrabutylammonium hydroxide  in anhydrous DMF (4.0 mL). The mixture was stirred at 45 °C for 1.5 h under anhydrous condition. Then 2-chlorobenzyl chloride , potassium iodide (0.1 eq) were added to the reaction mixture slowly and stirred at 45 °C for 16 h. Saturated NaCl solution (25 mL) was added and then the reaction mixture was extracted with ethyl acetate (3 × 25 mL). The combined organic layer was washed with water (2 × 50 mL), followed by brine solution (1 × 50 mL). The organic layer was dried over anhydrous NaEthyl 4-(4-bromophenyl)-1-(4-methoxy-4-oxobutyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (1a). White solid, m.p.: 92.4–95.0 °C, yield: 8.0%, Rf value: 0.5 (CH2Cl2: CH3OH=20:1). 1H NMR  δ 7.44 , 7.14 , 5.53 , 5.35 , 4.12 , 3.98–3.88 , 3.71 , 3.66 , 2.57 , 2.35–2.24 , 2.00–1.77 , 1.20 . 13C NMR  δ 173.35 (C=O), 165.98 (C=O), 153.11 (C=O), 150.50 (Ar-C), 143.74 (C-N), 131.86 (2 × Ar-C), 128.82 (2 × Ar-C), 120.95 (Br-Ar-C), 103.30 (C=C), 60.24 (CH2), 52.28 (CH), 51.88 (CH3), 41.43 (CH2), 30.67 (CH2), 24.98 (CH2), 16.08 (CH3), 14.56 (CH3). HRMS (ESI): m/z calcd for C19H23BrN2O5 [M + H]+ 439.0869, found 439.0868.Ethyl 4-(4-bromophenyl)-1-(3-ethoxy-3-oxopropyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (1b). White solid, m.p.: 126.8–127.0 °C, yield: 52.2%, Rf value: 0.6 (CH2Cl2: CH3OH=20:1). 1H NMR  δ 7.48–7.42 , 7.25 , 5.37 , 4.19–4.05 , 3.83–3.73 , 3.29–3.20 , 2.70 , 2.49–2.38 , 2.33 , 1.25 . 13C NMR  δ 171.71 (C=O), 165.37 (C=O), 152.05 (C=O), 148.21 (Ar-C), 142.66 (C-N), 132.08 (2 × Ar-C), 129.58 (2 × Ar-C), 121.40 (Br-Ar-C), 100.21 (C=C), 60.57 (2 × CH2), 59.97 , 33.09 (CH2), 18.10 (CH3), 14.54 (2 × CH3). HRMS (ESI): m/z calcd for C19H23BrN2O5 [M + H]+ 439.0869, found 439.0870.Ethyl 4-(4-bromophenyl)-1-(2-chlorobenzyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (1c). White solid, m.p.: 125.6–127.8 °C, yield: 35.1%, Rf value: 0.5 (CH2Cl2: CH3OH=20:1). 1H NMR  δ 7.41 , 7.36 , 7.26 , 7.16 , 6.90 , 6.48 , 5.44 , 5.06 , 4.11 , 2.38 , 1.18 . 13C NMR  δ 165.33 (C=O), 152.34 (C=O), 148.46 (2 × Ar-C), 141.90 (C-N), 134.59 (Ar-C-Cl), 132.88 (2 × Ar-C), 132.15 (2 × Ar-C), 130.04 (Ar-C), 129.59 (Ar-C), 129.34 (Ar-C), 128.00 (Ar-C), 121.56 (Br-Ar-C), 100.15 (C=C), 60.01 (CH2), 59.16 , 18.21 (CH3), 14.53 (CH3). HRMS (ESI): m/z calcd for C21H20BrClN2O3 [M + H]+ 463.0424, found 463.0439.Ethyl 1-(4-bromobenzyl)-4-(4-bromophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (1d). White solid, m.p.: 190.4–191.9 °C, yield: 32.3%, Rf value: 0.7 (CH2Cl2: CH3OH=20:1). 1H NMR  δ 7.44 , 7.13 , 7.01 , 5.72 , 5.42 , 5.10 , 4.87 , 4.12 , 2.44 , 1.19 . 13C NMR  δ 165.90 (C=O), 153.29 (C=O), 150.16 (Ar-C), 143.76 (C-N), 138.63 (Ar-C), 131.90 (4 × Ar-C), 128.98 (4 × Ar-C), 121.06 (Br-Ar-C), 120.43 (Br-Ar-C), 103.75 (C=C), 60.33 (OCH2), 52.53 (CH-NH), 45.05 (N-CH2), 16.54 (CH3), 14.53 (CH3). HRMS (ESI): m/z calcd for C21H20Br2N2O3 [M + H]+ 508.9898, found 508.9901.Ethyl 4-(4-bromophenyl)-1-(4-methoxybenzyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (1e). White solid, m.p.: 136.8–139.7 °C, yield: 43.6%, Rf value: 0.5 (CH2Cl2: CH3OH=20:1). 1H NMR  δ 7.43–7.37 , 7.11 , 7.05 , 6.86–6.80 , 5.75 , 5.39 , 5.16 , 4.78 , 4.09 , 3.81 , 2.48 , 1.18 . 13C NMR  δ 165.95 (C=O), 158.70 (C=O), 153.42 (Ar-C), 150.43 (Ar-C), 143.86 (C-N), 131.83 (2 × Ar-C), 130.91 (2 × Ar-C), 128.99 (2 × Ar-C), 128.15 (Ar-C), 120.98 (Br-Ar-C), 114.41 (2×Ar-C), 103.66 (C=C), 60.27 (CH2), 55.68 (CH3), 55.44 (CH), 52.49 (CH2), 16.55 (CH3), 14.53 (CH3). HRMS (ESI): m/z calcd for C22H23BrN2O4 [M + H]+ 459.0919, found 459.0917.Ethyl 4-(4-bromophenyl)-6-methyl-2-oxo-1-propyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate (1f). White solid, m.p.: 114.7–115.3 °C, yield: 20.0%, Rf value: 0.3 (CH2Cl2: CH3OH=20:1). 1H NMR  δ 7.45 , 7.15 , 5.59 , 5.36 , 4.12 , 3.88 , 3.56 , 2.54 , 1.69–1.54 , 1.27 , 1.21 , 0.92 . 13C NMR  δ 167.36 (C=O), 154.39 (C=O), 151.87 (Ar-C), 145.26 (C-N), 133.17 (2 × Ar-C), 130.18 (2 × Ar-C), 122.22 (Br-Ar-C), 104.32 (C=C), 61.50 (OCH2), 53.73 (CH-NH), 45.12 (N-CH2), 24.38 (CH2), 17.51 (CH3), 15.90 (CH3), 12.72 (CH3). HRMS (ESI): m/z calcd for C17H21BrN2O3 [M + H]+ 381.0814, found 381.0807.Ethyl 4-(4-bromophenyl)-1-butyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (1g). White solid, m.p.: 117.5–119.3 °C, yield: 69.7%, Rf value: 0.3 (CH2Cl2: CH3OH=20:1). 1H NMR  δ 7.42 , 7.13 , 5.39 , 5.33 , 4.10 , 3.90 , 3.58 , 2.52 , 1.64 , 1.30 , 1.18 , 0.92 . 13C NMR  δ 166.02 (C=O), 153.12 (C=O), 150.58 (Ar-C), 143.92 (C-N), 131.81 (2 × Ar-C), 128.94 (Ar-C), 128.72 (Ar-C), 120.89 (Br-Ar-C), 103.17 (C=C), 60.18 (OCH2), 52.30 (CH-NH), 31.90 (N-CH2), 19.89 (CH2), 16.16 (CH3), 14.57 (CH3), 14.10 (CH3). HRMS (ESI): m/z calcd for C18H23BrN2O3 [M + H]+ 395.0970, found 395.0977.Ethyl 4-(4-bromophenyl)-1-hexyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (1h). White solid, m.p.: 161.3–161.6 °C, yield: 55.8%, Rf value: 0.5 (CH2Cl2: CH3OH=20:1). 1H NMR  δ 7.42 , 7.13 , 5.50 , 5.33 , 4.10 , 3.90 , 3.57 , 2.52 , 1.59 , 1.49 , 1.27 , 1.19 , 0.88 . 13C NMR  δ 166.04 (C=O), 153.20 (C=O), 150.68 (Ar-C), 143.84 (C-N), 131.79 (2 × Ar-C), 128.78 (2 × Ar-C), 120.91 (Br-Ar-C), 103.25 (C=C), 60.19 (OCH2), 52.12 (CH-NH), 42.07 (N-CH2), 31.51 (CH2), 29.84 (CH2), 26.35 (CH2), 22.60 (CH2), 16.17 (CH3),14.51 (CH3). HRMS (ESI): m/z calcd for C20H27BrN2O3 [M + H]+ 423.1283, found 423.1270.Ethyl 4-(4-bromophenyl)-1-(3-cyanopropyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (1i). White solid, m.p.: 128.8–129.7 °C, yield: 27.2%, Rf value: 0.4 (CH2Cl2: CH3OH=20:1). 