8-Amino-3-benzyl-1,2,4-triazolo[4,3-a]pyrazines. Synthesis and anticonvulsant activity.

Eleven substituted 8-amino-3-benzyl-1,2,4-triazolo[4,3-a] pyrazines were synthesized and tested for anticonvulsant activity against maximal electroshock-induced seizures (MES) in rats. The compounds were prepared in four stages from the phenylacetonitriles. I. The intermediate (2,2,2-triethoxyethyl)benzenes III were condensed with 2-chloro-3-hydrazinopyrazine (IV) to provide the 3-benzyl-8-chloro-1,2,4-triazolo[4,3-a]pyrazines V. The latter were converted to the 8-amine targets VI with methylamine or ammonia. Several compounds exhibited potent activity against MES; the 3-(2-fluorobenzyl)-8-(methylamino) and 3-(2,6-difluorobenzyl)-8-(methylamino)congeners (4 and 12) exhibited the best anticonvulsant activity with oral ED50S of 3 mg/kg. The 1,2,4-triazolo[4,3-a]pyrazine ring system serves as a bioisostere of the purine ring for anticonvulsant activity; however, these agents exhibit less propensity to cause emesis.

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.