Abstract
Role of aldose reductase (ALR2) in diabetic complications such as retinopathy, nephropathy, neuropathy, and cataract <i>etc</i>. is well-evident. ALR2 in the first step of polyol pathway reduces glucose to sorbitol whose elevated level leads to diabetic cataract, characterize by clouding of the lens in the eye that affects vision. Inhibition of ALR2 enzyme with small molecules as inhibitor is a rapid approach for diabetic management. In the present study the synthetic route to synthesize desired benzopyrazines and a library of sixteen (16) methyl benzopyrazines were screened against aldose reductase. From the bioactivity results, the 3'-hydroxyphenyl benzopyrazine 6l was found most active (IC<sub>50</sub> = 1.34 ± 0.07 <i>µ</i>M) while 3'-bromophenyl analogue 6i showed comparable activity for ALR2 (IC<sub>50</sub> = 3.48 ± 0.66 <i>µ</i>M) as compared to standard sorbinil (IC<sub>50</sub> = 3.14 ± 0.02 <i>µ</i>M). Both compounds (6l and 6i) showed excellent selectivity for ALR2 over aldehyde reductase (ALR1) which has important role in detoxification of toxic aldehydes. The structure of two regio-isomers were fully characterize by <sup>1</sup>H and <sup>13</sup>C NMR two dimensional NMR techniques including COSY, NOESY, HSQC, and HMBC. Regio-isomers separation was proved to be difficult in different solvent systems. Only an isomer of 3'-bromo benzopyrazine 6i' was isolated that help to assign the structure of regioisomers from NMR data. All the benzopyrazines were fully characterized by using different spectral techniques including <sup>1</sup>H, <sup>13</sup>C NMR, IR spectroscopy, and mass spectrometry.
Highlights
Diabetes mellitus (DM) is chronic lifetime condition which disrupts body’s ability to use glucose from food as energy source
Silica gel 60 aluminium-backed plates having 0.063-0.200 mm as the stationary phase were used for thin layer chromatography (TLC) and flash silica was used for column chromatography
The dicarbonyl intermediate 4 was reacted without purification with 4-methylbenzene-1,2diamine at room temperature to afford corresponding benzopyrazine (Figure 3)
Summary
Diabetes mellitus (DM) is chronic lifetime condition which disrupts body’s ability to use glucose from food as energy source. The diabetic complications associated with hyperglycemia are blindness, renal failure, neuropathy, and cardiac arrest etc. Under normal conditions glucose metabolize via glycolytic pathway [2]. During hyperglycemia normal pathway of glucose metabolism gets saturated and substantial amount of glucose enters into the polyol pathway. Aldose reductase (ALR2, EC 1.1.1.21) reduces the glucose to sorbitol which further oxidized to fructose with sorbitol dehydrogenase. ALR2 is a cytosolic enzyme that belongs to the class of aldo-keto reductase (AKR) superfamily. It is the first rate limiting enzyme of polyol pathway which reduce glucose to sorbitol. Intracellular sorbitol cannot pass through the cell membrane, accumulates within the cell causing osmotic stress that results in diabetic cataract complication [3]. Inhibition of ALR2 is considered an intelligent approach to reduce the progression of long term
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