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...