Semisynthesis, biological activities, and mechanism studies of Mannich base analogues of magnolol/honokiol as potential α-glucosidase inhibitors.

Magnolol and honokiol, derived from a Magnolia officinalis Rehd. et Wils, are a class of natural biphenolic lignans. Currently, the discovery of new α-glucosidase inhibitors from natural analogues is of interest. Here, four series of thirty new Mannich base analogues of magnolol/honokiol were prepared and evaluated for their α-glucosidase inhibitory activities. Among these Mannich base analogues of magnolol/honokiol, 3k and 3l exhibited more potent inhibitory effects on α-glucosidase than the reference drug acarbose, and their IC50 values were 14.94 ± 0.17 µM and 13.78 ± 1.42 µM, respectively. Some interesting structure-activity relationships (SARs) were also analyzed. The enzyme inhibition kinetics indicated that 3k and 3l were noncompetitive inhibitors. This result was in agreement with molecular docking studies, where the binding sites of 3k and 3l to α-glucosidase were different from that of the competitive inhibitor acarbose to α-glucosidase. Moverover, compounds 3k and 3l exhibited low toxicity to normal cells (LO2). Thus, analogues 3k and 3l could be deeply developed for the discovery of natural products based antidiabetic candidates.

Discovery of honokiol thioethers containing 1,3,4-oxadiazole moieties as potential α-glucosidase and SARS-CoV-2 entry inhibitors.

Honokiol, isolated from a traditional Chinese medicine (TCM) Magnolia officinalis, is a biphenolic compound with several biological activities. To improve and broaden its biological activity, herein, two series of honokiol thioethers bearing 1,3,4-oxadiazole moieties were prepared and assessed for their α-glucosidase and SARS-CoV-2 entry inhibitory activities. Among all the honokiol thioethers, compound 7l exhibited the strongest α-glucosidase inhibitory effect with an IC50 value of 18.9 ± 2.3 µM, which was superior to the reference drug acarbose (IC50 = 24.4 ± 0.3 µM). Some interesting results of structure-activity relationships (SARs) have also been discussed. Enzyme kinetic study demonstrated that 7l was a noncompetitive α-glucosidase inhibitor, which was further supported by the results of molecular docking. Moreover, honokiol thioethers 7e, 9a, 9e, and 9r exhibited potent antiviral activity against SARS-CoV-2 pseudovirus entering into HEK-293 T-ACE2h. Especially 9a displayed the strongest inhibitory activity against SARS-CoV-2 pseudovirus entry with an IC50 value of 16.96 ± 2.45 µM, which was lower than the positive control Evans blue (21.98 ± 1.98 µM). Biolayer interferometry (BLI) binding and docking studies suggested that 9a and 9r may effectively block the binding of SARS-CoV-2 to the host ACE2 receptor through dual recognition of SARS-CoV-2 spike RBD and human ACE2. Additionally, the potent honokiol thioethers 7l, 9a, and 9r displayed relatively no cytotoxicity to normal cells (LO2). These findings will provide a theoretical basis for the discovery of honokiol derivatives as potential both α-glucosidase and SARS-CoV-2 entry inhibitors.

Semisynthesis and neurotrophic activity studies of novel neomajucin/majucin derivatives as neurotrophin small molecule mimetics.

Majucin-type Illicium sesquiterpenes with potent neurotrophic activity are considered to be promising candidates for the treatment of various neurodegenerative disease. Owing to the low-abundance metabolites in Illicium genus, there are few studies on their structural modifications, structure-activity relationships, and pharmacophoric motif. Herein, structural modifications were conducted on the hydroxyl groups at C-3 and C-6 positions of two majucin-type compounds neomajucin (1) and majucin (2), and 39 neomajucin/majucin based esters were synthesized and evaluated for their neurite outgrowth-promoting activities. Among all the target derivatives, compounds 1a, 1j, 1r, 2b, 2d, 3a, 3b, 3d and 3h displayed more potent neurite outgrowth-promoting activity than their precursors. Some interesting structure-activity relationships (SARs) were also observed. Moreover, compound 1a showed good neuroprotective effect on MPP+-induced PC12 cell damage. Finally, compounds 1a and 3a exhibited relatively no cytotoxicity to normal human H9C2 cardiac cells. This work will shed light on the development of neomajucin/majucin derivatives as potential neurotrophic agents.

Discovery, semisynthesis and neurite outgrowth-promoting activity of novel merrillianone/cycloparviforalone based esters as neurotrophic agents.

Natural products (NPs) are very important sources for the development of new drugs. Merrillianone and cycloparvifloralone, isolated from the roots, stems, and fruits of Illicium henryi Diels, are two natural sesquiterpene compounds. In continuation of our effort to discovery more effective neurotrophic compounds from NPs, a series of novel merrillianone/cycloparviforalone based esters 2a-i, 3a-g and 3i-q were prepared and their structures were characterized by 1H NMR, 13C NMR and IR spectral analyses. Furthermore, the spatial structure of compound 2h was unambiguously confirmed by X-ray crystallography. The neurite outgrowth-promoting activity results indicated that most of the target derivatives exhibited more potent neurite outgrowth-promoting activity than merrillianone and cycloparviforalone. Among all target derivatives, the neurite outgrowth-promoting activity of compounds 2a, 3a and 3b was about 2-fold stronger than that of their precursors merrillianone and cycloparviforalone, respectively. Besides, compounds 2a and 3a displayed relatively low cytotoxicity to normal GES-1 cells. Moreover, these derivatives had good hydrolytic stability. Finally, some interesting results of the structure-activity relationships (SARs) were also discussed. This work will pave the way for the development of merrillianone/cycloparviforalone derivatives as potential neurotrophic agents.