Design and synthesis of hydrazinecarbothioamide sulfones as potential antihyperglycemic agents

Abstract

New hydrazinecarbothioamides with a phenylsulfonyl group were synthesized and their structures were identified by different spectroscopic data ( 1 H NMR, 13 C NMR, two-dimensional NMR, mass spectrometry, elemental analysis, and single-crystal X-ray analysis). The mechanism describing the formation of the products was also discussed.The antidiabetic activity of the isolated products was investigated histochemically. The synthesized sulfonylalkylthiosemicarbazide exhibited antihyperglycemic activity in streptozotocin-induced diabetic mice. Compounds 5a and 5c significantly lowered the blood glucose level to 103.3 ± 1.8 and 102 ± 3.9 mg/dl, respectively. Also, they caused a significant decrease in malondialdehyde levels and normalized the glutathione levels in streptozotocin-induced diabetic mice, compared with the diabetic group. The results suggest that the synthesized hydrazinocarbothioamides may effectively inhibit the development of oxidative stress in diabetes. K E Y W O R D S4-substituted hydrazinecarbothioamides, antihyperglycemic activity, bis(2-(phenylsulfonyl)ethyl)sulfane, glutathione, malondialdehyde, sulfonylalkylthiosemicarbazide | INTRODUCTIONDue to the significant impact of sulfone compounds in biological applications, the development of new sulfone-containing compounds remains one of the central challenges of organic chemistry. [1,2] There are many sulfones widely reported in the literature with a broad spectrum of biological activities such as anticancer, [3] antimicrobial, [4] antiinflammatory, [5] antiproliferative, [6,7] antimalarial [8] and anti-HIV activities. [9] Catalytic chemoselective addition of amino alcohols to α,βunsaturated sulfonyl derivatives leads to the regioselective formation of amino and hydroxy adducts, depending on different catalysts and reaction conditions. [10,11] N-Substituted hydrazinecarbothioamides are considered as one of the most important classes of compounds containing nitrogen, sulfur, and oxygen used for heterocyclization and formation of different heterocyclic rings such as thiadiazole and thiadiazepine, and from the reaction with several π-deficient compounds. [12][13][14][15] The literature approach was applied to 4-(1-phenyl-1Htetrazole-5-ylsulfonyl)butanenitrile (PTSB), a growth inhibitory compound with a previously unknown mode of action, and the thioredoxin/ thioredoxin reductase system was identified as its target. [16] Another patent showed compounds having CH 2 CH 2 SO 2 Ar functional group as histone deacetylase inhibitors. [17][18] The synthesis of various heterocyclic