Lintao Yu

Copper-Catalyzed Oxidative Amination of sp3 C–H Bonds under Air: Synthesis of 1,3-Diarylated Imidazo[1,5-a]pyridines

A copper(II)-catalyzed tandem reaction between pyridine ketone and benzylamine was developed by using clean O2 as an oxidant. This transformation proceeded via an efficient condensation-amination-oxidative dehydrogenation process, affording 1,3-diarylated imidazo[1,5-a]pyridines in excellent yields.

Cobalt-Catalyzed Decarboxylative Acetoxylation of Amino Acids and Arylacetic Acids.

The first cobalt-catalyzed decarboxylative acetoxylation reaction was accomplished. This methodology is applicable to a wide range of amino acids and arylacetic acids.

Design, synthesis and evaluation of novel ferulic acid-memoquin hybrids as potential multifunctional agents for the treatment of Alzheimer’s disease

A novel series of ferulic acid-memoquin hybrids were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimers disease (AD). The in vitro studies showed that most of the compounds exhibited a significant ability to inhibit acetylcholinesterase (AChE) (IC50 of 3.2-34.7μM) and self-induced β-amyloid (Aβ1-42) aggregation (30.8-39.1%, 25μM), to act as potential antioxidants (ORAC-FL value of 0.9-1.3). In particular, compound 17d had the greatest ability to inhibit AChE (IC50=3.2μM), and Aβ1-42 aggregation (30.8%) was also an excellent antioxidant and neuroprotectant. Moreover, it is capable of disaggregating self-induced Aβ aggregation. Furthermore, 17d could cross the blood-brain barrier (BBB) in vitro. The results showed that compound 17d is a potential multifunctional agent for the treatment of AD.

Design, synthesis and biological evaluation of 3,4-dihydro-2(1H)-quinoline-O-alkylamine derivatives as new multipotent cholinesterase/monoamine oxidase inhibitors for the treatment of Alzheimer’s disease

A new family of multitarget molecules able to interact with acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), as well as with monoamino oxidase (MAO) A and B, has been synthesized. Novel 3,4-dihydro-2(1H)-quinoline-O-alkylamine derivatives have been designed using a conjunctive approach that combines the JMC49 and donepezil. The most promising compound TM-33 showed potent and balance inhibitory activities toward ChE and MAO (eeAChE, eqBuChE, hMAO-A and hMAO-B with IC50 values of 0.56μM, 2.3μM, 0.3μM and 1.4μM, respectively) but low selectivity. Both kinetic analysis of AChE inhibition and molecular modeling study suggested that TM-33 binds simultaneously to the catalytic active site and peripheral anionic site of AChE. Furthermore, our investigation proved that TM-33 could cross the blood-brain barrier (BBB) in vitro, and abided by Lipinskis rule of five. The results suggest that compound TM-33, an interesting multi-targeted active molecule, offers an attractive starting point for further lead optimization in the drug-discovery process against Alzheimers disease.

Phenylethanoid Glycosides from Houttuynia cordata and Their Hepatoprotective Activities

