Design,synthesis and evaluation of pterostilbene β-amino alcohol derivatives as multifunctional agents for Alzheimer's disease treatment

A series of pterostilbene β-amino alcohol derivatives were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer’s disease (AD). In vitro assays demonstrated that most of the derivatives were selective acetylacholinesterase (AChE) inhibitors with moderate multifunctional properties. Among them, compound 5f exhibited the best inhibitory activity for EeAChE (IC₅₀ = 24.04 μM), that was better than pterostilbene under our experimental condition. In addition, compound 5f displayed reasonable antioxidant activity and could confer significant neuroprotective effect against H₂O₂-induced PC-12 cell injury. Moreover, 5f also showed self-induced Aβ_1-42 aggregation inhibitory potency and displayed high BBB permeability in vitro. These multifunctional properties highlight 5f as a promising candidate for further studies directed to the development of novel drugs against AD.     

Synthesis and biological evaluation of pyrimidine derivatives as novel human Pin1 inhibitors

Pin1 (Protein interacting with NIMA1) is a cis–trans isomerase and promotes the amide bond rotation of phosphoSer/Thr-Pro motifs in its substrates. Inhibition of Pin1 might be a novel strategy for developing anticancer agents. Herein, a series of pyrimidine derivatives were synthesized and their Pin1 inhibitory activities were evaluated. Among them, four compounds (2a, 2f, 2h and 2l) displayed potent inhibitory activities against Pin1 with IC₅₀ values lower than 3?µM. This series of pyrimidine-based inhibitors presented time-dependent inhibition against Pin1. The structure–activity relationships on the 2-, 4- and 5-positions of the pyrimidine ring were analyzed in details, which would facilitate further exploration of new Pin1 inhibitors.     

Design,synthesis and biological evaluation of imidazole and oxazole fragments as HIV-1 integrase-LEDGF/p75 disruptors and inhibitors of microbial pathogens

We describe here the synthesis of libraries of novel 1-subtituted-5-aryl-1H-imidazole, 5-aryl-4-tosyl-4,5-dihydro-1,3-oxazole and 5-aryl-1,3-oxazole fragments via microwave (MW)-assisted cycloaddition of para-toluenesulfonylmethyl isocyanide (TosMIC) to imines and aldehydes. The compounds obtained were biologically evaluated in an AlphaScreen HIV-1 IN-LEDGF/p75 inhibition assay with six imidazole-based compounds (16c, 16f, 17c, 17f, 20a and 20d) displaying more than 50% inhibition at 10 µM, with IC₅₀ values ranging from 7.0 to 30.4 µM. Additionally the hypothesis model developed predicts all active scaffolds except 20d to occupy similar areas as the N-heterocyclic (A) moiety and two aromatic rings (B and C) of previously identified inhibitor 5. These results indicate that the identified compounds represent a viable starting point for their use as templates in the design of next generation inhibitors targeting the HIV-1 IN and LEDGF/p75 protein-protein interaction. In addition, the in vitro antimicrobial properties of these fragments were tested by minimum inhibitory concentration (MIC) assays showing that compound 16f exhibited a MIC value of 15.6 μg/ml against S. aureus, while 17f displayed a similar MIC value against B. cereus, suggesting that these compounds could be further developed to specifically target those microbial pathogens.     

Design,synthesis and biological evaluation of novel inhibitors against cyanobacterial pyruvate dehydrogenase multienzyme complex E1

