Synthesis and Antiviral Activities of Some 2,4,6-Trisubstituted 1,3,5-Triazines

Abstract

We describe the synthesis and results of biological evaluation of newly designed 2,4,6-trisubstituted symmetrical 1,3,5-triazine (TAZ) derivatives. Among the tested trisubstituted TAZ derivatives, some C Ssymmetrical alkoxy-amino-substituted TAZ derivatives, including 7ggp and 6dpp, showed significant antiviral activity against herpes simplex virus type 1 (HSV-1). The compound with the highest level of antiviral activity was C 3 -symmetrical trialkoxy-TAZ derivative 4bbb, which showed a considerably high selectivity index (IC 50 /EC 50 256.6). The structure-activity relationships for anti-HSV-1 activity of the tested 2,4,6-trisubstituted TAZ derivatives are also described.Key words 1,3,5-triazine; anti-herpes simplex virus type 1; cytotoxic activity; C S symmetry; C 3 symmetry; plaque reduction assay Supramolecular interaction of two-fold (C 2 ) or three-fold (C 3 ) symmetrical geometry macromolecules with many bioactive compounds is one of the common features of many important biological processes, [1][2][3] and small molecules having C 3 -, C S -, or C 2 -symmetrical geometry often appear in various biologically active compounds contrasted on a symmetrical template. [4][5][6] We have therefore expected that such small symmetrical molecules would be promising new candidates or leads in the search for biologically active compounds that interfere with the sugar recognition process in a controlled biological response. From this aspect of molecular symmetry, we have already reported a few examples of such types of new symmetrical molecules for the purpose of finding new biological active compounds. 7-9)We have recently reported some molecular modifications of 2,4,6-trichloro-1,3,5-triazine (TCTAZ) to C 3 -, or C Ssymmetrical trisubstituted TAZ molecules and the results of biological evaluation of synthesized symmetrical 2,4,6-trisubstituted TAZ derivatives. 7) Among previously targeted TAZ derivatives, some alkoxy-amino-substituted derivatives showed significant anti-herpes simplex virus type 1 (HSV-1) activities. The previous analysis of anti-HSV-1 active molecular features indicated that a C S -symmetrical TAZ derivative with two alkoxy groups and one amine moiety seemed to be a required structure for preferred anti-HSV-1 activity with a good selectivity index.For an extension of our study, we examined further modifications of this symmetrical class of compounds in order to investigate the structure-activity relationship (SAR) of alkoxyamino-substituted TAZ molecules as well as their biological evaluation. In this paper, we report the results of preparation of newly targeted C S -symmetrical TAZ derivatives together with the results of biological evaluation of obtained symmetrical 2,4,6-trisubstituted TAZ derivatives.Chemistry In our previous article, 7) we reported that synthesis of target alkoxy-amino-trisubstituted TAZ derivatives is easily achieved by a procedure via alkoxy-substituted chloro-TAZ intermediates starting from TCTAZ (1). This procedure consists of two-stage nucleophilic substitutions of compound...

Antiviral Activity and Molecular Geometry of Some New Symmetrical Tris(aminoalkyl)amine Derivatives

“…After stirring for 20 min at r.t., the reaction mixture was refluxed for 1 h. After cooling to r.t., a small amount of NaBH 4 (945 mg, 25.0 mmol) was added to the mixture and the mixture was stirred for 2.5 h at 0°C. It was then diluted with aqueous ammonium chloride (NH 4 Cl, 10%, 100 mL) and extracted with CH 2 Cl 2 (3×200 mL). The combined organic layer was washed with brine (50 mL) and dried over anhydrous magnesium sulfate (MgSO 4 ) .…”

“…After evaporation of the solvent, CHCl 3 (20 mL), brine (5 mL), and 5% NaHCO 3 (5 mL) were added to the obtained yellow solid, and then the resulting mixture was vigorously stirred for 1 h. After separation of the organic layer, the aqueous layer was reextracted with CHCl 3 (2×20 mL). The combined organic layer was dried over MgSO 4 , and evaporation of the solvent gave a brown oil. The product was purified by flash chromatography (CH 2 .0 mmol) in benzene (2 mL) at r.t., and then the mixture was stirred for 2 h. After removal of the solvent by evaporation, 1 M NaOH solution (20 mL) was added to the resulting residue and then the mixture was extracted with EtOAc (3×40 mL).…”

“…[3][4][5] In our previous studies on bioactive compounds in the tripodal receptor-type tris(2-aminoethyl) amine (TAEA) series, we found that some of the new C 3 -and C S -symmetrical derivatives synthesized previously showed significant bioactivities against herpes simplex virus type 1 (HSV-1) or cytotoxic activities to Vero cells. 6) Regarding amide-type TAEA derivatives, we have reported that some symmetrical molecules have selective carbohydrate recognition properties.…”

“…The high reactivity of isothiocyanate to amine is thought to be the reason for obtaining such experimental results. Amideurea-type TAEA derivatives (14,15) from the acylations of these isolated compounds (12, 13) with acetic anhydrate (4) were obtained in good to excellent yields (68-92%) (see Table S5 for Supplementary materials).…”

“…IR (KBr) cm 12 g, 32%) as a white solid and 12k (0.903 g, 15%) (19,4.78 g, 17.3 mmol) in CH 2 Cl 2 (25 mL) at 0°C under an N 2 atmosphere. After stirring for 30 min, the reaction mixture was stirred at r.t. for another 1 h. The resulting mixture was poured into water (100 mL), and then the aqueous layer was extracted with CH 2 Cl 2 (2×100 mL).…”