1H NMR  δ 7.42 , 7.09 , 5.33 , 4.14 – 4.03 , 3.95–3.84 , 3.74 , 2.52 , 2.38 – 2.18 , 1.96 , 1.84 , 1.16 . 13C NMR  δ 166.04 (C=O), 153.20 (C=O), 150.69 (Ar-C), 143.84 (C-N), 131.78 (2 × Ar-C), 128.79 (2 × Ar-C), 120.91 , 103.24 (C=C), 60.19 (OCH2), 52.11 (CH-NH), 42.07 (N-CH2), 22.60 (CH3), 16.17 (CH2), 14.59 (CH2), 14.43 (CH3). HRMS (ESI): m/z calcd for C18H20BrN3O3 [M + Na]+ 428.0586, found 428.0577.Ethyl 4-(4-bromophenyl)-6-methyl-1-(4-nitrobenzyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (1j). White solid, m.p.: 183.3–184.6 °C, yield: 9.4%, Rf value: 0.6 (CH2Cl2: CH3OH=20:1). 1H NMR  δ 8.17 , 7.47–7.44 , 7.29 , 7.17–7.10 , 5.69 , 5.45 , 5.10 , 4.11 , 2.40 , 1.18 . 13C NMR  δ 165.88 (C=O), 153.21 (C=O), 149.95 (NO2-Ar-C), 147.20 (Ar-C), 147.00 (C-N), 143.70 (Ar-C), 131.96 (2 × Ar-C), 129.02 (2 × Ar-C), 127.77 (2 × Ar-C), 124.25 (2 × Ar-C), 121.12 (Br-Ar-C), 103.87 (C=C), 60.39 (OCH2), 52.59 (CH-NH), 45.51 (N-CH2), 16.56 (CH3), 14.52 (CH3). HRMS (ESI): m/z calcd for C21H20BrN3O5 [M + H]+ 474.0665, found 474.0658.Ethyl 1-(4-methoxy-4-oxobutyl)-4-(4-methoxyphenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (2a). White solid, m.p.: 87.8–90.4 °C, yield: 21.7%, Rf value: 0.4 (CH2Cl2: CH3OH=20:1). 1H NMR  δ 7.15 , 6.80 , 5.77 , 5.30 , 4.14–4.03 , 3.96–3.84 , 3.77 , 3.67 , 3.63 , 2.54 , 2.29 , 1.98–1.87 , 1.86–1.76 ,1.20–1.13 . 13C NMR  δ 173.38 (C=O), 166.18 (C=O), 159.01 (Ar-C), 153.29 (C-N), 149.61 (Ar-C), 136.54 (Ar-C), 127.75 (Ar-C), 127.71 (Ar-C), 114.24 (Ar-C), 104.21 (C=C), 60.11 (OCH2), 55.57 (OCH3), 52.27 (OCH3), 51.82 (CH-NH), 41.37 (N-CH2), 30.72 (CH2), 25.05 (CH2), 16.06 (CH3), 14.58 (CH3). HRMS (ESI): m/z calcd for C20H26BrN2O6 [M + H]+ 391.1869, found 391.1869.Ethyl 4--1-(4-methoxy-4-oxobutyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (3a). Yellow solid, m.p.: 141.5–142.7 °C, yield: 33.5%, Rf value: 0.5 (CH2Cl2: CH3OH=20:1). 1H NMR  δ 7.55 , 7.44 , 7.35 , 5.87 , 5.44 , 4.21–4.09 , 4.04–3.90 , 3.76–3.68 , 3.68–3.65 , 2.63–2.54 , 2.38–2.27 , 2.04–1.78 , 1.23 . 13C NMR  δ 173.29 (C=O), 166.08 (C=O), 153.25 (Ar-C), 150.06 (Ar-C), 143.48 (Ar-C), 140.20 (Ar-C), 139.68 (Ar-C), 129.37 (2 × Ar-C), 127.89 (2 × Ar-C), 127.21 (2 × Ar-C), 127.06 (2 × Ar-C), 103.72 (C=C), 60.16 (OCH2), 52.46 (OCH3), 51.74 (CH-NH), 41.41 (N-CH2), 30.67 (CH2), 24.99 (CH2), 16.07 (CH3), 14.56 (CH3). HRMS (ESI): m/z calcd for C25H28N2O5 [M + Na]+ 459.1896, found 459.1903. Ethyl 4--1-(2-chlorobenzyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (3c). White solid, m.p.: 189.8–190.9 °C, yield: 25.8%, Rf value: 0.5 (CH2Cl2: CH3OH=20:1). 1H NMR  δ 7.57 , 7.45 , 7.41–7.33 , 7.15 , 6.97 , 5.77 , 5.55 , 5.11 , 4.14 , 2.40 , 1.21 . 13C NMR  δ 166.03 (C=O), 153.25 (C=O), 149.75 (Ar-C), 143.39 (Ar-C), 140.25 (C-N), 139.88 (Ar-C), 135.98 (Ar-C), 131.35 (Ar-C), 129.83 (2 × Ar-C), 129.42 (2 × Ar-C), 129.03 (2 × Ar-C), 127.93 (2 × Ar-C), 127.78 (2 × Ar-C), 127.30 (2 × Ar-C), 127.13 (Ar-C), 104.07 (C=C), 60.33 (OCH2), 52.60 (CH-NH), 43.80 (N-CH2), 16.12 (CH3), 14.53 (CH3). HRMS (ESI): m/z calcd for C27H25ClN2O3 [M + H]+ 461.1632, found 461.1631. Ethyl 4--1-(4-bromobenzyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (3d). White solid, m.p.: 175.3–177.8 °C, yield: 13.3%, Rf value: 0.5 (CH2Cl2: CH3OH=20:1). 1H NMR  δ 7.59 , 7.56–7.52 , 7.47 , 7.41 , 7.38 , 7.33 , 7.04 , 5.79 , 5.52 , 5.14 , 4.88 , 4.14 , 2.46 , 1.22 . 13C NMR  δ 166.00 (C=O), 153.46 (C=O), 149.81 (Ar-C), 143.42 (C-N), 140.24 (Ar-C), 139.83 (Ar-C), 138.64 (Ar-C), 131.92 (2 × Ar-C), 131.82 (2 × Ar-C), 129.40 (2 × Ar-C),128.94 (2 × Ar-C), 127.92 (2 × Ar-C), 127.24 (Ar-C), 127.12 (2 × Ar-C), 120.34 (Br-Ar-C), 104.13 (C=C), 60.27 (OCH2), 52.59 (CH-NH), 44.97 (N-CH2), 16.50 (CH3), 14.52 (CH3). HRMS (ESI): m/z calcd for C27H25BrN2O3 [M + Na]+ 527.0946, found 527.0945.Ethyl 4--1-(4-methoxybenzyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (3e). White solid, m.p.: 163.5–165.8 °C, yield: 24.8%, Rf value: 0.5 (CH2Cl2: CH3OH=20:1). 1H NMR  δ 7.56 , 7.50 , 7.44 , 7.36 , 7.32 , 7.08 , 6.81 , 5.71 , 5.48 , 5.17 , 4.82 , 4.11 , 3.75 , 2.46 , 1.19 . 13C NMR  δ 166.06 (C=O), 158.59 (C=O), 153.60 (Ar-C), 150.08 (Ar-C), 143.52 (C-N), 140.26 (Ar-C), 139.76 (Ar-C), 130.92 (2 × Ar-C), 129.40 (2 × Ar-C), 128.10 (2 × Ar-C), 127.91 (2 × Ar-C), 127.35 (2 × Ar-C), 126.96 (2 × Ar-C), 114.32 (2 × Ar-C), 104.05 (C=C), 60.21 (OCH2), 55.40 (OCH3), 52.59 (CH-NH), 44.75 (N-CH2), 16.51 (CH3), 14.52 (CH3). HRMS (ESI): m/z calcd for C28H28N2O4 [M + Na]+ 457.2127, found 457.2127.Ethyl 4--1-butyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (3g). White solid, m.p.: 161.2–165.8 °C, yield: 19.9%, Rf value: 0.5 (CH2Cl2: CH3OH=20:1). 1H NMR  δ 7.58–7.50 , 7.43 , 7.37–7.30 , 5.42 , 4.13 , 3.98–3.87 , 3.62 , 2.55 , 1.64–1.50 , 1.31 , 1.21 , 0.92 . 13C NMR  δ 166.12 (C=O), 153.25 (C=O), 150.18 (Ar-C), 143.64 (C-N), 140.24 (Ar-C), 139.67 (Ar-C), 129.38 (2 × Ar-C), 127.87 (2 × Ar-C), 127.18 (2 × Ar-C), 127.09 (2 × Ar-C), 127.08 (Ar-C), 103.52 (C=C), 60.12 (OCH2), 52.49 (CH-NH), 41.87 (N-CH2), 31.91 (CH2), 19.88 (CH2), 16.15 (CH3), 14.56 (CH3), 14.10 (CH3). HRMS (ESI): m/z calcd for C24H28N2O3 [M + H]+ 393.2168, found 393.2178.Ethyl 4--1-hexyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (3h). White solid, m.p.: 114.4–117.4 °C, yield: 50.5%, Rf value: 0.4 (CH2Cl2: CH3OH=20:1). 