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We described the discovery and optimization of a novel series of pyrimidopyrimidine derivatives as G-protein coupled receptor 119 (GPR119) agonists against type 2 diabetes. Most designed compounds displayed significant GPR119 agonistic activities. Optimized analogues 15a and 21e exhibited highly potent agonistic activities with single digit EC 50 values (2.2 nM and 8.1 nM, respectively). Therefore, 15a and 21e were evaluated for their oral glucose tolerance test (oGTT) in C57BL/6N mice. Compound 15a reduced the blood glucose area of under curve from 0 to 2 h (AUC 0–2h ) to 13.5% at the dose of 15 mg/kg comparing with Metformin reduced 18% of AUC 0–2h at the dose of 300 mg/kg. [ABSTRACT FROM AUTHOR]

A class of senkyunolide analogues bearing benzofuranone fragment were designed, synthesized and evaluated for their neuroprotective effect in models of oxygen glucose deprivation (OGD) and oxidative stress. All tested compounds showed neuroprotection profile based on the cell viability assay. In particular, derivatives 1f – 1i possessing furoxan-based nitric oxide releasing functionality exhibited significant biological activities in OGD models. More importantly, compound 1g containing short linker with furoxan displayed the most potent neuroprotection at the concentration of 100 μM (cell survival up to 145.2%). Besides, 1g also showed the middle level neuroprotective effect in model of oxidative stress. [ABSTRACT FROM AUTHOR]

A class of novel pyrimidine derivatives bearing diverse conformationally restricted azabicyclic ether/amine were designed, synthesized and evaluated for their GPR119 agonist activities against type 2 diabetes. Most compounds exhibited superior hEC 50 values to endogenous lipid oleoylethanolamide (OEA). Analogs with 2-fluoro substitution in the aryl ring showed more potent GPR119 activation than those without fluorine. Especially compound 27m synthesized from endo -azabicyclic alcohol was observed to have the best EC 50 value (1.2 nM) and quite good agonistic activity (112.2% max) as a full agonist. [ABSTRACT FROM AUTHOR]

A series of GPR119 agonists based on a 5-nitropyrimidine scaffold bearing endo -azabicyclic substituents were synthesized and evaluated for their GPR119 agonistic activities. Most compounds exhibited much stronger EC 50 values than that of oleoylethanolamide (OEA). Among them, derivatives from endo -azabicyclic alcohols displayed more potent GPR119 agonistic activities than compounds with endo -azabicyclic amines. Especially the optimized compounds ( 6 , 7 , 8 , 12 , 17 ) were shown to have potent biological activities and were identified as full agonists. Isopropyl carbamate compound 8 synthesized from endo -azabicyclic alcohol was observed to have the best EC 50 value (0.6 nM). Generally 2-fluoro substitution of the aryl group at the C4 position of 5-nitropyrimidine scaffold resulted in the increase of biological activity. [ABSTRACT FROM AUTHOR]

Phytochemical investigation of Corydalis decumbens has resulted in the isolation of one known Alkaloids named 1R,9S,7′S-O-methylegenine(1) and two new Alkaloids, 1S,9R,7′S-O-methyl egenine (2) and 1S,9S,7′S-O-methylegenine(3). Their structures were elucidated by various spectroscopic techniques. The absolute configurations of compounds 1 – 3 were determined by ECD calculations analysis.The anti-inflammatory activity of these compounds was evaluated in vitro with inhibition rates of release of β-glucuronidase from polymorphonuclear leukocytes of rats in the range of 32.4–41.3% at 10 μM and the results displayed that these compound showed potential anti-inflammatory activity and one of them is a promising compound for the development for new drug in the treatment for rheumatic arthritis. [ABSTRACT FROM AUTHOR]

Modification of Hederacolchiside A 1 (HA 1 ) on 28-COOH gave a series of novel triterpenoid saponin compounds containing ester or amide group. Comparing with natural product HA 1 , several derivatives showed decreased toxicity in the mice acute toxicity trial and increased the anticancer activity in vitro. Especially compound 1 exhibited the strongest antiproliferative activities against human cancer cell lines tested (IC 50 = 1.1–4.6 μM) and potent tumor inhibition rate in vivo (46.8%). [ABSTRACT FROM AUTHOR]