Houttuynia cordata Thunb., belonging to the Saururacea family, is well known by the name “Yu-Xing-Cao.” It is widely distributed in China and has been used as a plant medicine for relieving fever, promoting urination, and reducing swelling in folk [1]. Modern pharmacology has shown that H. cordata has antiviral, anti-inflammatory, and immunostimulating activities [2]. Previous phytochemical investigations of H. cordata showed the presence of flavonoids [3], alkaloids [4], organic acids, and essential oils [5]. To the best of our knowledge, there have been no reports on the hepatoprotective activities of H. cordata, which prompted us to further investigate its pharmacological potentials. As a result, 13 compounds (1–13) were isolated and identified as phenylethanoid glycosides on the basis of extensive spectroscopic analysis. These compounds were identified by their MS and NMR spectra, and all the data were in good agreement with those reported in the references. General. NMR spectra (1H NMR, 13C NMR) were recorded on Bruker-400, with TMS as internal standard. The ESI-MS data were acquired on an Agilent 1100 series LC/MSD Trap SL mass spectrometer. Column chromatography was run on Sephadex LH-20 (Amersham Pharmacia, Sweden) and silica gel H, 100–200 mesh and 200–300 mesh (Qingdao Marine Chemical Inc., Qingdao, China). TLC was performed on precoated silica gel GF254 plates, and the spots were visualized under UV light (254 or 356 nm) or by spraying with 10% H2SO4 in 95% EtOH followed by heating [15]. Plant Material. H. cordata was harvested from Nanyang, Henan Province, China, in August 2013. A voucher specimen (No. NNU201308) has been deposited in Nanyang Normal University. Extraction and Isolation. The whole air-dried and powdered plant of H. cordata (6.0 kg) was extracted three times with 95% EtOH (8 L 3) and heating under reflux to give 700 g of crude extract. The combined extracts were successively partitioned with petroleum ether, EtOAc, and n-BuOH to yield three fractions: petroleum ether soluble fraction (85.0 g), EtOAc soluble fraction (128.5 g), and n-butanol soluble fraction (245.0 g). The n-butanol soluble fraction was subjected to column purification with macroporous adsorbent resin (Diaion-101) and eluted with 15%, 30%, 50%, and 95% ethanol to obtain four fractions: A (35.5 g), B (64.0 g), C (42.8 g), and D (17.4 g). The B part was purified on a Sephadex LH-20 column with a gradient system of MeOH–H2O to give three subfractions: B-a, B-b, B-c. Repeated separation of B-a (8.80 g) by silica gel (100–200 mesh or 200–300 mesh) yielded 8 (11.00 mg), 5 (8.50 mg), 7 (10.50 mg), and 10 (9.60 mg). The B-b part was repeatedly chromatographed over Sephadex LH-20 and silica gel successively to yield 12 (7.60 mg), 13 (12.50 mg), 3 (13.10 mg), and 4 (9.10 mg). Similarly, the C part was chromatographed over Sephadex LH-20 and silica gel and eluted with different mobile phases, yielding 6 (14.00 mg), 9 (16.00 mg), 11 (9.30 mg), 1 (13.80 mg), and 2 (9.70 mg). Plantainoside A (1). C23H26O11, white powder. 1H NMR (400 MHz, CD3OD, , ppm, J/Hz): 6.69 (1H, d, J = 2.0, H-2), 6.66 (1H, d, J = 8.0, H-5), 6.54 (1H, dd, J = 8.0, 2.0, H-6), 3.90 (1H, m, H), 3.74 (1H, m, H), 2.79 (2H, t, J = 7.0, H), 4.44 (1H, d, J = 8.0, H-1 ), 5.05 (1H, d, J = 9.0, H-3 ), 7.08 (1H, d, J = 2.0, H-2 ), 6.80 (1H, d, J = 8.0, H-5 ), 6.97 (1H, dd, J = 8.0, 2.0, H-6 ), 7.58 (1H, d, J = 16.0, H-7 ), 6.33 (1H, d, J = 16.0, H-8 ) [6].

Design, synthesis and biological evaluation of phthalimide-alkylamine derivatives as balanced multifunctional cholinesterase and monoamine oxidase-B inhibitors for the treatment of Alzheimer’s disease

A series of novel phthalimide-alkylamine derivatives were synthesized and evaluated as multi-functions inhibitors for the treatment of Alzheimers disease (AD). The results showed that compound TM-9 could be regarded as a balanced multi-targets active molecule. It exhibited potent and balanced inhibitory activities against ChE and MAO-B (huAChE, huBuChE, and huMAO-B with IC50 values of 1.2μM, 3.8μM and 2.6 μM, respectively) with low selectivity. Both kinetic analysis of AChE inhibition and molecular modeling study suggested that TM-9 binds simultaneously to the catalytic active site and peripheral anionic site of AChE. Interestingly, compound TM-9 abided by Lipinskis rule of five. Furthermore, our investigation proved that TM-9 indicated weak cytotoxicity, and it could cross the blood-brain barrier (BBB) in vitro. The results suggest that compound TM-9, an interesting multi-targeted active molecule, offers an attractive starting point for further lead optimization in the drug-discovery process against Alzheimers disease.

Design, synthesis and biological evaluation of 2-acetyl-5-O-(amino-alkyl)phenol derivatives as multifunctional agents for the treatment of Alzheimer’s disease

A series of 2-acetyl-5-O-(amino-alkyl)phenol derivatives was designed, synthesized and evaluated as multi-function inhibitors for the treatment of Alzheimers disease (AD). The results revealed that compound TM-3 indicated selective AChE inhibitory potency (eeAChE, IC50 = 0.69 μM, selective index (SI) = 32.7). Both kinetic analysis of AChE inhibition and molecular modeling study suggested that TM-3 could simultaneously bind to the catalytic active site and peripheral anionic site of AChE. And TM-3 was also a highly selective MAO-B inhibitor (IC50 = 6.8 μM). Moreover, TM-3 could act as antioxidant (ORAC value was 1.5eq) and neuroprotectant, as well as a selective metal chelating agent. More interestingly, compound TM-3 could cross the blood-brain barrier (BBB) in vitro and abided by Lipinskis rule of five. Therefore, compound TM-3, a promising multi-targeted active molecule, offers an attractive starting point for further lead optimization in the drug-discovery process against AD.

A new route to naphthyl ketones via copper-mediated intramolecular aerobic oxidative cyclization of alkynes and sulfonylcrotonates

Herein we report a copper-mediated intramolecular aerobic oxidative cyclization of alkynes and sulfonylcrotonates. This method provides simple, efficient and easy to operate access to a variety of highly functionalized naphthyl ketones with excellent functional group tolerance.