1H NMR  δ 7.57–7.48 , 7.42 , 7.33 , 5.99 , 5.42 , 4.13 , 3.99–3.87 , 3.57 , 2.54 , 1.68–1.44 , 1.25 , 1.21 , 0.85 . 13C NMR  δ 166.13 (C=O), 153.31 (C=O), 150.26 (Ar-C), 143.58 (C-N), 140.22 (Ar-C), 139.64 (Ar-C), 129.35 (2 × Ar-C), 127.86 (2 × Ar-C), 127.13 (3 × Ar-C), 127.04 (2 × Ar-C), 103.56 (C=C), 60.12 (OCH2), 52.34 (CH-NH), 42.04 (N-CH2), 31.48 (CH2), 29.83 (CH2), 26.3 (CH2), 22.54 (CH2), 16.15 (CH3), 14.57 (CH3), 14.33 (CH3). HRMS (ESI): m/z calcd for C26H32N2O3 [M + H]+ 421.2491, found 421.2488.1-(4-methoxy-4-oxobutyl)-6-methyl-4-(4-morpholinophenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4a). Orange solid, m.p.: 123.1–125.4 °C, yield: 20.3%, Rf value: 0.7 (CH2Cl2: CH3OH=10:1). 1H NMR  δ 7.14 , 6.83 , 5.49 , 5.29 , 4.14–4.05 , 3.95–3.86 , 3.87–3.82 , 3.68 , 3.65 , 3.16–3.09 , 2.55 , 2.38–2.25 , 1.99–1.89 , 1.84 , 1.22 – 1.14 . 13C NMR  δ 173.32 (C=O), 166.16 (C=O), 153.27 (Ar-C), 150.77 (C-N), 149.33 (Ar-C), 135.01 (Ar-C), 127.15 (2 × Ar-C), 115.33 (Ar-C), 104.18 (C=C), 66.52 (2 × OCH2), 60.02 (OCH3), 52.21 (N-CH2), 51.79 (N-CH2), 48.87 (N-CH2), 41.32 (CH-NH), 30.69 (CH2), 25.01 (CH2), 16.00 (CH3), 14.55 (CH3). HRMS (ESI): m/z calcd for C23H31N3O6 [M + Na]+ 468.2111, found 468.2105.Ethyl 1-(4-methoxy-4-oxobutyl)-6-methyl-4-(4-nitrophenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (5a). Yellow solid, m.p.: 108.4–111.2 °C, yield: 17.8%, Rf value: 0.7 (CH2Cl2: CH3OH=10:1). 1H NMR  δ 8.16 , 7.42 , 5.66 , 5.47 , 4.11 , 3.96–3.83 , 3.73–3.60 , 2.56 , 2.32–2.23 , 1.98–1.74 , 1.18 . 13C NMR  δ 173.24 (C=O), 165.77 (C=O), 152.93 (Ar-C), 151.64 (C-N), 151.16 (Ar-C), 147.21 (Ar-C), 127.89 (2 × Ar-C), 124.28 (Ar-C), 102.758 (C=C), 60.30 (OCH2), 52.37 (OCH3), 51.75 (N-CH2), 41.47 (CH-NH), 30.62 (CH2), 16.08 (CH3), 14.50 (CH3) HRMS (ESI): m/z calcd for C19H23N3O7 [M + H]+ 406.1614, found 406. 1611.Ethyl 1-(4-methoxy-4-oxobutyl)-6-methyl-2-oxo-4-(pyridin-4-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate (6a). Yellow solid, m.p.: 97.8–100.3 °C, yield: 21.7%, Rf value: 0.6 (CH2Cl2: CH3OH=10:1). 1H NMR  δ 8.54 , 7.20 , 6.00 , 5.39 , 4.15 , 3.90 , 3.67 , 3.66–3.60 , 2.56 , 2.29 , 1.79 , 1.21 . 13C NMR  δ 173.14 (C=O), 165.73 (C=O), 153.04 (2 × Pyridine-C), 152.474 (C=O), 151.02 (2 × Pyridine-C), 150.27 (C-N), 121.45 (2 × Pyridine-C), 102.45 (C=C), 60.19 (CH2), 51.75 (Ar-CH), 41.40 (CH2), 30.57 (CH2), 24.83 (CH2 2), 15.97 (CH3), 14.41 (CH3). HRMS (ESI): m/z calcd for C18H23N3O5 [M + H]+ 362.1716, found 362.1704.4-(4-bromophenyl)-1-(2-chlorobenzyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (7c). White solid, m.p.: 186.4–188.5 °C, yield: 14.6%, Rf value: 0.5 (CH2Cl2: CH3OH=10:1). 1H NMR  δ 7.51 , 7.38 , 7.24 , 7.08 – 7.04 , 5.83 , 5.36 , 5.05 , 2.19 . 13C NMR  δ 169.09 (C=O), 153.52 (C=O), 143.36 (Ar-C), 138.64 (Ar-C), 136.65 (C-N), 131.83 (Ar-C-Cl), 131.39 (2 × Ar-C), 129.83 (2 × Ar-C), 129.28 (Ar-C), 129.00 (Ar-C), 127.82 (Ar-C), 127.30 (Ar-C), 121.10 (Br-Ar-C), 109.76 (C=C), 53.96 (CH), 43.34 (CH2), 16.36 (CH3). HRMS (ESI): m/z calcd for C19H17BrClN3O2 [M − H]− 432.0114, found 432.0110.1-(4-bromobenzyl)-4-(4-bromophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (7d). White solid, m.p.: 280.3–280.7 °C, yield: 58.2%, Rf value: 0.7 (CH2Cl2: CH3OH=10:1). 1H NMR  δ 7.56–7.43 , 7.15 , 7.03 , 5.17 , 4.92 , 4.67 , 2.02 . 13C NMR  δ 169.06 (C=O), 153.73 (C=O), 143.42 (Ar-C), 139.33 (C-N), 138.70 (Ar-C), 131.80 (4 × Ar-C), 129.19 (2 × Ar-C), 129.07 (2 × Ar-C), 121.03 (Br-Ar-C), 120.29 (Br-Ar-C), 109.88 (C=C), 53.91 (CH), 44.61 (CH2), 16.75 (CH3). HRMS (ESI): m/z calcd for C19H17Br2N3O2 [M + H]+ 477.9766, found 477.9769.4-(4-bromophenyl)-1-(4-methoxybenzyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (7e). White solid, m.p.: 256.4–257.9 °C, yield: 73.8%, Rf value: 0.6 (CH2Cl2: CH3OH=10:1). 1H NMR  δ 7.80 , 7.48 , 7.34 , 7.14 , 6.99 , 6.81 , 5.16 , 4.92 , 4.58 , 3.69 , 2.04 . 13C NMR  δ 168.97 (C=O), 158.48 (Ar-C-O), 153.71 (C=O), 143.42 (Ar-C), 138.98 (C-N), 131.59 (2 × Ar-C), 131.52 (2 × Ar-C), 129.08 (2 × Ar-C), 128.01 (Ar-C), 120.81 (Br-Ar-C), 114.19 (2 × Ar-C), 109.58 (C=C), 55.44 (CH3), 53.73 (CH), 44.29 (CH2), 16.59 (CH3). HRMS (ESI): m/z calcd for C20H20BrN3O3 [M + Na]+ 452.0586, found 452.0571.4-(4-bromophenyl)-6-methyl-2-oxo-1-propyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide (7f). White solid, m.p.: 238.4–239.5 °C, yield: 21.7%, Rf value: 0.5 (CH2Cl2: CH3OH=10:1). 1H NMR  δ 7.60 , 7.49 , 7.15 , 5.09 , 3.73–3.61 , 2.47 , 2.13 , 0.72 . 13C NMR  δ 169.36 (C=O), 153.59 (C=O), 143.56 (Ar-C), 138.96 (C-N), 131.74 (2 × Ar-C), 129.06 (2 × Ar-C), 120.88 (Br-Ar-C), 109.67 (C=C), 53.71 (CH), 43.37 (CH2), 23.24 (CH2), 16.60 (CH3), 11.46 (CH3). HRMS (ESI): m/z calcd for C15H18BrN3O2 [M + Cl]− 386.0271, found 386.0269.Methyl 4-(4-(4-bromophenyl)-6-methyl-2-oxo-5-(phenylcarbamoyl)-3,4-dihydropyrimidin-1(2H)-yl)butanoate (8a). White solid, m.p.: 182.4–185.0 °C, yield: 25.2%, Rf value: 0.5 (CH2Cl2: CH3OH=10:1). 1H NMR  δ 9.89 , 7.77 , 7.54 , 7.27 , 7.22 , 7.03 , 5.22 , 3.86–3.76 , 3.59 , 3.43 , 2.24 , 2.15 , 1.80 , 1.70–1.60 . 