CINNAMIC ACID DERIVATIVES/QUERCITOL BIOCONJUGATES AS ANTIOXIDANT AND α-GLUCOSIDASE INHIBITOR AND SYNTHESIS OF SULFENAMIDE DERIVATIVESFROM THIOLS USING HYPERVALENT IODINE(III) REAGENTS

Abstract

In this research, we focus on two distinct research themes: (1) bioactive compound from natural (+)-proto-quercitol and (2) synthetic methodology for the synthesis of sulfenamides and related compounds using hypervalent iodine(III). The first project involves structural modification of natural carbasugar with cinnamic acid derivatives to enhance their glucosidase inhibitory and antioxidant property. In this work, 31 novel compounds (quercityl-cinnamate derivatives (2.1ER-2.8ES) and quercityl-cinnamamide derivatives (2.1AR-2.8AS)) were prepared, fully characterized and investigated for their α-glucosidase inhibitory effect against baker’s yeast and rat intestine (maltase and sucrase) in vitro. Most compounds potentially inhibit α-glucosidase from rat intestine with IC50 value in the range of 0.41-527.41 µM, which are 1.2-208 times greater than corresponding starting cinnamic acid derivatives. Of the prepared compounds, 2.8AS possesses the highest maltase inhibitory activity with an IC50 value of 0.41 µM, which is equipotent to some clinically used antidiabetic drugs, acarbose and voglibose (IC50 = 1.5 and 0.25 µM, respectively). In addition, its radical scavenging ability (SC50 = 0.07 mM) is comparable to that of commercial antioxidant BHA (SC50 = 0.10 mM). In addition, kinetic study revealed that mechanistically, 2.8AS is non-competitive inhibitor for maltase. Moreover, docking analysis confirmed that 2.8AS could bind to the maltase in an allosteric site on the catalytic domain, which is different from the pocket site (active site) of acarbose. For synergistic effect of 2.8AS, inhibitory activity against maltase exerted by a mixture of acarbose and 2.8AS was significantly improved up to 1.1-5.7 times, when compared with acarbose alone. The outcome of this research suggests that this combination may provide a significant clinical benefit in delaying postprandial hyperglycemia. The aim of the second project is to develop an efficient synthetic methodology for sulfenamide. Treatment of hypervalent iodine(III) to thiols in the presence of amines provides the corresponding sulfenamides in fair to good yields (43–90%). The methodology is successfully extended to indole as a representative of an electron-rich aromatic compound, allowing a successful construction of an S–C bond in a one-pot fashion. The key benefits of this reaction include lower toxicity, low cost of DIB reagent, and mild reaction conditions (room temperature, undried solvents and open flask).