Synthesis and Biological Evaluation of Symmetrical 2,4,6-Trisubstituted 1,3,5-Triazine Derivatives

Abstract

We describe the synthesis and biological evaluation of newly designed 2,4,6-trisubstituted symmetrical 1,3,5-triazine (TAZ) derivatives. Among the tested trisubstituted symmetrical TAZ derivatives, various C 3 -or C S -symmetrical alkoxy-amino-substituted TAZ derivatives showed significant antiviral activity against herpes simplex virus type 1 (HSV-1) and/or cytotoxic activity against Vero cells. The structure-activity relationships for anti-HSV-1 activity of these symmetrical 2,4,6-trisubstituted TAZ derivatives are also described. Experimental results indicated that a C S -symmetrical TAZ structure with introduction of two alkoxy groups and one amine moiety seems to be the minimally required structure for anti-HSV-1 activity.Key words 1,3,5-triazine; anti-herpes simplex virus type 1; cytotoxic activity; C 3 symmetry; C S symmetry; plaque reduction assay Molecular recognition of two-fold (C 2 ) or three-fold (C 3 ) symmetrical geometry macromolecules is one of the common features in many important biological responses, 1,2) and we have therefore already designed a few symmetrical target molecules for the purpose of finding biologically active new leads or candidates.3-5) With reference to the molecular symmetry, small molecules having C 3 -, C S -, or C 2 -symmetrical geometry frequently appear in various biologically active compounds. [6][7][8] Such small symmetrical molecules are usually constructed on a corresponding symmetrical template.From this point of view, we have recently reported some molecular modifications of tris(2-aminoethyl) amine (TAEA) derivatives to C 3 -or C S -symmetrical tripodal receptor type molecules and the results of biological evaluation of these symmetrical compounds.3) We have also reported an interesting lectin-like property for sugar recognition of some of these tripodal receptor type TAEA molecules. 4)In order to achieve a suprafacial three-dimensional interaction of a bioactive symmetrical molecule for its binding site, the nature of substituents in the molecule is thought to be very important for preferential interactions. Such interactions are dictated largely by van der Waals interactions or formation of hydrogen bonds. The introduction of amine (basic nitrogen atom) and/or a bivalent oxygen group such as a hydroxy or alkoxy group into a C 3 -symmetrical 1,3,5-triazine (TAZ) template seems to be interesting, because it is well known that amine functionalities behave as both hydrogen acceptors and hydrogen donors in appropriate circumstances. These facts may indicate that molecules with some amine and/or bivalent oxygen functionalities on a heterocyclic C 3 -symmetrical TAZ template can produce a property for suprafacial hydrogenbonding interaction.For an extension of our studies, we planned to investigate the synthesis of 2,4,6-trisubstituted symmetrical TAZ derivatives [9][10][11][12][13][14][15][16] as well as to evaluate their biological properties. In this paper, we report the results of new synthetic routes for C 3 -or C S -symmetrical 2,4,6-trisubstituted TAZ derivativ...

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

“…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 1 with alcohols (Step 1) and then amines (Step 2) in one pot.…”

“…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][8][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.…”

“…[7][8][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.…”

“…This procedure consists of two-stage nucleophilic substitutions of compound 1 with alcohols (Step 1) and then amines (Step 2) in one pot. The predominant formation of a monoalkoxy-diamino-TAZ derivative (6) or dialkoxy-monoamino-TAZ derivative (7) in an employed reaction depended on the stoichiometry of TCTAZ and alcohol in the first reaction stage (Step 1). As an amine nucleophile for introduction on a TAZ template in this study, we employed only 4-piperidinemethanol (pH) because many molecules having this amine substituent designed previously showed considerable antiviral activities.…”

Synthesis of Tri-Arm Star Shaped 1, 3, 5-Triazines Catalyzed by 1,5,7-TRIAZABICYCLO[4.4.0] Dec-5-Ene (Tbd)

“…2,4,6-Trisubstituted-1,3,5-triazine derivatives are very efficient and important compounds having considerable properties like antifungal, 1 antitumor, 2 antibacterial 3 and antiviral 4 activities.…”