13C NMR  δ 173.33 (C=O), 166.18 (C=O), 153.36 (C=O), 143.19 (Ar-C), 139.38 (C-N), 138.66 (Ar-C-NH), 131.75 (2 × Ar-C), 129.02 (2 × Ar-C), 128.82 (2 × Ar-C), 123.80 (Ar-C), 120.91 (2 × Ar-C), 120.04 (Br-Ar-C), 110.23 (C=C), 53.86 (CH), 51.74 (CH3), 40.95 (CH2), 30.71 (CH2), 25.16 (CH2), 16.66 (CH3). HRMS (ESI): m/z calcd for C23H24BrN3O4 [M + H]+ 486.1028, found 486.1016.1-(4-bromobenzyl)-4-(4-bromophenyl)-6-methyl-2-oxo-N-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide (8d). White solid, m.p.: 171.8–175.2 °C, yield: 16.7%, Rf value: 0.4 (CH2Cl2: CH3OH=10:1). 1H NMR  δ 9.87 , 7.94 , 7.54–7.45 , 7.26–7.15 , 7.10 , 6.98 , 5.28 , 4.93 , 4.72 , 2.00 . 13C NMR  δ 165.58 (C=O), 152.83 (C=O), 144.02 (Ar-C), 139.51 (C-N), 139.06 (Ar-C-NH), 131.75 (Ar-C), 128.92 (4 × Ar-C), 123.55 (6 × Ar-C), 120.79 (Ar-C), 120.04 (4 × Ar-C), 105.40 (C=C), 55.00 (CH), 48.99 (CH2), 17.44 (CH3). HRMS (ESI): m/z calcd for C25H21Br2N3O2 [M + H]+ 556.0058, found 556.0043.4-(4-bromophenyl)-1-(4-methoxybenzyl)-6-methyl-2-oxo-N-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide (8e). White solid, m.p.: 191.7–193.5 °C, yield: 28.7%, Rf value: 0.5 (CH2Cl2: CH3OH=10:1). 1H NMR  δ 9.90 , 7.92 , 7.53 , 7.29–7.20 , 7.09 , 7.03 , 6.88 , 5.31 , 4.97 , 4.69 , 3.74 , 2.06 . 13C NMR  δ 166.19 (C=O), 158.68 (Ar-C-O), 153.74 (C=O), 143.43 (Ar-C), 139.48 (C-N), 139.05 (Ar-C-NH), 131.86 (2 × Ar-C), 131.61 (2 × Ar-C), 129.15 (2 × Ar-C), 129.10 (2 × Ar-C), 128.21 (Ar-C), 123.95 (Ar-C), 121.09 (2 × Ar-C), 120.28 (Br-Ar-C), 114.39 (2 × Ar-C), 109.96 (C=C), 55.60 (CH3), 54.35 (CH), 44.57 (CH2), 16.94 (CH3). HRMS (ESI): m/z calcd for C26H24BrN3O3 [M + H]+ 506.1079, found 506.1069.Ethyl 4-(4-bromophenyl)-1,3-bis(2-chlorobenzyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate. White solid, m.p.: 145.1-146.6 °C, yield: NA. 1H NMR  δ 7.48-7.41 , 7.41 -7.33 , 7.31-7.24 , 7.24-7.12 , 5.38 , 5.29 , 5.12 , 4.11 , 4.05 , 2.39 , 1.19 . 13C NMR  δ 165.47 (C=O), 153.08 (C=O), 149.52 (Ar-C), 140.96 (C-N), 135.74 (Ar-C), 134.47 (Ar-C), 133.00(Ar-C), 132.20(Ar-C), 131.56 (2 × Ar-C), 130.12 (2 × Ar-C), 129.95 (Ar-C), 129.87 (Ar-C), 129.78 (Ar-C), 129.41 (Ar-C), 129.22 (Ar-C), 127.95 (Ar-C), 127.83 (Ar-C), 127.43 (Ar-C), 121.70 (Br-Ar-C), 104.15 (C=C), 60.54 (CH), 57.84 (CH2), 47.89 (CH2), 45.28 (CH2), 16.29 (CH3), 14.48 (CH3). HRMS (ESI): m/z calcd for C28H25BrCl2N2O3 [M+H]+ 587.0504, found 587.0520.1 selectivity, we designed orthogonal tests table of different aspects to optimize the reaction, including temperature, time, amount of solvent, dosing interval, the presence of a phase transfer catalyst, different mole equivalent of base and halohydrocarbons. Each condition set include two variables of low dose and high dose (L8(27) were applied to analyze the influence of the seven factors above on the selectivity and yield of N1-alkylation of DHPMs.In order to investigate the effects of reaction conditions on Nigh dose . Orthogo1-alkylation of DHPMs in tetrabutylammonium hydroxide system were shown in 1-alkylation selectivity. According to the importance of influence, they were sorted into temperature (R 36.9), dosing interval (R 22.3), reaction time (R 19.5), phase transfer catalyst (R 16.5) and mole ratio of halohydrocarbons (R 11.9). Two other factors, the mole equivalent of base and the amount of solvent, had little effect on yield (R<10). Therefore, the yield could be increased by raising the reaction temperature and prolonging the reaction time. Meanwhile the selectivity was maintained.Results of orthogonal tests for N1-alkylation of DHPMs was synthesized from compound 1, compound 2. The optimal conditions were the mole ratio 1:1.8:1.7 , DMF 20 mL/g, TBA was added as a catalyst. After the reaction of compound 1 and TBA in DMF for 1.5 h, compound 2 and potassium iodide(KI) were added to the mixture and stirred for 16 h at 45 °C.In accordance with the requirements of saving raw materials and lowering costs, 1.7 equivalents of tetrabutylammonium hydroxide, and other conditions selected better factors for orthogonal tests were selected. The N2 culture flasks at 37 °C in a humidified air incubator with 5% CO2. The high-glucose Dulbecco´s modified Eagle medium (DMEM) supplemented with 10% fetal bovine serum , and penicillin-streptomycin  was used to culture cells. For all cell lines, the medium was renewed every 2 days until cells reach approximately 90–95% confluence. Then, they were detached by trypsin  and before the experiments, cells were counted using a hemocytometer and suitably diluted in the adequate complete culture medium.U87, U251, Hela and A549 cell lines were obtained from Stem Cell Bank, Chinese Academy of Sciences. They were maintained in 75 cmBIIB021 was purchased from Aladdin Industrial Co. . The remaining compounds were synthesized in the authors laboratory. All compounds were dissolved individually in DMSO in a concentration of 10 mM and stored at −20 °C. From this stock solution, the various working solutions of the compounds in different concentrations were prepared by adequate dilutions in the complete culture medium before each experiment.4 cells/mL was seeded in 96-well culture plates and left to adhere for 24 h. After adherence, the medium was replaced by the several solutions of the compounds in study  in the appropriate culture medium for approximately 72 h. Untreated cells were used as the negative control. Each