Synthesis and Antiviral Evaluation of Some <i>C</i>₃-Symmetrical Trialkoxy-Substituted 1,3,5-Triazines and Their Molecular Geometry

Abstract

As one of our projects, we here report some new molecular modifications of 2,4,6-trichloro-1,3,5-triazine (TCTAZ: 1) to symmetrical 2,4,6-trialkoxy-or 2,4,6-triaryloxy-substituted 1,3,5-triazine (TAZ) molecules, as well as the results of anti-herpes simplex virus type 1 (anti-HSV-1) activity evaluation of synthesized 2,4,6-trisubstituted TAZ derivatives. Among the tested 2,4,6-trisubstituted TAZ derivatives, we reconfirmed that a C 3 -symmetrical TAZ derivative, 4e, shows the highest level of anti-HSV-1 activity with a good selectivity index. In this paper, we also report the results of the preparation of newly targeted TAZ derivatives and the structure-activity relationships (SARs) of these trialkoxy-substituted TAZ derivatives and related compounds. The sugar recognition properties of C 3 -symmetrical TAZ derivative 4e are also described.Key words 1,3,5-triazine; C 3 symmetry; anti-herpes simplex virus type 1; structure-activity relationship; plaque reduction assay; isothermal titration calorimetryThe glycocalyx at the cell surface, containing glycoproteins, proteoglycans and glicolipids, plays an important role in various cell-to-cell communications. Specific interactions of these carbohydrates with lectins (protein receptors) are important biological processes, including the processes of bacterial or viral infection and tumor metastasis. 1-3)From the viewpoint of molecular symmetry, many host receptors that consist of homo-oligometric units (homomultiligands) often construct symmetric macromolecule architectures such as C 2 -or C 3 -symmetrical geometry receptor systems. These phenomena of macromolecules connected with many biological stages have encouraged scientists to develop new multivalent symmetrical synthetic molecules to find new bioactive compounds or leads. Results of many works related to the above conception have been published over the past few decades. [4][5][6][7] The terms identical twin-drugs and tripletdrugs (symmetrical bivalent and trivalent molecules) are now commonly used in medicinal chemistry and related scientific fields. In connection with our synthetic works on such symmetrical molecules, we have already designed and synthesized a few new symmetrical molecules and evaluated their bioactivities in order to find new types of bioactive compounds. 8-17)In connection with the above projects, we have recently reported some molecular modifications of 2,4,6-trichloro-1,3,5-triazine (TCT AZ) (1) to symmetrical 2,4,6-trisubstituted 1,3,5-triazine (TAZ) molecules and the results of biological evaluation of synthesized symmetrical 2,4,6-trisubstituted TAZ derivatives. 8,9) Among previously targeted trisubstituted TAZ derivatives, we found that a C 3 -symmetrical TAZ derivative with three isopropoxy groups on a TAZ template such as compound 4e showed a high level of anti-herpes simplex virus (HSV)-1 activity and low cytotoxity, and it therefore seemed to be a potential lead in the search for preferred anti-HSV-1 activity with a good selectivity index (SI).In this paper, we report the results of...

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

“…l H-and 13 C-NMR spectra were obtained by JEOL JNM A-500 and ECG600R (only for compounds 7cm, 9d and 16o). Chemical shifts were expressed in δ ppm downfield from an internal TMS signal for l H-NMR and the carbon signal of the corresponding solvent [CDCl 3 (77.00 ppm), dimethyl sulfoxide (DMSO)-d 6 C heteronuclear multiple-bond connectivity (HMBC). Microanalyses were performed with a Yanaco MT-6 CHN corder.…”

“…[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 pathway for the synthesis of C 3 -symmetrical tripodal receptor-type TAEA derivatives (3,5,7,8) is shown in Chart 1. All reductive amination reactions with various aryl aldehydes (2) were performed as one-pot reactions, and the desired amine-type TAEA derivatives (3) were obtained in a manner similar to that for the preparation of compound 3a.…”

“…13) Acetylation of compounds 3 with acid anhydride (4) gave new amide-type TAEA derivatives (5). Urea-type TAEA derivatives (7,8) were also obtained by addition reactions of aminetype derivatives (3) or TAEA (1) to iso(thio) cyanate (6). All of these target C 3 -symmetrical TAEA derivatives (3,5,7,8) were obtained in moderate to excellent yields (44-95%) (see Tables S1-S3 for Supplementary materials of the online version for details).…”

Preparation of Some Novel Trisubstituted 1,3,5-Triazines and Hybrid Linker Mode 1,3,5-Triazine Derivatives and Their Biological Evaluation

“…4 To develop new multivalent symmetrical bioactive compounds or leads, we have recently designed and synthesized a few new molecules with such geometry and evaluated their bioactivities in order to find new types of bioactive leads. [5][6][7][8][9][10][11][12][13][14] In connection with this project, we have recently reported the preparation of various C3-symmetrical trivalent 1,3,5-triazine (TAZ) derivatives and the results of biological evaluation of the synthesized symmetrical TAZ derivatives. 7,12 Among previously targeted C3-symmetrical TAZ derivatives, we found that C3-symmetrical tri-substituted TAZ derivatives (A and B) showed high levels of anti-HSV-1 activity (EC50 = 0.98 and 1.87 μM, respectively) and considerably low levels of cytotoxic activity (CC50 > 200 μM) against Vero cells, 7,12 and these TAZ derivatives are considered to be potential new leads in the search for antiviral active molecules (Figure 1).…”