2-Acetylpyridine thiocarbonohydrazones. Potent inactivators of herpes simplex virus ribonucleotide reductase.
A series of 2-acetylpyridine thiocarbonohydrazones was synthesized for evaluation as potential antiherpetic agents. The compounds were prepared by the condensation of 2-acetylpyridine with thiocarbonohydrazide followed by treatment with isocyanates or isothiocyanates. Many were found that were potent inactivators of ribonucleotide reductase encoded by HSV-1 and weaker inactivators of human enzyme. Several thiocarbonohydrazones (e.g. 38 and 39) inactivated HSV-1 ribonucleotide reductase at rate constants as much as seven times that of lead compound 2. In general, those substituted with weak electron-attracting groups offered the best combination of potency and apparent selective activity against the HSV-1 enzyme. Seven new thiocarbonohydrazones (21, 25, 31, 36, 38, 39, and 40) were apparently greater than 50-fold more selective than 2 against HSV-1 ribonucleotide reductase versus human enzyme. The results indicated new compounds worthy of further study as potentiators of acyclovir in combination topical treatment of herpes virus infections.
Blumenkopf
T A
TA
Wellcome Research Laboratories, Burroughs Wellcome Co., Research Triangle Park, North Carolina 27709.
Harrington
J A
JA
Koble
C S
CS
Bankston
D D
DD
Morrison
R W
RW
Bigham
E C
EC
Styles
V L
VL
Spector
T
T
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D006835:Hydrazones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007700:Kinetics; D015394:Molecular Structure; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors*; D018139:Simplexvirus / Q000201:enzymology*; D013329:Structure-Activity Relationship
D000998:Antiviral Agents; D006835:Hydrazones; D011725:Pyridines; D012264:Ribonucleotide Reductases