experiment was performed in triplicate and independently repeated. Then, the medium was removed, 20 µL of the MTT solution (5 mg/mL), prepared in the appropriate serum-free medium, was added to each well, followed by incubation for approximately 3 h at 37 °C. Then, the MTT containing medium was removed and the formazan crystals were dissolved in DMSO. The absorbance was measured at 570 nm using a microplate reader Bio-rad Xmark spectrophotometer . After background subtraction, cell proliferation values were expressed as percentage relatively to the absorbance determined in negative control cells.The in vitro antiproliferative effects were evaluated by the 3--2,5-diphenyltetrazolium bromide  assay ,32. Afte6) were inoculated subcutaneously in right frank regions. The mice were divided into four groups randomly as control, BIIB021 (30 mg/kg), 303 (100 mg/kg), and 305(100 mg/kg) with eight mice per group. The mice were intra-gastric administration once a day for compound 3d and 3g starting from the second day, and body weights was measured every 3 days. At the end of treatment, animals were euthanized and the tumors were stripped and weighed after two weeks. All data were expressed as mean ± SD (n = 5). * p < 0.05, compared with control group. The use of animals was approved by the Animal Experimentation Ethics Committee of Yantai University (protocol number 20180601) in accordance with the guidelines for ethical conduct in the care and use of animals.C57 mice  were used to establish the xenograft tumors following our published Protocol ,34. In bThe logarithm of the partition coefficient (Log P) properties of compounds were calculated by ACD/labs 6.00.The GALAHAD module of Sybyl-X 2.0  was used to generate pharmacophore. Thirteen DHPMs derivatives were selected with good activity against anticancer. All the structures are attached in 1 and N3 dialkylation of DHPMs. Selective alkylation of N1 was achieved with the use of tetrabutylammonium hydroxide. All the synthesized derivatives were screened for their anti-proliferative activity in U87, U251, Hela and A549 cell lines using the MTT assay. The study demonstrated that these compounds were more selective toward glioma tumor types. Introduction of the aryl or alkyl chain in the R3, and low electron-donating group in the R1 of DHPMs exhibited potent anti-proliferative activity. The in vivo efficacy study showed that compound 3d may have the potential to serve as lead compound for novel anti-tumor drugs to treat glioma. The study may provide a foundation for the future development of DHPMs as a new anti-tumor drug.A wide range of organic bases had been selected to study the N


Diagnosis of urethral cavernous hemangioma (UCH) is very rare. It can be easy to misdiagnose and mistreat due to its atypical clinical manifestations and a lack of relevant knowledge. The study is to explore the diagnosis, differential diagnosis, and treatment of UCH.The first patient was a 15-year-old male, who was admitted to the hospital for more than 1 year with repeated hematuria. UCH was diagnosed by cystoscope biopsy, and cured with local injection of pingyangmycin. The second patient was a 49-year-old male, who was admitted for repeated painless gross hematuria and intermittent urethral bleeding after penile erection for more than 20 years. The case had been misdiagnosed as seminal vesiculitis, urethritis, or prostatitis, for over 20 years, until it was diagnosed as UCH by MR examination of the penis. It was treated by injection of pingyangmycin into the hemangioma’s lumen and base. A small incision in the ventral penile area was separated from the location of the hemangioma, which was injected with pingyangmycin again. A biopsy of resected tissue further confirmed the diagnosis of UCH.UCH is an easily misdiagnosed disease. Intermittent painless hematuria is important characteristic of UCH. Local injection of pingyangmycin is a good option for treatment of UCH.The online version of this article (10.1186/s12894-019-0441-0) contains supplementary material, which is available to authorized users. Urethral cavernous hemangioma (UCH) is an unusual disease and a few cases have been reported –7. It caThe first patient was a 15-year-old male. After 1 year of repeated gross hematuria, he was admitted to the Department of Nephrology in our hospital on November, 2002. Urinary system ultrasound, intravenous pyelography, contrast enhancement and plain CT scans of the kidney, and renal biopsy were performed. However a cause of the patient’s hematuria could not be identified. Later, the patient was transferred to pediatric surgery and cystourethroscopy was performed. The results showed urethral mucosa edema, mass and miliary bulging, and bleeding of the membranous urethra. The urethral mucosa biopsy was also performed, and the pathological report displayed submucosal vascular dilatation of the urethra which is consistent with UCH  or the urethral bleeding caused by sexual activity.At present, the common treatment of hemangioma includes drugs, physical therapy, and surgery. Drug treatments include oral propranolol, oral or injection of glucocorticoid, local injection of pingyangmycin, etc. , 9. PhysPingyangmycin is a commonly used antitumor drug. This drug mainly inhibits the synthesis of deoxynucleic acid and