Cyanobacterial pyruvate dehydrogenase multienzyme complex E1 (PDHc E1) is a potential target enzyme for finding inhibitors to control harmful cyanobacterial blooms. In this study, a series of novel triazole thiamin diphosphate (ThDP) analogs were designed and synthesized by modifying the substituent group of triazole ring and optimizing triazole-benzene linker as potential cyanobacterial PDHc E1 (Cy-PDHc E1) inhibitors. Their inhibitory activities against Cy-PDHc E1 in vitro and algicide activities in vivo were further examined. Most of these compounds exhibited prominent inhibitory activities against Cy-PDHc E1 (IC₅₀ 1.48–4.48 μM) and good algicide activities against Synechocystis PCC6803 (EC₅₀ 0.84–2.44 µM) and Microcystis aeruginosa FACHB905 (EC₅₀ 0.74–1.77 µM). Especially, compound 8d showed not only the highest inhibitory activity against Cy-PDHc E1 (IC₅₀ 1.48 μM), but also the most powerful inhibitory selectivity between Cy-PDHc E1 (inhibitory rate 98.90%) and porcine PDHc E1 (inhibitory rate only 9.54%). Furthermore, the potential interaction between compound 8d and Cy-PDHc E1 was analyzed by a molecular docking method and site-directed mutagenesis and enzymatic analysis and fluorescence spectral analysis. These results indicated that compound 8d could be used as a hit compound for further optimization and might have potential to be developed as a new algicide.     

Synthesis,in vitro and in vivo biological evaluation of novel graveolinine derivatives as potential anti-Alzheimer agents

A novel series of graveolinine derivatives were synthesized and evaluated as potential anti-Alzheimer agents. Compound 5f exhibited the best inhibitory activity for acetylcholinesterase (AChE) and had surprisingly potent inhibitory activity for butyrylcholinesterase (BuChE), with IC₅₀ values of 0.72 μM and 0.16 μM, respectively. The results from Lineweaver–Burk plot and molecular modeling study indicated non-competitive inhibition of AChE by compound 5f. In addition, these derivatives showed potent self-induced β-amyloid (Aβ) aggregation inhibition. Moreover, 5f didn’t show obvious toxicity against PC12 and HepG2 cells at 50 μM. Finally, in vivo studies confirmed that 5f significantly ameliorates the cognitive performances of scopolamine-treated ICR mice. Therefore, these graveolinine derivatives should be thoroughly and systematically studied for the treatment of Alzheimer’s disease.     

Novel 5,6-disubstituted pyrrolo[2,3-d]pyrimidine derivatives as broad spectrum antiproliferative agents: Synthesis,cell based assays,kinase profile and molecular docking study

Two new series of 5-subtituted and 5,6-disubstituted pyrrolo[2,3-d]pyrimidine octamides (4a–o and 6a–g) and their corresponding free amines 5a–m and 7a–g have been synthesized and biologically evaluated for their antiproliferative activity against three human cancer cell lines. The 5,6-disubstituted octamides 6d–g as well as the amine derivative 7b have shown the best anticancer activity with single digit micromolar GI₅₀ values over the tested cancer cells, and low cytotoxic effects (GI₅₀?>?10.0?µM) against HFF-1 normal cell. A structure activity relationship (SAR) study has been established and disclosed that terminal octamide moiety at C2 as well as disubstitution with fluorobenzyl piperazines at C5 and C6 of pyrrolo[2,3-d]pyrimidine are the key structural features prerequisite for best antiproliferative activity. Moreover, the most active member 6f was tested for its antiproliferative activity over a panel of 60 cancer cell lines at NCI, and exhibited distinct broad spectrum anticancer activity with submicromolar GI₅₀ and TGI values over multiple cancer cells. Kinase profile of compound 6f over 53 oncogenic kinases at 10?µM concentration showed its highly selective inhibitory activity towards FGFR4, Tie2 and TrkA kinases. The observed activity of 6f against TrkA (IC₅₀?=?2.25?µM), FGFR4 (IC₅₀?=?6.71?µM) and Tie2 (IC₅₀?=?6.84?µM) was explained by molecular docking study, which also proposed that 6f may be a type III kinase inhibitor, binding to an allosteric site rather than kinase hinge region. Overall, compound 6f may serve as a promising anticancer lead compound that could be further optimized for development of potent anticancer agents.     

