Preparation and Antiviral Activity of Some New C3- and CS-Symmetrical Tri-Substituted Triazine Derivatives Having Benzylamine Substituents.

We report the preparation of new C3- and CS-symmetrical molecules constructed on a triazine (TAZ) template. Anti-herpes simplex virus type 1 (anti-HSV-1) and cytotoxic activities against Vero cells of synthesized TAZ derivatives were evaluated. The results suggested that the presence of an electron-donating group(s) on the benzene ring in benzylamine groups on the TAZ template is an important structural factor for expressing a high level of anti-HSV-1 activity and low cytotoxicity for these C3 types of TAZ derivatives. Among the tested TAZ derivatives, compounds 4f and 7h showed the highest anti HSV-1 activities (EC50=0.98 and 1.23 µM, respectively) and low cytotoxic activities to Vero cells (50% cytotoxic concentration (CC50)=292.2 and >200 µM, respectively).

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

We report the preparation of new tripodal receptor-type C3- and CS-symmetrical molecules constructed on a tris(2-aminoethyl)amine (TAEA) template. Both the anti-herpes simplex virus type 1 (anti-HSV-1) activity and cytotoxic activity of synthesized receptor-type derivatives were evaluated in order to find a characteristic structural feature for these bioactivities of compounds. Among the compounds of synthesized symmetrical TAEA-related derivatives, compound 13k showed high anti-HSV-1 activity (50% effective concentration (EC50)=16.7 µM) and low cytotoxicity (50% cytotoxic concentration (CC50)=>200 µM). The presence of a hydrogen bond donor proton in the molecule is thought to be an important structural factor for expressing potential anti-HSV-1 activities.

Synthesis and Antiviral Evaluation of Some C(3)-Symmetrical Trialkoxy-Substituted 1,3,5-Triazines and Their Molecular Geometry.

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 C3-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 C3-symmetrical TAZ derivative 4e are also described.

Synthesis and antiviral activities of some 2,4,6-trisubstituted 1,3,5-triazines.

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 CS-symmetrical 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 C3-symmetrical trialkoxy-TAZ derivative 4bbb, which showed a considerably high selectivity index (IC50/EC50=256.6). The structure-activity relationships for anti-HSV-1 activity of the tested 2,4,6-trisubstituted TAZ derivatives are also described.

Synthesis and biological evaluation of symmetrical 2,4,6-trisubstituted 1,3,5-triazine derivatives.

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 C3- or CS-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 CS-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.

Molecular symmetry and biological activities of new symmetrical tris(2-aminoethyl)amine derivatives.

In terms of molecular symmetry and bioactivity, new C3- and CS-symmetrical derivatives based on the tris(2-aminoethyl)amine scaffold were designed and synthesized. The synthesized compounds were evaluated for antiviral activity with herpes simplex virus type 1 (HSV-1) by a plaque reduction assay and for cytotoxic activity with Vero cells. Most of the compounds showed no significant anti-HSV-1 activity, but some of the symmetrical derivatives showed high levels of cytotoxic activitiy.

Synthesis and antiviral activities of N-mono- and/or N,N'-di-carbamoyl and acyl derivatives of symmetrical diamines.

N-carbamoyl and N-acyl diamine derivatives were synthesized from symmetrical diamines by their addition to iso(thio)cyanates, cleavage reaction of acid anhydride, or N-acylation by acyl chloride. (1R,2R)-1,2-Diaminocyclohexane [(1R,2R)-1], meso-1,2-diaminocyclohexane (meso-1), (1R,2R)-1,2-diphenylethylenediamine [(1R,2R)-3], or meso-1,2-diphenylethylenediamine (meso-3) were used as the starting symmetrical diamines. The target compounds synthesized herein were evaluated for antiviral activity with herpes simplex virus type 1 (HSV-1). A few derivatives of 1,2-diaminocyclohexane [(1R,2R)-7aa and cis-7b] with adamantyl group(s) showed significant antiviral activity (EC(50)=16.0, 27.0 microg/ml).

N-monocarbamoyl derivatives of symmetrical diamines with antiviral activity.