ribonucleic acid, decomposes deoxyribonucleic acid, breaks the DNA chain and produces oxygen free radicals, prevents DNA replication, and interferes with cell division and proliferation . HemangiOur study is limited because it included only two patients from China. And no female patients included. Our application of pingyangmycin injection for treatment of UCH may be optimal only to patients with small tumor size.In conclusion, UCH is a hemangioma deep in the penis. The most common presentation of UCH is intermittent hematuria which is typically painless. This disease is easily misdiagnosed. For patients complaining with long lasting hematuria or bloody sperm, we should inquire about the characteristics of urinating blood and its relationship with the discharge of sperm. For suspected patients, we should take a cystoscopy and MR of the penis. It is advisable to apply pingyangmycin injection for treatment, and the prognosis is generally good.Additional file 1:Video S1. Urethroscopy examination video. After artificial erection of the penis, urethroscopy showed that the 0.3 cm fissure located in the 11 o’clock urethral mucosa 2 cm away from the urethral meatus. The fissure bled and the bleeding was aggravated when the penis was squeezed. (AVI 2906 kb)


Accompanying the advent of wireless networking and the Internet of Things (IoT), traditional augmented reality (AR) systems to visualize virtual 3D models of the real world are evolving into smart and interactive AR related to the context of things for physical objects. We propose the integration of AR and IoT in a complementary way, making AR scalable to cover objects everywhere with an acceptable level of performance and interacting with IoT in a more intuitive manner. We identify three key components for realizing such a synergistic integration: (1) distributed and object-centric data management (including for AR services); (2) IoT object-guided tracking; (3) seamless interaction and content interoperability. We survey the current state of these respective areas and herein discuss research on issues about realizing a future smart and interactive living environment. Recently, augmented reality (AR) and the Internet of Things (IoT) have received significant attention as key enabling technologies for making spaces smarter and more interactive ,2,3,4. AAR and IoT might have different objectives with seemingly unrelated concepts, but they can, in fact, be complementary to each other ,12. FirsTo further promote this idea, that is, the synergistic marriage of AR and IoT, this paper surveys the current state of AR services in terms of their scalability and examines notable approaches to their integration into the IoT framework as a control interface. Here, the issue of scalability refers to the number of objects that can be supported without significant latency. Note that AR system performance depends largely on data management and object recognition and/or tracking. Additionally, to use AR as an interface with IoT, we examine previous studies that showed how AR can offer an intuitive and natural method to communicate with IoT objects, compared to other methods  with no visual, contextual, or spatial registration). We believe that data management, object-guided tracking, and the interface design are key components for the development of an efficient IoT–AR infrastructure , and we To clearly highlight the current problems, as well as the requirements and potential benefits of the proposed idea, in John is on a business trip to New York. He feels a little chilly in the hotel and tries to raise the temperature of his room, however, he cannot find the thermostat. Using a standard AR enabled IoT service mobile app, he finds and connects to the IoT thermostat (using near-field communication such as Bluetooth), and the app shows an AR-based control interface with which John easily adjusts the temperature, without having to fiddle with the actual device or call the front desk for help . This scAs another futuristic scenario in terms of AR tracking to connect IoT sensors, Alice wants to study the functionalities of her new TV and she is playing the AR manual for the TV. The AR manual provides step-by-step instructions to learn operations, and visual AR contents of next operation in the TV’s parts are registered with AR tracking information. Although Alice has prebuilt feature datasets, she cannot have robust AR tracking performance due to small feature points of the textureless TV. Thus, she pushes a graphical user interface (GUI) button for guided AR tracking, then she is able to execute robust registration selected by the TV’s tracking characteristic, which is the stored object’s tracking attribute in the IoT sensor. According to the described scenario, in the near future we will be able to apply object-optimized AR tracking to consider each object’s characteristics .The final scenario is about augmented reality interaction. As an example of physical objects in everyday life, Richard is using his AR remote control system to turn on small appliances in his home ,24 see a. He is Here, we allude to three key components: distributed AR data management; object-guided tracking; context-based augmented reality (AR) interaction, and the resulting advantages of combining Internet of Things (IoT) and