Pharmaceuticals · 7 authors, 3 centres
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Two novel thioketone alkaloids, Spiroleiferthione A and Oleiferthione A, were isolated from Moringa oleifera seeds. Spiroleiferthione A is a rare 2-thiohydantoin with an unprecedented spiro skeleton that showed moderate, dose-dependent inhibition of high glucose-induced human renal mesangial cell proliferation, suggesting potential for diabetic nephropathy research. This study expands the known structural diversity of sulfur-containing compounds from M. oleifera seeds.
**Background:** Thiohydantoins and imidazole-2-thione derivatives are rare in nature, with fewer than 50 naturally occurring thiohydantoins reported. Moringa oleifera Lam. seeds are known for diverse pharmacological activities including anti-inflammatory, hepatoprotective, and antidiabetic properties. This study aimed to discover novel sulfur-containing compounds from M. oleifera seeds and evaluate their bioactivities.
**Methods:** Dried M. oleifera seeds (10 kg) were extracted with water, fractionated using macroporous resin, MCI gel, and silica gel column chromatography, and purified by RP-HPLC to yield two compounds. Structural elucidation employed HRESIMS, 1D and 2D NMR, IR, UV, ECD spectroscopy, GIAO NMR calculations, and single-crystal X-ray crystallography. Bioassays included antimicrobial testing against four bacterial strains (E. coli, S. aureus, S. enterica, P. aeruginosa) at 100 μM, inhibition of LPS-induced NO production in RAW 264.7 macrophages at 50 μM, and inhibition of high glucose (30 mM)-induced HRMC proliferation at 10, 20, and 50 μM.
**Key Results:** Spiroleiferthione A (1, C14H16N2SO4, 1.5 mg isolated) was identified as a rare 2-thiohydantoin with an unprecedented heterocyclic spiro skeleton. Its absolute configuration was determined as (5R,7R,8S) based on DFT NMR chemical shift calculations (R² = 0.9993, MAE = 1.01, RMS = 1.29) and ECD matching. Oleiferthione A (2, C12H14N2OS, 2.0 mg isolated) was confirmed by X-ray crystallography (CCDC: 2168388) as 1-(4′-hydroxybenzyl)-4,5-dimethyl-1,3-dihydro-2H-imidazole-2-thione. Neither compound showed antimicrobial activity at 100 μM. Compounds 1 and 2 showed weak NO inhibition (42.81 ± 1.56% and 33.53 ± 2.34% at 50 μM, respectively) compared to L-NMMA (59.31 ± 2.19%). Compound 1 demonstrated moderate, dose-dependent inhibition of high glucose-induced HRMC proliferation (p < 0.05 at tested doses; p < 0.001 at highest dose vs. 30 mM glucose group).
**Clinical Implications:** The moderate, dose-dependent inhibition of HRMC proliferation by Spiroleiferthione A suggests potential protective effects against diabetic nephropathy progression. This represents the first investigation of antidiabetic nephropathy activity for 2-thiohydantoin derivatives. However, in vivo studies and mechanistic investigations were not performed due to compound quantity limitations. The total synthesis of these thioketone derivatives may enable more comprehensive bioactivity evaluation. The discovery enriches the structural diversity of sulfur-containing compounds from M. oleifera seeds and provides a foundation for future research on thioketone alkaloids.