Abstract: 5-Nitropyrimidine analogs substituted with conformationally restricted azabicyclic amines and alcohols were prepared and evaluated their agonistic activity against human GPR119. The analogs bearing endo-azabicyclic amines and alcohols (7, 8, 11, and 12) exhibited full agonistic activities while the analogs with exo-azabicyclic amines and alcohols were proved as partial agonists (9, 10, 13, and 14) regardless of their EC50 values. 5-Nitropyrimidine analogs with (2-fluoro-4-methylsulfonyl)phenylamino group (8, 10, 12, 14) showed more potent GPR119 activation activities than the analogs without fluorine in all cases (7, 9, 11, 13). [Copyright &y& Elsevier]

Abstract: GPR119 agonist has emerged as a promising target for the treatment of type 2 diabetes. A series of novel 2,4-disubstituted quinazoline analogues was prepared and evaluated their agonistic activity against human GPR119. The analogues bearing azabicyclic amine substituents (12a, 12c and 12g) exhibited better EC50 values than that of OEA though they appeared to be partial agonists. [Copyright &y& Elsevier]

[Display omitted] • Novel melatonin-based compounds were designed and synthesized. • 5 displayed potent inhibitory activity and the excellentive selectivity against BuChE. • 5 could scavenge free radicals and induce expression of the Nrf2. • 5 displayed the good abilities to penetrate BBB. Here, we have designed and synthesized a series of melatonin-alkylbenzylamine hybrids as multitarget agents for the treatment of Alzheimer's disease (AD). Most of them exhibited a potent multifunctional profile involving cholinesterase inhibition and antioxidant effects. Among these compounds, compound 5 was most the potent antioxidant (ORAC = 5.13) and also an excellent selective inhibitor of BuChE (hu BuChE IC 50 = 1.20 μM, hu AChE IC 50 = 177.49 μM, SI = 147.91). Moreover, kinetic study indicated compound 5 was a mixed-type inhibitor for hu BuChE. Furthermore, it could induce expression of the Nrf2 as well as its downstream markers at the protein level in cells. More importantly, compound 5 display no acute toxicity in mice at doses up to 2500 mg/kg. And we found compound 5 could improve memory function of scopolamine-induced amnesia mice. These results highlighted compound 5 as a possible hit molecule for further investigation of new anti-AD drugs. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) possessed intricate pathogenesis. Currently, multi-targeted drugs were considered to have the potential to against AD by simultaneously triggering molecules in functionally complementary pathways. Hence, a series of molecules based on the pharmacophoric features of Dimethyl fumarate, Tranilast, and Dithiocarbate were designed and synthesized. These compounds showed significant AChE inhibitory activity in vitro. Among them, compound 4c 2 displayed the mighty inhibitory activity to hAChE (IC 50 = 0.053 μM) and held the ability to cross the BBB. Kinetic study and molecular docking pointed out that 4c 2 bound well into the active sites of hAChE, forming steady and sturdy interactions with key residues in hAChE. Additionally, 4c 2 as an Nrf2 activator could promote the nuclear translocation of Nrf2 protein and induce the expressions of Nrf2-dependent enzymes HO-1, NQO1, and GPX4. Moreover, 4c 2 rescued BV-2 cells from H 2 O 2 -induced injury and inhibited ROS accumulation. For the anti-neuroinflammatory potential of 4c 2 , we observed that 4c 2 could lower the levels of pro-inflammatory cytokines (NO, IL-6 and TNF-α) and suppressed the expressions of iNOS and COX-2. In particular, 4c 2 was well tolerated in mice (2500 mg/kg, p.o.) and efficaciously recovered the memory impairment in a Scopolamine-induced mouse model. Overall, these results highlighted that 4c 2 was a promising multi-targeted agent for treating AD. [Display omitted] • A series of dual-target compounds were designed and synthesized. • 4c 2 was the most potent AChE inhibitor and could penetrate the BBB. • 4c 2 exerted anti-oxidative stress and anti-inflammatory effects as an Nrf2 activator. • 4c 2 could reverse Scopolamine-induced memory deficit in mice. [ABSTRACT FROM AUTHOR]

