Biological activity of methyl 2-[5-oxo-3,4-di-(2-pirydyl)-1,4,5,6-tetrahydro-1,2,4-triazine-6-ylidene] acetate.

The NCNN group is an essential part of various heterocycles bearing high biological activities. 1,2,4-Triazines and their condensed derivatives found applications as pharmaceuticals and in agriculture. For example vardenafil ñ phosphodiesterase inhibitor, is useful in the treatment of male erectile dysfunctions (1), apazone exhibit anti-inflammatory and analgesic actions (2), lamotrigine is used as anticonvulsant agent and in the treatment of bipolar depression (3). Moreover, ceftriaxon ñ well-known antibiotic (4) and also cytostatic nucleoside analog ñ azaribine (5), possess in the structure the 1,2,4-triazine ring. Pymetrozine represents a new chemical class of insecticides (6, 7). There is an interest in the synthesis and design of compound structurally based on this heterocyclic system because of their higher antimicrobial activity than that of standard drug and antifungal activity comparable with the standard drug (8, 9). They have been also reported to associate with antimycobacterial (10), antitumor (11, 12), antiviral (13-15), anxiolytic and antidepressant (16, 17) effects. In our previous study on the reaction of the Nsubstituted amidrazones with dimethyl acetylenedicarboxylate in absolute ethanol at the temperature of -10C, derivatives of dimethyl 2-[(1-aryl-amino-1arylmethylidene)hydrazono]succinate were obtained. Only synthesis with amidrazone containing two 2-pirydyl substituents gave methyl 2-[5-oxo-3,4-di(-2-pyridyl)-1,4,5,6-tetrahydro-1,2,4-triazine-6-ylidene)acetate under above-mentioned conditions. Cyclization of other linear products was carried out in methanol solution in the presence of triethylamine. The following substances were obtained: methyl 2-(5-oxo-3,4-diphenyl-1,4,5,6-tetrahydro1,2,4-triazine-6-ylidene)acetate (1), methyl 2-(5oxo-3-phenyl-4-p-tolyl-1,4,5,6-tetrahydro-1,2,4-triazine-6-ylidene)acetate (2), methyl 2-[5-oxo-4phenyl-3-(2-pyridyl)-1,4,5,6-tetrahydro-1,2,4-triazine-6-ylidene]acetate (3), methyl 2-[5-oxo-3-(2pyridyl)-4-p-tolyl-1,4,5,6-tetrahydro-1,2,4-triazine6-ylidene]acetate (4), methyl 2-[4-(4-nitrophenyl)5-oxo-3-(2-pyridyl)-1,4,5,6-tetrahydro-1,2,4-triazine-6-ylidene]acetate (5), methyl 2-[5-oxo-3,4-di(-2-pyridyl)-1,4,5,6-tetrahydro-1,2,4-triazine-6-ylidene)acetate (6) (Figure 1, Table 1) (18). The acute toxicity of compounds 1-6 in mice was low (> 2000 mg/kg i.p.). Depending on the type of substituent methyl 2-(5-oxo-1,2,4-triazine-6-ylidene)acetate derivatives show different activity. The role of compounds 3 and 4 as biocidal plant protection agents such as herbicides, bactericidal, fungicidal, antimicrobial, protozacides, anticoccidial, parasiticides, insectides, acaricides and pestides, was presented in earlier report (19). Compounds 1 and 3 at a 500 μg mL concentration did not affect the microflora of the human digestive tract (20) nor at a 10 ñ 400 μg mL concentration, the morphotic elements of the green monkey kidney cells (21). Depending on the compound 3 dose and the viral species examined (VSV, EMCV and AV-5) it decreased proliferation comparable with the medical compound called Vratizolin (22). We present here more extensive antimicrobial testing results for compound 6 because of promising activity of this type molecules.