Abstract

Background/Objectives: Pigmented rice is increasingly recognized as a functional food because of its rich phytochemical composition and health-promoting potential. However, local red rice cultivars from the three southern border provinces of Thailand remain insufficiently characterized. This study comparatively evaluated four whole-grain red rice cultivars—Hawm Gra Dang Ngah 59 (HGDN 59), Hawm Mue Lau (HML), Lued Pla Lai (LPL), and Se Bu Kan Tang (SBKT)—for their chemical composition, antioxidant activities, and antidiabetic potential. Methods: Whole-grain rice samples were extracted with 95% ethanol and assessed for extraction yield, total phenolic content, and total flavonoid content. Antioxidant activity was measured using DPPH^•, FRAP, and anti-lipid peroxidation assays, while antidiabetic activity was measured using α-amylase and α-glucosidase inhibition assays. LC-MS/MS-based chemical profiling, pathway classification, PCA-based chemical space analysis, molecular docking against α-glucosidase, and physicochemical/ADMET prediction were also performed. Results: Among the tested cultivars, HGDN 59 showed the most favorable overall profile, with the highest phenolic content, strongest antioxidant activity, and marked α-glucosidase inhibitory activity. LC-MS/MS analysis combined with docking-based screening revealed that HGDN 59 contained several abundant compounds, including ent-Epicatechin-(4α→6)-ent-epicatechin, cinnamtannin A1, apiin, and α-tocotrienol. These compounds exhibited strong binding affinities toward α-glucosidase (−10.7 to −9.6 kcal/mol), comparable to or slightly more favorable than acarbose. ADMET prediction indicated that most polyphenolic compounds exceeded Lipinski’s rule of five, while α-tocotrienol demonstrated favorable absorption property. Conclusions: This is the first study to suggest that HGDN 59 exhibits potential α-glucosidase inhibitory activity in vitro and may serve as a promising functional food candidate for the dietary management of postprandial glycemic response.