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

Abstract

We report the preparation of new tripodal receptor-type C 3 -and C S -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 (EC 50 ) 16.7 µM) and low cytotoxicity (50% cytotoxic concentration (CC 50 ) >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.Key words tris(2-aminoethyl)amine; C 3 symmetry; C S symmetry; anti-herpes simplex virus type 1; tripodal receptor-type; plaque reduction assay It is well known that many types of receptors or functionalized proteins on membranes in a native state often have a high order of symmetrical interfaces. 1) C 3 -or C 2 -symmetrical molecules have frequently been found in various synthetic biologically active compounds.2) Aiming to develop new synthetic bioactive compounds, we targeted such symmetric geometrical molecules constructed on a symmetrical template. [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. 7) These mid-size molecules that show lectin-like carbohydrate recognition properties might have interesting functions as new ligands or drug candidates. Considering the formation of strong drug-host interaction for host sugar recognition by multivalent molecules, attempts to synthesize such non-peptide mid-size molecules are also thought to be valid in the search for bioactive new seeds. 5,8)Since it is well known that many amide functionalities usually have the ability to form a strong hydrogen bond, and it has also often been reported that some molecules derived from TAEA behave as acceptors for an ion or a small molecule, 11,12) we introduced a few amide functionalities into a tripodal receptor-type TAEA template. These molecular modifications may lead to new bioactive symmetrical molecules that have good properties for non-covalent interaction and bioactivities.Here, we describe the synthesis of some new non-peptide molecules with amine or amide-relating functionalities constructed on a symmetrical tris(2-aminoethyl) amine (TAEA) template and on a spread tris(3-aminopropyl) amine (TAPA) template. The results of biological evaluations of the synthesized derivatives are also described (Fig. 1). Results Synthesis of New Target Derivati...

Antimicrobial Properties of New Polyamines Conjugated with Oxygen-Containing Aromatic Functional Groups

“…The purification to obtain spectroscopically pure compounds was easily achieved via simple precipitation and the recrystallisation of the hydrochloride salts. To our knowledge, the synthesis of compounds 1a-5a is reported here for the first time, except for 3a, which was described before by Sumoto's group [26], but with a different procedure to the one reported here. The 1 H, 13 C, and ATR-IR spectra of the new compounds, as well as the X-ray diffraction structure of compound 3a, can be found in the Electronic Supplementary Materials.…”

“…Another group of bioactive compounds bearing this moiety is psychoactive and stimulant drugs [24,25]. There are also examples of its derivatives that show antimicrobial activity [26][27][28][29][30].…”

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).…”

Antiviral Activity of Some C3-Symmetrical N-Methyl Benzylamine-Substituted 1,3,5-Triazines and Related Compounds

“…1,2 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. [3][4][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 1,3,5triazine (TAZ) derivatives and the results of biological evaluation of the synthesized symmetrical TAZ derivatives. 5,11 Among previously targeted C3-symmetrical TAZ derivatives, we found that C3-symmetrical tri-substituted TAZ derivative 3d-H (A) showed a high level of anti-HSV-1 activity (EC50 = 0.98 μM) and a considerably low level of cytotoxic activity (CC50 => 200 μM) against Vero cells.…”