Enzymes Inhibitory Properties of Compounds from Roots of <i>Mitragyna inermis</i> Willd (Rubiaceae): <i>In Vitro</i> , Molecular Docking and ADME Evaluations

Objective: Mitragyna inermis is important in traditional pharmacopeia and is used in treating diabetes and neurological diseases among others. This study involves inhibition of cholinesterases, α-amylase, α-glucosidase, tyrosinase and urease by compounds from M. inermis . Methods: Compounds were isolated from roots of M. inermis, identified using 1D and 2D NMR data and evaluated for their enzymes inhibitory effect. Results: The compounds were identified as emodin ( MGA-1 ), citreorosein ( MGA-2 ), a mixture ( MGA-3 ) of 1-O-primeverosyl-8-hydroxy-3,7-dimethoxyxanthone ( MGA-3a ) and 1-O-primeverosyl-37,8-trimethoxyxanthone ( MGA-3b ) and (+)-bornesitol ( MGA-4 ). These compounds are isolated from this plant for the first time and complete 1 H NMR and 13 C NMR data of MGA-3a and MGA-3b properly assigned. Compounds exhibited good acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition, with MGA-3 (IC 50 = 25.65 ± 0.63 µg/mL) more active than galantamine (IC 50 = 42.10 ± 0.44 µg/mL). All compounds, MGA-1 (IC 50 = 76.89 ± 0.50 µg/mL), MGA-2 (IC 50 = 43.87 ± 0.46 µg/mL), MGA-3 (IC 50 = 74.73 ± 0.59 µg/mL) and MGA-4 (IC 50 = 39.18 ± 0.33 µg/mL) were more active than acarbose (IC 50 = 87.70 ± 0.68 µg/mL) in the α-glucosidase assay while in α-amylase inhibitory assay, only MGA-4 (IC 50 = 28.69 ± 0.52 µg/mL) was more active than acarbose (IC 50 = 32.25 ± 0.36 µg/mL). Compounds inhibited metalloenzymes (urease and tyrosinase) with MGA-1 (IC 50 = 22.94 ± 0.61 µg/mL) and MGA-2 (IC 50 = 20.48 ± 0.53 µg/mL) having greater antityrosinase activity than kojic acid (IC 50 = 23.75 ± 0.30 µg/mL). Molecular docking suggested good structure-activity relationship revealed through binding affinities and negative binding energies. ADME predictions suggested that all compounds had good lipophilicities, only MGA-1, MGA-2 and MGA-4 had acceptable molecular weights, topological surface area, hydrogen bond donors (HBD) and hydrogen bond acceptors (HBA). No compound could cross the blood-brain-barrier (BBB) and none showed alerts suggesting that the compounds do not contain substructures that are medicinally problematic. Conclusion: The compounds showed medicinal potential by inhibiting enzymes related to Alzheimer's disease, diabetes, hyperpigmentation and ureolytic bacterial infections.