AR. Additionally, the AR system can track the relationship between a physical object and tracking information such as 3D features from images. Next, the user has the capability, in terms of efficient operation of IoT objects, to look through it with helpful AR content associated with the IoT environment. This is based on the help of both the IoT communication capability and the graphical AR environment. Then, any valuable application and service to connect everyday IoT objects and provide the user’s AR experience, such as an AR manual, training, control, and instructions, offers comprehensive platforms for ways that users can access and interact with mobile AR that cover everything and everyone to engage with the physical space . Note thAugmented reality (AR) frameworks and services along with dataset management for everyday objects are described briefly in this section. Additionally, several architectures, data processes, data structures, and content representation for the physical objects to interact with AR in the published works are given. Internet of Things (IoT) and AR services commonly need to manage generic data and service content for their constituent objects or augmentation targets, respectively, which are physical everyday objects. Through having an IoT object communicate its own control interface information, the AR client can be configured to invoke certain control operations through AR interaction. Thus, the AR client has essential information to be contained in the IoT object, for example, features for AR recognition and tracking, generic content and information about the object itself, control interface, and organized additional contents for the operation. Note that the information exchange between the AR client and the IoT objects can occur directly between them or through the regional IoT server . Herein,To interact with real objects using AR interfaces in the early days, people were concerned with an AR framework that was capable of executing ubiquitous communication between physical objects and the AR device . Recent Many studies have been interested in augmented reality issues based on the cloud as the computing resource . These wA more recent trend is to improve the way to use the adjacent computing resources in the user’s surroundings, rather than enabling computing services on the end of the network at a long distance, such as a remote server or the cloud . It willSome research has proposed details of the content structure for resource management as another issue to provide AR datasets. Kim et al. presented an AR content structure for building mobile AR applications in HTML5, as on the Web . They usThe situation is similar with IoT services and content. Most IoT services are implemented as applications. One promising direction is to use the Web to support interactions with physical objects, as exemplified by Google’s Physical Web . Here, oAdditionally, we should consider the characteristics of AR contents according to IoT devices because there are many different types of IoT devices. Note that this is a similar concept that the website components have the different configuration in mobile and desktop computing devices. Thus, to make the IoT enabled AR platform to be naturally applied everywhere, depending on the nature of the IoT device, it should adaptively control the degree of AR content representation.Augmented reality (AR) research primarily focuses on overlaying a virtual 3D model, that is, on how to realistically integrate augmentation with the real world. Recently, AR technologies related to the context of physical objects have increased . These aFast, correct, and stable recognition and spatial tracking  of objects represent the most important technical challenges for AR. Another recently popular technique is a feature-based method that identifies an object and computes its pose using primitive geometric features and their properties detected by a sensor . DiffereRegarding objects without rich features , template image matching is used often; however, this method has many disadvantages for use in robust 3D tracking . A few nThus, scaling such methods for millions of IoT objects would be even more difficult . Placing and attaching markers to thousands of everyday objects also is not a practical solution. Additionally, because there is no single universal recognition and tracking method to cover all types of objects, a multitude of algorithms can be used collectively. Therefore, in a typical situation, before the object is recognized, one cannot determine a priori which algorithm would be the best to apply to its recognition in the first place. Plus, all algorithms must be attempted exhaustively, which will again result in significant latency.The most prevalent application of Internet of Things (IoT) currently involves object control, either remotely or in situ. IoT objects consist of sensors for incoming data, networking modules for wireless capability, and actuators to control the object’s functionality . ExpressSome research in the augmented reality (AR) field is about simulation related to the control of the object’s function and usability measurement . AR alsoRecently, there have been a few attempts to merge the two, for example, using AR  as the control and simulation interface