Synthesis of Rosmarinic Acid Amides as Antioxidative and Hypoglycemic Agents

Abstract

Type 2 diabetes mellitus (T2DM) is an important metabolic disorder for which there is an urgent need for new antidiabetic drugs. α-Glucosidase inhibition is an established protocol for T2DM therapy. Because hyperglycemia causes oxidative tissue damage, the development of agents with both α-glucosidase inhibition and antioxidant activity from natural or natural-derived polyphenols such derivatives of rosmarinic acid (RA) represents an attractive therapeutic option. We report a study on amides 1−10 derived from RA and their evaluation for yeast α-glucosidase inhibition and antioxidant activity (DPPH and ORAC tests). All amides showed higher inhibitory activity than that of RA, were by far more potent than the antidiabetic drug acarbose, and proved to be effective antioxidants. A molecular docking study displayed significant binding interactions of RA amides with the active site of α-glucosidase. This in silico optimization study led to the design and synthesis of amides 9 (IC 50 = 42.3 μM) and 10 (IC 50 = 35.2 μM), showing the most potent α-glucosidase inhibition and good antioxidative properties. A kinetic study showed that 10 acts as a mixed type inhibitor.

Mass Spectrometry and 1H-NMR Study of Schinopsis lorentzii (Quebracho) Tannins as a Source of Hypoglycemic and Antioxidant Principles

“…This peak was tentatively assigned to a catechin-fisetinidol isomer (9 ). The peak at t R = 39.2 min showing a [M − H] − at m/z 647 was attributed to a trigalloyl quinic acid isomer (11 ), as confirmed by the fragment ions at m/z 495 (M-H-152, loss of one unit of galloyl) and m/z 477 (M-H-170, loss of gallic acid). The complex envelope of overlapped peaks between 40 and 50 min showed several m/z signals attributable to fisetidinol-catechin oligomers, among which, we report here some identifications.…”

“…The ORAC of the SL-T and SL-A extracts and A-1–A-9 fractions were measured according to a previously described method [ 11 ]. Extracts and fractions were dissolved in water or methanol at 0.1 mg/mL and subsequently, diluted with phosphate buffer (50 mM, pH 7.4) to get final working solutions in the range 0.125–0.0125 mg/mL.…”

“…Fraction A-6 shows a TIC chromatogram with a low intense peak at t R = 21 min, assigned to the above mentioned digalloyl quinic acid isomers (5 and/or 5 ). An intense broad peak between 37 and 43 min is the main feature of this fraction; this includes a trigalloyl quinic acid isomer (11 ) and the oligomers 9 , 19, and 23. The most intense peak gave a [M − H] − at m/z 285, identified with the flavonoid fisetin (16) and confirmed by the fragment ions at m/z 163 (M-H-122, loss of B ring by a benzofuran-forming fission mechanism (BFF), m/z 241 (M-H-44, loss of CO 2 ), and m/z 267 (M-H-18, loss of a molecule of water).…”

“…Moreover, the well-known antioxidant properties of polyphenols represent a further advantage in the search for potential dual-action antidiabetic agents, able to join hypoglycemic properties and reduction in oxidative damage associated with diabetes complications [ 2 ]. Consequently, several analogues of natural polyphenols have been evaluated as hypoglycemic agents, namely stilbenoid glycosides [ 9 ], bisphenol neolignans [ 10 ], rosmarinic acid amides [ 11 ], 3,4-dihydroxypyrrolidine-based compounds [ 12 ], and biscoumarins [ 13 ].…”

Antihyperglycaemic potential of rosmarinic acid attenuates glycoprotein moiety in high-fat diet and streptozotocin-induced diabetic rats

“…RA also protects pancreatic cells from glucolipotoxicity (Govindaraj and Sorimuthu Pillai 2015). Rosmarinic Acid Amides also acted as an antioxidant and hypoglycaemic agent in vitro (Cardullo et al 2019). However, no scientific reports are available on the protective effect of rosmarinic acid on plasma and tissue glycoprotein moiety in diabetes.…”