Some new N-monocarbamoyl symmetrical diamines have been prepared by the addition of symmetrical amines to isocyanates or isothiocyanates. 2,6-Diaminopyridine (1), (1R,2R)-1,2-diaminocyclohexane [(1R,2R)-2], meso-1,2-diaminocyclohexane (meso-2), or (1R,2R)-1,2-diphenylethylenediamine (3) were used as the starting symmetrical diamine frameworks. All of the newly synthesized compounds were subjected to an evaluation of antiviral activity with herpes simplex virus (HSV)-1. N-Monocarbamoyl 2,6-diaminopyridines (5a, b) showed significant antiviral activity (EC(50)=17.0, 6.2 microg/ml) comparable to that of N-monododecanoyl 2,6-diaminopyridine (A2). As a result, compound 5a showed a better selectivity index (CC(50)/EC(50) = ca. 10.0) than that of A2.

N-long-chain monoacylated derivatives of 2,6-diaminopyridine with antiviral activity.

N-Monoacyl-2,6-diaminopyridines (2a-c) and N,N'-diacyl-2,6-diaminopyridines (3a-c) were synthesized from 2,6-diaminopyridine by acylation with the corresponding acyl halide or by dehydration with the corresponding carboxylic acid using 1,3-dicyclohexylcarbodiimide (DCC). The antiviral activities of N-monoacyl- and N,N'-diacyl-2,6-diaminopyridines (2a-c and 3a-c) were estimated using plaque reduction assay with HSV-1. All N-monoacyl derivatives (2a-c) showed significant anti-herpes simplex virus (HSV)-1 activity (EC(50) = 15.3-18.5 microg/ml). The CC(50) values of 2a-c measured using Vero cells ranged at 37.5-50.0 microg/ml. These compounds showed no significant antibacterial activities with Escherichia coli or Staphylococcus aureus even at a concentration of 1 mg/ml. The N,N'-diacyl derivatives (3a-c) showed no significant anti-HSV-1 activity.

Synthesis and antiviral activities of some 4,4'- and 2,2'-dihydroxytriphenylmethanes.

We synthesized some 4,4'- and 2,2'-dihydroxytriphenylmethane derivatives 3a--e and 4a--c by condensation of phenol 1 and aromatic aldehyde 2 in moderate to good yields (30--83%). Most of them showed significant antiviral activity against herpes simplex virus type 1 (anti-HSV-1 activity) in a plaque reduction assay. The most potent antiviral activity (EC(50)=0.79 microg/ml) was observed in the 4,4'-dihydroxytriphenylmethane derivative 3b. This compound 3b showed lower cytotoxicity (CC(50)=30.2 microg/ml), compared to that of the prototype 3a.

Synthesis and antiviral activities of some 4,4'-dihydroxytriphenylmethanes.

4,4'-Dihydroxytriphenylmethanes were synthesized using Brønsted acid or Lewis acid in yields of 24-86% as target compounds for developing antiviral agents. Most of the 4,4'-dihydroxytriphenylmethanes showed significant activity against herpes simplex virus type 1 (anti-HSV-1 activity) in a plaque reduction assay. Higher cytotoxicity was observed generally in halogenated 4,4'-dihydroxytriphenylmethanes (2a-d) than in non-halogenated derivatives. The non-halogenated derivative, 4,4',4"-trihydroxy-3"-methoxytriphenylmethane (3), showed remarkable antiviral activity with an EC(50) value of 1.8 microg/ml.

Synthesis and DNA strand breakage activity of some 1,4-diazepines.

Reactions of 1,3-propanediamine with alpha-dicarbonyl compounds (1a-e) were examined and various condensed heterocyclic compounds such as 1,4-diazepines (2) and 3-pyrimidine derivatives (3) were obtained. Some of 1,4-diazepines (2) showed DNA strand breakage activity.

Synthesis of 2,2'-dihydroxybisphenols and antiviral activity of some bisphenol derivatives.

New diphenylmethane-type 2,2'-dihydroxybisphenols (5a-d) were prepared regioselectively in good yields. We evaluated the antiviral activity of some bisphenol derivatives synthesized by the plaque reduction assay. Most of the compounds showed significant antiviral activity and the 4,4'-dihydroxybisphenol derivative (10) showed higher activity than 2,2'-bisphenol derivatives. This compound had EC50 value of 1.8 microg/ml.