for IoT objects. Moreover, people have recently tried direct control for everyday objects in the AR environment. Rekimoto and Ayatsuka proposed a visual tagging system called CyberCode, which is based on an AR 2D barcode to identify and detect objects . The sysWhat is more, the actual user experience will depend vastly on the AR device. Kruijff el al. provided a classification of perceptual issues in augmented reality and suggested predominant issues for a specific device  . Most prMost previous works had difficulty dealing with the representation of the augmented reality (AR) object for users to access a new place that they had not visited . PreviouFurthermore, IoT datasets can be very large for processing when data are generated over a certain amount of time . Thus, fPresenting another issue, in complex situations, to handle a lot of everyday IoT objects with huge amounts of IoT devices in the surrounding environment, AR augmentation content needs to define and optimize the representation complexity of a virtual object related to sensing information of the IoT objects according to the viewpoint-relative position. The optimized level of detail (LOD) technique is helpful to increase the efficiency of rendering by decreasing the workload on an AR computing device. The performance problem in a scaled environment such as IoT is manifested by the amount of time needed to look up and match the target object and handle and/or process associated data and/or content among millions of candidate objects through the network. Allowing for IoT objects having their own computational, networking, and storage capabilities, data and/or content can be distributed, stored, and exchanged (even without the Internet infrastructure). Instead, IoT objects themselves can communicate the necessary data to clients on a need-to-know basis (including the information required for their recognition and tracking). That is, the data are now delegated and distributed to individual objects in the environment. Such a scheme has the added advantage of faster and more robust object recognition and tracking. The proposal is depicted in The AR client in The proposal described in the previous section on data and/or content distribution to Internet of Things (IoT) objects can also be used to easily solve this problem . That is, in addition to generic data and service content, individual IoT objects of interest in the vicinity of the AR client can communicate the information required to recognize and track itself, including features, algorithm type, and even physical condition . The AR client is “guided” by the target object itself to localize and track it . Note thSoon, according to high-speed networking and anywhere communication, users will be able to track virtual objects that have direct communication with IoT objects . TherefoRegarding the IoT, AR-based interaction and object control have been shown to be much more intuitive, direct, and helpful compared to graphical user interface (GUI) - and menu-based interfaces on handheld devices, for example. GUI- and menu-based interfaces still have the advantage of consistent design and guaranteed minimum usability . Thus, oAdditionally, to develop specific applications enabled by the IoT infrastructure, we need to abstract the object functionality with a set of sensors. Usually, it is based on works dealing with IoT middleware. Specifically, the visual programming of sensors and actuators allows the user to direct operation . Figure Recently, smart Internet of Things (IoT) users will operate and interact with physical objects that can receive augmented reality (AR) datasets anytime and anywhere and can enrich their visual perception. We surveyed various AR approaches  to enhance the usability of physical IoT objects in the user’s surrounding area and provided the classification and taxonomy for IoT enabled AR. Expressly, we summarized the recently developed data management techniques to handle AR datasets connecting everyday objects, AR tracking for everyday objects, and direct control-based AR interaction for physical things categorized as the three key components. Moreover, we reviewed recent AR applications and suggested future scenarios related to IoT objects. Additionally, we suggested the open issues that require further research to enhance the user’s AR experience for highly connected IoT objects in the surrounding environment. We described how the current bare IoT infrastructure can be extended to include smarter and more effective user interactions. Individual or meaningful sets and groups of IoT objects can be imbued with data and/or content in a distributed manner and efficiently utilized by the client. The distribution makes it possible to scale and customize interaction techniques such as AR. We plan to demonstrate our proposal in the future, using an actual prototype system and validate our claims in terms of its improved usability and performance. We plan to continue to upgrade our survey with different system architectures and research issues in accordance with display types such as mobile phones, wearable glasses, and projection-based spatial AR. Additionally, we will summarize recent approach with an IoT-centric survey to add the proposed AR-centric approach in the environment to combine AR and IoT.