Naturally occurring cyclic antimicrobial peptides (AMPs) such as tyrocidine A (Tyrc A) and gramicidin S (GS) are appealing targets for the development of novel antibiotics. However, their therapeutic potentials are limited by undesired hemolytic activity and relatively poor activity against Gram-negative bacteria. Inspired by polycationic lipopeptide polymyxin B (PMB), the so called 'last-resort' antibiotic for the treatment of infections caused by multidrug-resistant Gram-negative bacteria, we synthesized and biologically evaluated a series of polycationic analogues derived from Tyrc A. We were able to obtain peptide 8 that possesses 5 positive charges exhibiting potent activities against both Gram-negative and Gram-positive bacteria along with totally diminished hemolytic activity. Intriguingly, antibacterial mechanism studies revealed that, rather than the 'pore forming' model that possessed by Tyrc A, peptide 8 likely diffuses membrane in a 'detergent-like' manner. Furthermore, when treating mice with peritonitis–sepsis, peptide 8 showed excellent antibacterial and anti-inflammatory activities in vivo. [Display omitted] • Totally ten polycationic cyclopeptides derived for Tyrocidine A were synthesized. • Several peptides display broad antibacterial spectrum and very low hemolysis. • Peptide 8 shows excellent antibacterial and anti-inflammatory activities in vivo. • Peptide 8 likely diffuses membrane in a 'detergent-like' manner. [ABSTRACT FROM AUTHOR]

In this study, a series of multifunctional hybrids against Alzheimer's disease were designed and obtained by conjugating the pharmacophores of xanthone and alkylbenzylamine through the alkyl linker. Biological activity results demonstrated that compound 4j was the most potent and balanced dual ChEs inhibitor with IC 50 values 0.85 μM and 0.59 μM for eeAChE and eqBuChE, respectively. Kinetic analysis and docking study indicated that compound 4j was a mixed-type inhibitor for both AChE and BuChE. Additionally, it exhibited good abilities to penetrate BBB, scavenge free radicals (4.6 trolox equivalent) and selectively chelate with Cu2+ and Al3+ at a 1:1.4 ligand/metal molar ratio. Importantly, after assessments of cytotoxic and acute toxicity, we found compound 4j could improve memory function of scopolamine-induced amnesia mice. Hence, the compound 4j can be considered as a promising lead compound for further investigation in the treatment of AD. Image 1 • Novel xanthone-alkylbenzylamine hybrids were designed and synthesized. • 4j displayed potent and balanced inhibition for both AChE and BuChE. • 4j could selectively chelate with Cu2+ and Al3+, and scavenge free radicals. • 4j could cross the BBB and reverse the scopolamine-induced memory deficit in vivo. [ABSTRACT FROM AUTHOR]

In this paper, we intended to fabricate ultra-small nanocrystals (below 50 nm) by formation of hydrogen bonds between model drug and stabilizer. The absorption mechanisms, pharmacokinetic performance in rats and therapeutic effect for myocardial ischemia were studied after in vitro characterization. Poor water solubility and low bioavailability hinder the clinical application of about 70% of newly synthesized compounds. Nanocrystal technology has become a preferred way to improve bioavailability by improving solubility. However, it remains challenging to produce nanocrystals with ultra-small particle sizes to further enhance the extent of bioavailability. Herein, we constructed ultra-small puerarin nanocrystals (Pue-NCs) (20–40 nm) via formation of hydrogen bond during HPH. We confirmed the formation of hydrogen bonds by 1H NMR and FTIR, and observed the distribution of polymer chains by SEM and TEM. The absorption mechanisms were studied in Caco-2 cell monolayers, and the results showed that the major transport mechanism for puerarin was passive diffusion, meanwhile, for Pue-NCs, the passive transport and micropinocytosis-mediated endocytosis coexisted. The absolute bioavailability of Pue-NCs was 35.28%, which was 11.54 folds compared to that of puerarin. Therapeutic equivalence was demonstrated between Pue-NCs and puerarin injection at 50 mg/kg and 15 mg/kg, respectively, in isoproterenol-induced myocardial ischemia model. This study provides a novel strategy for preparing ultra-small nanocrystals by HPH to increase bioavailability of poorly soluble drugs. [ABSTRACT FROM AUTHOR]