Alkaloids and Styryl lactones from Goniothalamus ridleyi King and Their α-Glucosidase Inhibitory Activity

Gonioridleylactam (1), a new compound, is a unique dimeric aristolactam isolated from the EtOAc extract of the twigs of Goniothalamus ridleyi King. The structure of gonioridleylactam (1) consists of two different aristolactams linked together with two methylenedioxy bridges at C–3/C–3′ and C–4/C–4′, generating a ten-membered ring of [1,3,6,8]tetraoxecine. A new natural product, gonioridleyindole (3-hydroxymethyl-1-methyl-1H-benz[f]indole-4,9-dione, 2), together with eight known compounds (3–10) were also isolated from this plant. Their structures were extensively characterized by spectroscopic methods and comparisons were made with the literature. Compounds 1–4, 7, and 9 were evaluated for their α-glucosidase inhibitory activity. Of these, 3,5-demethoxypiperolide (7) displayed the highest α-glucosidase inhibitory activity, with an IC50 value of 1.25 µM.

Molecules 2023, 28, x FOR PEER REVIEW 2 of 8 paper describes the isolation, structure elucidation, and α-glucosidase inhibitory activity of compounds from G. ridleyi.

Structural Elucidation
Gonioridleylactam (1) was isolated as a yellowish solid. The HRESITOFMS spectrum of 1 displayed a sodium adduct ion at m/z 556.1271, corresponding to the molecular formula of C33H20N2O7. The UV spectrum showed maxima absorption bands at λmax 250, 277, and 322 nm, while the IR spectrum displayed the presence of NH (3394 cm −1 ) and amide carbonyl (1688 cm −1 ) functionalities. Following an intensive analysis of NMR spectroscopic data, the structure of 1 was determined as a dimeric aristolactam linked together with two different aristolactams (aristolactam units A and B). The 13

α-Glucosidase Inhibitory Activity
α-Glucosidase is a carbohydrate hydrolyzing enzyme that maintains postprandial blood glucose and insulin levels [19]. The inhibition of this enzyme can delay intestinal carbohydrate digestion to control hyperglycemia in diabetes mellitus [20]. Exploration for new α-glucosidase inhibitors and other antidiabetic drugs from natural sources has increased in recent years [21]. There are reports of the presence of α-glucosidase inhibitors such as flavonoids (quercetin) [22], terpenoids (wallitaxanes) [23], and alkaloids (5-hydroxynoracronycin) [19]. In this study, compounds isolated with a sufficient amount, 1-4, 7, and 9, were evaluated for their α-glucosidase inhibitory activity. Of these, 3,5demethoxypiperolid (7) showed the highest α-glucosidase inhibitory activity with an IC 50 value of 1.25 µM, which is better than that of the standard control (acarbose). Other tested compounds were weak or inactive ( Table 3). The observed α-glucosidase inhibitory activity of 3,5-demethoxypiperolid (7) indicates that this compound may have the potential as a lead compound for the further development of anti-diabetes agents.

Conclusions
Phytochemical investigation of the EtOAc extract of the twigs of Goniothalamus ridleyi King resulted in the discovery of a unique dimeric aristolactam and nine other compounds. The dimeric aristolactam contained two different aristolactam units linked together with two methylenedioxy bridges forming a [1,3,6,8]tetraoxecine ten-membered ring. The discovery of styryl lactones and alkaloids in this study as the major compounds was in good agreement with previous reports. In addition, the result of preliminary α-glucosidase inhibitory assay suggested that (5-(3-phenyl-2-propenylidene)-2(5H)-furanone) may have potential as the lead compound for the development of α-glucosidase inhibitory agent.

Plant Material
The twigs of G. ridleyi [24] were collected in April 2021 from Narathiwat Province, Thailand. This plant was identified by Mr. Abdulromae Baka (Independent Research Group on Plant Diversity in Thailand, Sichon, Nakhon Si Thammarat, 80120, Thailand). A voucher specimen (MFU-NPR0206) was deposited at the Natural Products Research Laboratory, School of Science, Mae Fah Luang University. Plant materials were dried and stored at room temperature.

α-Glucosidase Inhibitory Activity
The previously reported approach was used to perform a colorimetric α-glucosidase assay [25]. Briefly, the tested samples (50 µL) were combined with 50 µL of the α-glucosidase enzyme solution (0.05 U/mL) and preincubated at 37 • C for 5 min. The substrate (50 µL, c 1 mM), p-nitrophenyl α-D-glucoside, was added and incubated at 37 • C for 30 min. Then, 50 µL of Na 2 CO 3 (0.3 M) was added. The absorption of the mixture was measured at 405 nm. Acarbose was used as a positive control (185.7 µM).