Design,synthesis and evaluation of novel bivalent β-carboline derivatives as multifunctional agents for the treatment of Alzheimer's disease

To develop potent multi-target ligands against Alzheimer's disease (AD), a series of novel bivalent β-carboline derivatives were designed, synthesized, and evaluated. In vitro studies revealed these compounds exhibited good multifunctional activities. In particular, compounds 8f and 8g showed the good selectivity potency on BuChE inhibition (IC₅₀?=?1.7 and 2.7?μM, respectively), Aβ_1-42 disaggregation and neuroprotection. Compared with the positive control resveratrol, 8f and 8g showed better activity in inhibiting Aβ_1-42 aggregation, with inhibitory rate 82.7% and 85.7% at 25?μM, respectively. Moreover, compounds 8e, 8f and 8g displayed excellent neuroprotective activity by ameliorating the impairment induced by H₂O₂, okadaic acid (OA) and Aβ_1-42 without cytotoxicity in SH-SY5Y cells. Thus, the present study evidently showed that compounds 8f and 8g are potent multi-functional agents against AD and might serve as promising lead candidates for further development.     

Microwave assisted synthesis and in vitro cytotoxicities of substituted (Z)-2-amino-5-(1-benzyl-1H-indol-3-yl)methylene-1-methyl-1H-imidazol-4(5H)-ones against human tumor cell lines

The synthesis of several novel substituted (Z)-2-amino-5-(1-benzyl-1H-indol-3-yl)methylene-1-methyl-1H-imidazol-4(5H)-ones structurally related to aplysinopsin have been carried out under microwave irradiation and conventional heating methods. The analogs 3a, 3b, 3d–3g, 3k and 3l were evaluated for their in vitro cytotoxic activity against an NCI 60 human tumor cell line panel. Compound 3f exhibited good growth inhibitory properties against all but four of the human cancer cell lines examined, and afforded LC₅₀ values <10 μM for 30% of the cell lines in the panel. Compound 3e was an effective inhibitor of leukemia, CNS, melanoma, and breast cancer cell growth, but generally less effective as a cytotoxic agent. Thus, the aplysinopsin analog 3f was regarded as a useful lead compound for further structural optimization.     

Design,synthesis and evaluate of novel dual FGFR1 and HDAC inhibitors bearing an indazole scaffold

Both histone deacetylase (HDAC) and fibroblast growth factor receptor (FGFR) are important targets for cancer therapy. Although combining dual HDAC pharmacophore with tyrosine kinase inhibitors (TKIs) had achieved a successful progress, dual HDAC/FGFR1 inhibitors haven’t been reported yet. Herein, we designed a series of hybrids bearing 1H-indazol-3-amine and benzohydroxamic acids scaffold with scaffold hopping and molecular hybridization strategies. Among them, compound 7j showed the most potent inhibitory activity against HDAC6 with IC₅₀ of 34?nM and exhibited the great inhibitory activities against a human breast cancer cell line MCF-7 with IC₅₀ of 9?μM in vitro. Meanwhile, the compound also exhibited moderate FGFR1 inhibitory activities. This study provides new tool compounds for further exploration of dual HDAC/FGFR1 inhibition.     

Design,synthesis, and biological evaluation of histone deacetylase inhibitors possessing glutathione peroxidase-like and antioxidant activities against Alzheimer’s disease

A series of hybrids containing the pharmacophores of the histone deacetylase (HDAC) inhibitor, SAHA, and the antioxidant ebselen were designed and synthesized as multi-target-directed ligands against Alzheimer’s disease. An in vitro assay indicated that some of these molecules exhibit potent HDAC inhibitory activity and ebselen-related pharmacological effects. Specifically, the optimal compound 7f was found to be a potent HDAC inhibitor (IC₅₀?=?0.037?μM), possessing rapid hydrogen peroxide scavenging activity and glutathione peroxidase-like activity (ν₀?=?150.0?μM?min^?1) and good free oxygen radical absorbance capacity (value of ORAC: 2.2). Furthermore, compound 7f showed significant protective effects against damage induced by H₂O₂ and the ability to prevent ROS accumulation in PC12 cells.     

