Stereo-controlled Synthesis Of1,2-benzothiazine-1,1-dioxide Based Aldose Reductase Inhibitors

Diabetes is a chronic disease that effecting millions of people worldwide. Therefore, ithas become one of the main challenges faced by today’s international pharmaceuticalacademic to develop an effective drug against diabetic complications. The pathogenesis ofdiabetic complications such as retinopathy, neuropathy, nephropathy, cataracts, and strokeare attributed to multiple biochemical pathways. Substantial evidences revealed a key roleof polyol pathway in the development of diabetic complications. Aldose reductase (ALR2,EC1.1.1.21), which catalyzes the NADPH dependent reduction of glucose to sorbitol, isthe first and rate determining enzyme of the polyol pathway. Therefore, it has beenidentified as a potential target for therapeutic intervention to prevent diabetic complications.In the past few decades many compounds have been developed to inhibit ALR2withvarying degree of efficiency and selectivity. Recently, we have developed1,2-benzothiazine-1-1-dioxide carboxylate based ARIs, where we found the need ofstereo-controlled and enantioselective synthesis to check the effect of orientation ofcarboxylic acid group over aldose reductase inhibition activity.Wittig reaction is the well-established transformation for introducing double bond inplace of carbonyl functionality and also important for stereo-controlled synthesis. Firstly,Wittig reaction of1,2-benzothiazinone1,1-dioxide derivatives with stabilized ylide(carbethoxymethylene)triphenylphosphorane in nonpolar aprotic solvent selectivelysynthesized both exocyclic conjugated and endocyclic non-conjugated ester under varioustemperature conditions. At40°C only exocyclic conjugated ester was formed with highZ-selectively (83-87%) while at100-120°C endocyclic non-conjugated ester was formedpreferentially (77-96%) without the use of base. The isomers were separated by silica gelcolumn chromatography. Under base hydrolysis of both types of isomers produced onlyendocyclic non conjugated acid while no bond shifting was observed in acid hydrolysis. The structural and conformational study of these isomers was carried out using NOE andX-ray Crystallography.Secondly, saturated derivatives contained a chiral center at the C4position, to whichthe acetate side chain is attached, was synthesized by reduction of α,β-unsaturatedderivatives of1,2-benzothiazine1,1-dioxide carboxylate. The C4-carboxylate plays a keyrole for this class of ARIs in binding with the active site of enzyme commonly known asanion binding pocket. Therefore, it was suggested that the direction or orientation of thecarboxylate head would have a big impact on the inhibitory activity of ARIs, and studies onthis topic may then provide insight into the interaction mechanism of inhibitors bound tothe enzyme. Consequently, enantiomers of the1,2-benzothiazine-1,1-dioxide-based classprovide valuable probes for verifying the role of the configuration of the carboxylate headin the enzyme inhibition. To achieve the required target a copper catalyst system for theasymmetric1,4-hydrosilylations of α,β-unsaturated carboxylate class was developed.Synthesis of (+)-and ()-enantiomers of1,2-benzothiazine-1,1-dioxide acetates has beenachieved with good yield up to89%and excellent level of enantioselectivity up to97%ee.Which were further converted into their respective acid derivatives.Thirdly, comparative ARI analysis of synthesized isomers of unsaturated and theenantiomers of saturated derivatives of1,2-benzothiazine1,1-dioxide carboxylic acid wascarried out. All of the isomers were found to be active with IC50values ranging from0.057μM to43.86μM in rank order of Endocyclic> E-isomer> Z-isomer. Endocyclic,53b,2-[2-(4-bromo-2-fluorobenzyl)-1,1-dioxido-2H-1,2-benzothiazin-4(3H)-ylidene]acetic acid,exhibited most potent inhibition activity. The structure activity relationship of synthesizedenantiomers exhibited the aldose reductase inhibition activity in the rank order of()-enantiomers> racemic>(+)-enantiomers. Fourthly, comparative inhibition activity ofstereoisomers and enantiomers was further supported by molecular docking study whichdemonstrated the high binding affinity for endocyclic isomers compared to other isomersand for chiral derivatives () enantiomer had significant binding affinity in anion bindingpocket and thus boosted inhibition activity.