Synthesis of some novel pyridine compounds containing bis-1,2,4-triazole/thiosemicarbazide moiety and investigation of their antioxidant properties, carbonic anhydrase, and acetylcholinesterase enzymes inhibition profiles

Abstract

Some novel derivatives of thiosemicarbazide and 1,2,4-triazole-3-thiol were synthesized and evaluated for their biological activities. The title compounds were prepared starting from readily available pyridine-2,5-dicarboxylic acid. The reaction carboxylic acid with absolute ethanol afforded the corresponding dimethyl pyridine-2,5-dicarboxylate (1). The reaction of dimethyl-2,5-pyridinedicarboxylate (1) with hydrazine hydrate good yielded pyridine-2,5-dicarbohydrazide (2). Refluxing compound 2 with alkyl/aryl isothiocyanate derivatives for 3-8 h afforded 1,4-disubstituted thiosemicarbazides (3a-e). Base-catalyzed intra-molecular dehydrative cyclization of these intermediates furnished the 4,5-disubstituted bis-mercaptotriazoles (4a-e) in good yield (85%-95%). Among the target compounds, 2,2'-(pyridine-2,5-diyldicarbonyl)bis[N-(p-methoxyphenyl)hydrazinecarbothioamide] (3c) showed very high activity with value of 72.93% against 1,1-diphenyl-2-picrylhydrazyl free radical at the concentration of 25 mu g/mL. The inhibitory effects of the target compounds against acetylcholinesterase (AChE), hCA I, and II were studied. AChE, cytosolic hCA I and II isoforms were potently inhibited by synthesized these derivatives with K(i)s in the range of 3.07 +/- 0.76-87.26 +/- 29.25 nM against AChE, in the range of 1.47 +/- 0.37-10.06 +/- 2.96 nM against hCA I, and in the range of 3.55 +/- 0.57-7.66 +/- 2.06 nM against hCA II, respectively.