Identification of caffeoylquinic acid derivatives as natural protein tyrosine phosphatase 1B inhibitors from Artemisia princeps

Considerable attention has been paid to protein tyrosine phosphatase 1B (PTP1B) inhibitors as a potential therapy for diabetes, obesity, and cancer. Ten caffeoylquinic acid derivatives (1–10) from leaves of Artemisia princeps Pamp. (Asteraceae) were identified as natural PTP1B inhibitors. Among them, chlorogenic acid (3) showed the most potent inhibitory activity (IC₅₀ 11.1?μM). Compound 3 was demonstrated to be a noncompetitive inhibitor by a kinetic analysis. Molecular docking simulation suggested that compound 3 bound to the allosteric site of PTP1B. Furthermore, compound 3 showed remarkable selectivity against four homologous PTPs. According to these findings, compound 3 might be potentially valuable for further drug development.     

Design,synthesis and evaluation of new 4-arylthiazole-2-amine derivatives as acetylcholinesterase inhibitors

A series of new 4-arylthiazole-2-amine derivatives as acetylcholinesterase inhibitors (AChEIs) were designed and synthesized, Furthermore, their inhibitory activities against acetylcholinesterase in vitro were tested by Ellman spectrophotometry, and the results of inhibitory activity test showed that most of them had a certain acetylcholinesterase inhibitory activity in vitro. Moreover, the IC₅₀ value of compound 4f was to 0.66 μM, which was higher than that of Rivastigmine and Huperzine-A as reference compounds, and it had a weak inhibitory effect on butyrylcholinesterase. The potential binding mode of compound 4f with AChE was investigated by the molecular docking, and the results showed that 4f was strongly bound up with AChE with the optimal conformation, in addition, their binding energy reached −11.27 Kcal*mol⁻¹. At last, in silico molecular property of the synthesized compounds were predicted by using Molinspiration online servers. It can be concluded that the lead AChEIs compound 4f presented satisfactory drug-like characteristics.     

Structure optimization and bioactivity evaluation of ThDP analogs targeting cyanobacterial pyruvate dehydrogenase E1

Harmful cyanobacteria bloom (HCB) has occurred frequently in recent years and it is urgent to develop novel algicides to deal with this problem. In this paper, a series of novel thiamin diphosphate (ThDP) analogs 5a?5g were designed and synthesized targeting cyanobacterial pyruvate dehydrogenase complex E1 (Cy-PDHc E1). Our results showed that compounds 5a?5g have higher inhibitory activities against Cy-PDHc E1 (IC₅₀ 9.56–3.48 µM) and higher inhibitory activities against two model cyanobacteria strains Synechocystis sp PCC6803 (EC₅₀ 2.03–1.58 µM) and Microcystis aeruginosa FACHB905 (EC₅₀ 1.86–0.95 µM). Especially, compound 5b displayed highest inhibitory activities (IC₅₀ = 3.48 µM) against Cy-PDHc E1 and powerful inhibitory activities against cyanobacteria Synechocystis sp PCC6803 (EC₅₀ = 1.58 µM) and Microcystis aeruginosa FACHB905 (EC₅₀ = 1.04 µM). Moreover, the inhibitory activities of compound 5b were even higher than those of copper sulfate (EC₅₀ = 2.02 and 1.71 µM separately) which has been widely used as algicide against cyanobacteria PCC6803 and FACHB905. The more important was that compound 5b display much higher inhibitory selectivity between Cy-PDHc E1 (Inhibitory rate 97.4%) and porcine PDHc E1 (Inhibitory rate 11.8%) under the same concentration (100 μM). The inhibition kinetic experiment and molecular docking research showed that compound 5b can inhibit Cy-PDHc E1 by occupying the ThDP-binding pocket and then blocking Cy-PDHc E1 bound to ThDP as competitive inhibitor. The imagines of SEM and TEM showed that cellular microstructures were heavily destroyed under compound 5b stress. Our results demonstrated compound 5b could be taken as a potential lead compound targeting Cy-PDHc E1 to obtain environment-friendly algicide for harmful cyanobacterial blooms control.     

