Synthesis and Biological Evaluation of Some [1,2,4]Triazolo[4,3-a]quinoxaline Derivatives as Novel Anticonvulsant Agents

2-([1,2,4]Triazolo[4,3-a]quinoxalin-4-ylthio)acetic acid hydrazide (10) was used as a precursor for the syntheses of novel quinoxaline derivatives with potential anticonvulsant properties. The newly synthesized compounds have been characterized by IR, 1H？NMR, and mass spectral data followed by elemental analysis. The anticonvulsant evaluation was carried out for eleven of the synthesized compounds using metrazol induced convulsions model and phenobarbitone sodium as a standard. Among this set of tested compounds, two of them (14, and 15b) showed the best anticonvulsant activities. 1. Introduction Syntheses of quinoxalines have attracted a great deal of attention in view of their potent biological and pharmacological activities including anticonvulsant [1–4], antibacterial [5], antifungal [6], antiviral [7], antitubercular [8], antileishmanial [9], antiamoebic [10], analgesic [11], antihistaminic [12], antineoplastic [13], hypoglycemic [14], MAO-A inhibitor [15], antiarrhythmic [16], antiatherosclerotic [17], antiobese [18], and other diverse pharmacological activities. Earlier studies revealed that most of compounds derived from 1,2,4-triazoles have been found to be significant anticonvulsant [19] and tranquillizing agents [20]. Furthermore, compounds 1a–e in Figure 1 which contain [1,2,4]triazolo[4,3-a]quinoxaline moiety showed promising anticonvulsant activity [21]. Figure 1 We describe the synthesis and biological evaluation of novel [1,2,4]triazolo[4,3-a]quinoxaline derivatives expected to have anticonvulsant activity starting from 1,2-diaminobenzene and oxalic acid via quinoxaline ring build-up. 2. Results and Discussion 2.1. Chemistry The [1,2,4]triazolo[4,3-a]quinoxaline derivatives were prepared using established methodology as shown in Scheme 1. 2,3-Dichloroquinoxaline (3) was prepared by chlorination of 2,3-dihydroxyquinoxaline (2), which in turn was prepared by the condensation of the commercially available 1,2-diaminobenzene with oxalic acid in aqueous hydrochloric acid. Treatment of 3 with hydrazine hydrate yielded the corresponding 3-hydrazino compound, 4, which was subjected to ring closure to 5 by treatment with triethyl orthoformate. Reaction of 5 with thiourea in absolute ethanol afforded the isothiouronium intermediate which upon basic hydrolysis yielded [1,2,4]triazolo[4,3-a]quinoxaline-4-thiol (6). The potassium salt 7 was obtained after treatment of 6 with alcoholic KOH in a quantitative yield. Scheme 1 Reaction of the potassium salt 7 with substituted aniline in DMF gave the corresponding anilide 8a–d, and its reaction with alkyl