The assessment of antidiabetic properties of novel synthetic curcumin analogues: α-amylase and α-glucosidase as the target enzymes

Abstract

Diabetes mellitus is a metabolic disorder characterized by high blood glucose levels and instability in carbohydrate metabolism. For treating diabetes, one important therapeutic approach is reducing the postprandial hyperglycemia which can be managed by delaying the absorption of glucose through inhibition of the carbohydrate-hydrolyzing enzymes, α-amylase (α-Amy) and αglucosidase (α-Gls) in the digestive tract. In this work, a new class of curcumin derivatives incorporating pyrano[2,3-d]pyrimidine heterocycles was synthesized using a multicomponent reaction between curcumin, aldehydes, and barbituric acid. Using UV-Vis spectroscopic method, the synthetic compounds were assessed for their inhibitory properties against α-Amy and α-Gls enzymes. Also, the antioxidant potential of these compounds was measured spectroscopically and compared with Trolox which is known as a gold standard to measure antioxidant capacity. The results of present study suggest that the curcumin derivatives were able to efficiently inhibit both yeast and mammalian α-Gls. In comparison with the antidiabetic medicine acarbose, the synthetic curcumin derivatives were also capable to inhibit more effectively the yeast α-Gls. The partial inhibitory effects of these compounds against pancreatic α-Amy were also important in the terms of avoiding development of the possible gastrointestinal side effects. Moreover, some of the curcumin derivatives indicated stronger antioxidant activity than Trolox. Overall, these synthetic curcumin analogues might be considered as novel molecular templates for development of efficient antidiabetic compounds with promising inhibitory activities against α-Amy and α-Gls enzymes.

Insights into the recent progress in the medicinal chemistry of pyranopyrimidine analogs

“…On the other hand, pyranopyrimidine compounds "series 127a-g" were evaluated as antidiabetic agents, and found as potential inhibitors for α-amylase and α-glucosidase, as reported by Hasaninezhad et al 93 The results indicated that compounds 127 "Ar = 4-NO 2 -Ph" (Yeast: IC 50 = 12.41 ± 1.10 μM; Mouse: IC 50 = 106.80 ± 2.10 μM) and 127 "Ar = 2,6-Cl 2 -Ph" (Yeast: IC 50 = 27.60 ± 1.30 μM; Mouse: IC 50 = 46.04 ± 2.10 μM) accessible rational inhibitory activity on α-glucosidase presented by reduced inhibitory activity on α-amylase. Thus, the compounds showed significant antioxidant characteristics as vital antidiabetic agents.…”

“…the nitro substituents at the phenyl ring improved the AR inhibitory activity. 91 Ghaffarian et al 92 93 reported also the synthesis of these series of pyranopyrimidines incorporated curcumin moiety 127 using catalytic SAA-MNPs (8 mol%). In 2021, Mehrabi et al 13 and Esmaeili et al 94 synthesized these series of compounds 128 and 129 with different substituents by multicomponent one-pot synthesis using borax with 10% in ethanol at reflux temperature.…”

“…Thus, the compounds showed significant antioxidant characteristics as vital antidiabetic agents. 93 The antidiabetic activity of pyranopyrimidine-diones "series 128a-m" (Scheme 30) was estimated by Mehrabi et al 13 Also, compounds (series 129a′-m′) (Scheme 30) were assessed as antioxidant and glycohydrolase inhibitors as evaluated by Khodarahmi's group. 94 The results identified that compounds 129h′ Bisenieks et al 95 prepared a series of pyranopyrimidinediones 130a-g and their S-alkyl derivatives 131a-g from barbituric and thiobarbituric acids in multi-step synthetic routes (Scheme 31).…”

Recent advancements in the multicomponent synthesis of heterocycles integrated with a pyrano[2,3-d]pyrimidine core

“…Formerly, Hasaninezhad et al 95 and Yousefi et al 10 have reported the synthesis of pyrano[2,3- d ]pyrimidine derivatives 25 ( Scheme 15 ) from multicomponent one-pot reactions of curcumin, aryl aldehydes, and (thio)barbituric acids in ethanol under catalytic, and reflux conditions using the prepared metal nanoparticles such as SAA-MNPs (8 mol%). The antidiabetic properties of these series of bicyclic systems-based curcumin were investigated and the compounds were evaluated as potent inhibitors for α-amylase and α-glucosidase.…”

“…The compounds showed significant antioxidant characteristics as potent, and vital anti-diabetic agents. 95 Hasaninezhad et al 95 have also evaluated the antibacterial activity of these types of compounds using well diffusion assay against Lactobacillus plantarum and Escherichia coli species. The results indicated that compound 25 “Ar = 4-NO 2 -C 6 H 4 ” has a broad spectrum activity against E. coli species (inhibition zone diameter = 11 ± 0.1 mm) relative to ampicillin (inhibition zone diameter = 12 ± 0.5 mm).…”