Synthesis and biological evaluation of 1-benzyl-N-(2-(phenylamino)pyridin-3-yl)-1H-1,2,3-triazole-4-carboxamides as antimitotic agents

A library of 1-benzyl-N-(2-(phenylamino)pyridin-3-yl)-1H-1,2,3-triazole-4-carboxamides (7a–al) have been designed, synthesized and screened for their anti-proliferative activity against some selected human cancer cell lines namely DU-145, A-549, MCF-7 and HeLa. Most of them have shown promising cytotoxicity against lung cancer cell line (A549), amongst them 7f was found to be the most potent anti-proliferative congener. Furthermore, 7f exhibited comparable tubulin polymerization inhibition (IC₅₀ value 2.04 µM) to the standard E7010 (IC₅₀ value 2.15 µM). Moreover, flow cytometric analysis revealed that this compound induced apoptosis via cell cycle arrest at G₂/M phase in A549 cells. Induction of apoptosis was further observed by examining the mitochondrial membrane potential and was also confirmed by Hoechst staining as well as Annexin V-FITC assays. Furthermore, molecular docking studies indicated that compound 7f binds to the colchicine binding site of the β-tubulin. Thus, 7f exhibits anti-proliferative properties by inhibiting the tubulin polymerization through the binding at the colchicine active site and by induction of apoptosis.     

Synthesis,antitumor activity evaluation and mechanistic study of novel hederacolchiside A1 derivatives bearing an aryl triazole moiety

In an attempt to arrive at a more potent antitumor agent than the parent natural saponin hederacolchiside A₁, 23 hederacolchiside A₁ derivatives (4a-4w) were synthesized via Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition and screened in vitro for cytotoxicity against six human cancer cell lines. The structure-activity relationship of these compounds was elucidated, and the biological screening results showed that most of the compounds exhibited moderate to high levels of antitumor activities against the tested cell lines and some of them displayed more potent inhibitory activities compared with hederacolchiside A₁. Compound 4f showed a 2- to 7-fold more potent activity than hederacolchiside A₁. The mechanistic study of 4f revealed that this compound can induce cell apoptosis in HepG2 cells via mitochondrial-mediated intrinsic pathways.     

Synthesis,biological evaluation and molecular modeling of 2-amino-2-phenylethanol derivatives as novel β2-adrenoceptor agonists

A novel series of 2-amino-2-phenylethanol derivatives were developed as β₂-adrenoceptor agonists. Among them, 2-amino-3-fluoro-5-(2-hydroxy-1-(isopropylamino)ethyl)benzonitrile (compound 2f) exhibited the highest activity (EC₅₀ = 0.25 nM) in stimulating β₂-adrenoceptor-mediated cellular cAMP production with a 763.6-fold selectivity over the β₁-adrenoceptor. The (S)-isomer of 2f was subsequently found to be 8.5-fold more active than the (R)-isomer. Molecular docking was performed to determine the putative binding modes of this new class of β₂-adrenoceptor agonists. Taken together, these data show that compound 2f is a promising lead compound worthy of further study for the development of β₂-adrenoceptor agonists.     

Synthesis of new pyridazino[4,5-b]indol-4-ones and pyridazin-3(2H)-one analogs as DYRK1A inhibitors

New pyridazino[4,5-b]indol-4-ones and pyridazin-3(2H)-one analogs were synthesized and their inhibitory activities against DYRK1A, CDK5/p25, GSK3α/β and p110-α isoform of PI3K evaluated using harmine as reference. Both furan-2-yl 10 and pyridin-4-yl 19 from the two different series, exhibited submicromolar IC₅₀ against DYRK1A with no activities against the three other kinases. In addition, compound 10 exhibited antiproliferative activities in the Huh-7, Caco2 and MDA-MB-231 cell lines.     

