Structure-activity relationships among α-(N)-heterocyclic acyl thiosemicarbazones and related compounds as inhibitors of herpes simplex virus type 1-specified ribonucleoside diphosphate reductase

2-Acetylpyridine thiosemicarbazone, a potent antiviral drug, and 13 analogues were examined as inhibitors of partially purified herpes simplex virus type 1-specified ribonucleoside diphosphate reductase. N4,N4-Azacycloheptane derivatives were more active than their N4-unsubstituted analogues. Selenosemicarbazones were similar in potency to their thiosemicarbazone congeners, whereas a related semicarbazone was much less active. Maximum inhibition was observed when an ethylidene side-chain was present in the compounds. No discernible trend in potency was observed when the pyridine moiety was replaced by quinoline or isoquinoline. Thiosemicarbazide derivatives were less potent than their unsaturated thiosemicarbazone analogues. Inhibitory potencies increased at longer incubation times consistent with the hypothesis that thiosemicarbazones inactivate the enzyme in a time-dependent manner.