Thirty-three new 5-[4-(benzyloxy)phenyl]-1,3,4-oxadiazol-2(3H)-one derivatives including related analogues, designed as inhibitors of monoamine oxidase type B (MAO B), were synthesized and investigated both in vitro and ex vivo for their abilities to inhibit selectively rat brain MAO B over MAO A. Three inhibitors were found to act as reversible, highly potent, and selective MAO B inhibitors, namely the nitrile derivative 5-[4-(benzyloxy)phenyl]-3-(2-cyanoethyl)-1,3,4-oxadiazol-2(3H)-one (12a) and two closely related homologues, the corresponding oxadiazolethione 13a and the alcohol 14b. Their IC50 (MAO B) values are in the low nanomolar range of 1.4-4.6 nM and their selectivities, estimated by the ratio of IC50 values (A/B), are from 3200 to> 71,400. Compound 12a exhibited the highest activity against MAO B. Its IC50 was evaluated to be 1.4 nM with a quasitotal selectivity (> 71,400) toward this enzyme. In ex vivo studies, 12a showed a reversible and short duration of action. MAO B was markedly inhibited with the oral dose of 1 mg/kg without any alteration of MAO A, and the inhibition almost did not exceed 24 h. Its ED50 (1 h after oral administration) was evaluated to be 0.56 mg (1.7 mumol)/kg. Remarkably, MAO A was not affected at doses as high as 1500 mg/kg, po. In addition, no apparent toxicity or behavioral anomaly was observed during the treatment even at the maximum administrated dose. SAR studies emphasize the existence of three binding sites to the enzyme with a special importance of the terminal phenyl. Analysis of the inhibition kinetics indicated that 12a acts in a two-step mechanism as a competitive, slow, and tight-binding inhibitor of MAO B with a Ki value of 0.22 microM and an overall Ki* value at equilibrium of 0.7 nM.

Reactions of 2‐chloroformylhydrazones of aromatic aldehydes or ketones 2 with various hydrazines were converted to monocarbonohydrazone derivatives 3 or 5 and/or tetrahydro‐1,2,4,5‐tetrazin‐3(2H)‐one derivatives 6, 7. By oxidation with lead dioxide, compounds 6 were transformed into stable 3,4‐dihydro‐3‐oxo‐1,2,4,5‐tetrazin‐1(2H)‐yl radical derivatives 8.

Thirty new 2‐substituted‐4‐amino‐5‐alkyl or aryl‐2,4‐dihydro‐1,2,4‐triazol‐3‐ones and ten 2‐substituted‐5‐alkyl or aryl‐4‐(5‐nitro‐2‐furfurylidene)amino‐2,4‐dihydro‐1,2,4‐triazol‐3‐ones were synthesized and characterised by their sharp melting points, elemental analysis, ir and 1H nmr spectra. These new derivatives of 5‐nitro‐2‐furaldehyde were screened for their antibacterial activities. Most of the compounds showed good activity against one test organism, Staphylococcus aureus. For a few compounds, C.M.I. ranged from 4 to 8 μg/ml (higher results than nitrofurantoin).

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