Metabolomics and chemometrics approaches unravel the metabolic diversity and in-vitro antidiabetic potential of two Ziziphus species

Ziziphus is a highly versatile tree species widely recognized for its nutritional and medicinal attributes, yet, Ziziphus spina-christi and Z. lotus, native species of Arabia, have received limited attention in scientific research. This study aimed to explore the metabolic variation in different organs (seeds, fruits and leaves) of Z. lotus and Z. spina-christi and identify bioactive metabolites associated with their in-vitro anti-diabetic activities. Phytochemical analyses revealed the presence of diverse compounds, including amino acids, alkaloids, flavonoids, phenolic acids, and fatty acids. Comparative profiling of the organs demonstrated significant variability in the chemical composition, with amino acids predominant in fruits, cyclopeptide alkaloids in seeds, and flavonoidal glycosides in leaves. Multivariate statistical analysis, including PCA and OPLS-DA, revealed distinct clustering patterns based on the chemical profiles of the different plant parts rather than plant species and identified discriminant metabolites for each plant part. The inhibitory effects of the extracts on α-amylase and α-glycosidase enzymes showed dose-dependent suppression, with Z. spina-christi extracts exhibiting the maximum α-glycosidase inhibitory activity and Z. lotus fruit extract as the most potent α-amylase inhibitor. Glucose uptake assays demonstrated increased utilization in HepG2 cells treated with Z. lotus extracts. Furthermore, multivariate analyses provided insights into the clustering patterns of samples based on bioactivity and highlighting metabolites positively correlated to the tested bioactivity. Notably, caffeic acid, ferulic acid, betulinic acid, hemsine, zizyotin, apetaline, quercetrin, jujubogenin, and zizyphursolic acid were identified as potential bioactive compounds. These findings may contribute to the understanding of Ziziphus chemical diversity and highlight its potential as a source of putative natural antidiabetic agents.