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.