[Synthesis of optically active (R)- and (S)-tai-ding-an(TDA) and their anti-HSV activity evaluation].
Tai-Ding-An (3-phthalimido-2-oxo-n-butyraldehyde bisthiosemicarbazone, TDA) is an antiviral drug first synthesized in this institute. In order to clarify the difference between the two enantiomeric isomers of TDA, (R)- and (S)-TDA were synthesized from (R)- and (S)-alanine, respectively, via the following steps: fusing with phthalic anhydride gave 2-phthalimido alanine(2a or 2b). The resulting acid was reacted with thionyl chloride to offer the corresponding acid chloride(3a or 3b), which was treated with diazomethane to give the diazoketone(4a or 4b). Bromination of the ketone with hydrobromic acid gave the key intermediate 3-phthalimido-2-oxo-1-bromobutanone (5a or 5b). Compound 5a or 5b was oxidized with DMSO to give 6a or 6b, which was directly condensed with thiosemicarbazide to afford the desired (R)- or (S)-TDA. (R)-TDA, (S)-TDA and (RS)-TDA have been tested in cell culture for anti-Herpes simplex virus I (HSV-1) and HSV-2 activities by plaque reducing method. All of them showed inhibitory effects on HSV-1 and HSV-2 replication with IC50 of 0.0296 mmol.L-1, 0.0359 mmol.L-1 and 0.0418 mmol.L-1 for HSV-1 and 0.88 mmol.L-1, 1.04 mmol.L-1 and 1.06 mmol.L-1 for HSV-2. Not much difference was found among these compounds either on IC50 or on therapeutic indexes.
Wang
G X
GX
Institute of Materia Medica, Beijing.
Wang
L
L
Zhao
Z Z
ZZ
Tao
P Z
PZ
Wang
S Q
SQ
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002522:Chlorocebus aethiops; D018259:Herpesvirus 1, Human / Q000187:drug effects; D018258:Herpesvirus 2, Human / Q000187:drug effects; D010797:Phthalimides / Q000138:chemical synthesis* / Q000494:pharmacology; D013237:Stereoisomerism; D013882:Thiosemicarbazones / Q000138:chemical synthesis* / Q000494:pharmacology; D014709:Vero Cells; D010948:Viral Plaque Assay
D000998:Antiviral Agents; D010797:Phthalimides; D013882:Thiosemicarbazones; C031410:phtiobuzone