Discovery of novel selective Janus kinase 2 (JAK2) inhibitors bearing a 1H-pyrazolo[3,4-d]pyrimidin-4-amino scaffold

Janus kinases (JAKs) regulate various cancers and immune responses and are targets for the treatment of cancers and immune diseases. A new series of 1H-pyrazolo[3,4-d]pyrimidin-4-amino derivatives were synthesized and optimized by introducing a functional 3,5-disubstituted-1H-pyrazole moiety into the C-3 moiety of pyrazole template, and then were biologically evaluated as potent Janus kinase 2 (JAK2) inhibitors. Among these molecules, inhibitors 11f, 11g, 11h and 11k displayed strong activity and selectivity against the JAK2 kinase, with IC₅₀ values of 7.2?nM, 6.5?nM, 8.0?nM and 9.7?nM, respectively. In particular, the cellular inhibitory assay and western blot analysis further support the JAK2 selectivity of compound 11g also in cells. Furthermore, compound 11g also exhibited potent inhibitory activity in lymphocytes proliferation assay and delayed hypersensitivity assay. Taken together, the novel JAK2 selective inhibitors discovered in this study may be potential lead compounds for new drug discovery via further development of more potent and selective JAK2 inhibitors.     

Design,synthesis and anticancer evaluation of 1H-pyrazolo[3,4-d]pyrimidine derivatives as potent EGFRWT and EGFRT790M inhibitors and apoptosis inducers

In our attempt to develop effective EGFR-TKIs, two series of 1H-pyrazolo[3,4-d]pyrimidine derivatives were designed and synthesized. All the newly synthesized compounds were evaluated in vitro for their inhibitory activities against EGFR^WT. Compounds 15_b, 15_j, and 18_d potently inhibited EGFR^WT at sub-micro molar IC₅₀ values comparable to that of erlotinib. Moreover, thirteen compounds that showed promising IC₅₀ values against EGFR^WT were tested in vitro for their inhibitory activities against mutant EGFR^T790M. Compounds 17_d and 17_f exhibited potent inhibitory activities towards EGFR^T790M comparable to osimertinib. Compounds that showed promising IC₅₀ values against EGFR^WT were further tested for their anti-proliferative activities against three cancer cell lines bearing EGFR^WT (MCF-7, HepG2, A549), and two cancer cell lines bearing EGFR^T790M (H1975 and HCC827). Compounds 15_g, 15_j, 15_n, 18_d and 18_e were the most potent anticancer agents against the EGFR^WT containing cells, while compounds 15_e, 17_d and 17_f showed promising anti-proliferative activities against EGFR^T790M containing cells. Furthermore, the most active compound 18_d was selected for further studies regarding to its effects on cell cycle progression and induction of apoptosis in the HepG2 cell line. The results indicated that this compound is good apoptotic agent and arrests G₀/G₁and G₂/M phases of cell cycle. Finally, molecular docking studies were performed to investigate binding pattern of the synthesized compounds with the prospective targets, EGFR^WT (PDB: 4HJO) and EGFR^T790M (PDB: 3W2O).     

Spiroindolone analogues bearing benzofuran moiety as a selective cyclooxygenase COX-1 with TNF-α and IL-6 inhibitors

To design and discover a new compound can used as a COX with TNF-α and IL-6 inhibitors is highly challenge. A series of spiroindolone-bearing benzofuran moieties were resynthesized from the chalcone-based benzo[b]furan with substituted isatin, and amino acids. The requisite spiroindolone analogues were tested for their potential inhibitory activities against lipid metabolizing enzymes such as cyclooxygenase COX-1, COX-2, and the release of pro-inflammatory cytokines interleukin IL-6, and tumor necrosis factor TNF-α. Among the tested compounds, 5a, 5c, 5h, 5i, 5l, and 5p exhibited COX-1 inhibitor selectively with percent of inhibition 40.81–83.4% and IC₅₀ values ranging from 20.42 µM to 38.24 µM. In addition, all the synthesized target compounds possessed lipopolysaccharide-induced TNF-α, and IL-6 expression with a varying degree of COX-1 inhibition. Compounds 5d, 5e, 5f, 5g, and 5k markedly inhibited TNF-α, and IL-6 release in WI-38 fibroblast cells. Molecular docking of the most effective and highly selective compounds were investigated and shown important binding mechanisms which could affect pro-inflammatory enzymes and cytokines via the inhibition of COX-1, COX-2, IL-6, and TNF-α.