Synthesis and pharmacochemical investigation of some novel 1,2,4-4H-triazoles with potential antiviral activity.
We report the synthesis of some mercaptotriazole derivatives in an effort to discover underlying structural requirements for antiviral activity. A preliminary antiviral study was performed and the contribution of the compounds to free radical processes was investigated. Because lipophilicity influences both biological activity and antioxidant potential we calculated lipophilicity and attempted to correlate this with antioxidant activity. Treatment of the N-(aryl)piperazineacetohydrazides (compounds 1) with 2,4-dichlorophenylisothiocyanate gave the N-(aryl)piperazinethiosemicarbazides (compounds 2) in good yield. Cyclization of these compounds after treatment with NaOH solution provided the corresponding 5-(4-aryl-1-piperazinylmethyl)-4-(2,4-dichlorophenyl)-4H-1,2,4-triazole- 3-thiols (compounds 3) in good yield. Reaction of compounds 3 with 2,4-dichloro- or 4-fluorobenzyl chloride in acetone in the presence of potassium carbonate gave the target compounds (compounds 4) in about 70% yield. The antioxidant effect of the compounds on non-enzymatic lipid peroxidation of rat hepatic microsomal membranes was studied. Most of the examined compounds were active at concentration of 0.1 mM and most were found to prevent dimethylsulphoxide oxidation moderately (20-50%) at a concentration tenfold less than that of dimethylsulphoxide. The interaction of the synthesized compounds with 1,1-diphenyl-2-picrylhydrazyl stable free radical was also studied. Correlation was found between the two expressions of calculated lipophilicity, antioxidant activity and the lipophilicity of the synthesized compounds, and a correlation was derived between antioxidant activity and delta logP, which expresses the compounds' hydrogen-bonding capacity.
Papakonstantinou-Garoufalia
S S
SS
Department of Pharmaceutical Chemistry, School of Pharmacy, University of Athens, Greece.
Tani
E
E
Todoulou
O
O
Papadaki-Valiraki
A
A
Filippatos
E
E
De Clercq
E
E
Kourounakis
P N
PN
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000502:physiology; D051381:Rats; D011916:Rats, Inbred F344; D014230:Triazoles / Q000138:chemical synthesis* / Q000494:pharmacology
D000998:Antiviral Agents; D014230:Triazoles