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Lysine-specific demethylase 1 (LSD1), which belongs to the demethylase of non-histone proteins, is believed to promote cancer cell proliferation and metastasis by modifying histones. LSD1 dysfunction may play a key role in a variety of cancers, such as acute myeloid leukemia and non-small cell lung cancer, indicating that LSD1 is a promising epigenetic target for cancer therapy. Many different types of small molecule LSD1 inhibitors have been developed and shown to inhibit tumor cell proliferation, invasion, and migration, providing a new treatment strategy for solid tumors.This review summarizes the progress of LSD1 inhibitor research in the last four years, including selected new patents and article publications, as well as the therapeutic potential of these compounds.Natural products offer a promising prospect for developing novel potent LSD1 inhibitors, as structural design and activity of irreversible and reversible inhibitors have been continuously optimized since the discovery of the LSD1 target in 2004. The use of 'microtubule-binding agents' and 'dual-agent combination' has recently become a new anticancer technique, reducing the resistance and adverse reactions of traditional drugs. Several microtubule-binding drugs have been used successfully in clinical practice, providing structural scaffolds and new ideas for the development of safer drugs.

Aim: It has been reported that necrostatin-1 (Nec-1) is a specific necroptosis inhibitor that could attenuate programmed cell death induced by myocardial ischemia/reperfusion (I/R) injury. This study aimed to observe the effect and mechanism of novel Nec-1 analog (Z)-5-(3,5-dimethoxybenzyl)-2-imine-1-methylimidazolin-4-1 (DIMO) on myocardial I/R injury. Methods: Male SD rats underwent I/R injury with or without different doses of DIMO (1, 2, or 4 mg/kg) treatment. Isolated neonatal rat cardiomyocytes were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) treatment with or without DIMO (0.1, 1, 10, or 100 μM). Myocardial infarction was measured by TTC staining. Cardiomyocyte injury was assessed by lactate dehydrogenase assay (LDH) and flow cytometry. Receptor-interacting protein 1 kinase (RIP1K) and autophagic markers were detected by co-immunoprecipitation and Western blotting analysis. Molecular docking of DIMO into the ATP binding site of RIP1K was performed using GLIDE. Results: DIMO at doses of 1 or 2 mg/kg improved myocardial infarct size. However, the DIMO 4 mg/kg dose was ineffective. DIMO at the dose of 0.1 μM decreased LDH leakage and the ratio of PI-positive cells followed by OGD/R treatment. I/R or OGD/R increased RIP1K expression and in its interaction with RIP3K, as well as impaired myocardial autophagic flux evidenced by an increase in LC3-II/I ratio, upregulated P62 and Beclin-1, and activated cathepsin B and L. In contrast, DIMO treatment reduced myocardial cell death and reversed the above mentioned changes in RIP1K and autophagic flux caused by I/R and OGD/R. DIMO binds to RIP1K and inhibits RIP1K expression in a homology modeling and ligand docking. Conclusion: DIMO exerts cardioprotection against I/R- or OGD/R-induced injury, and its mechanisms may be associated with the reduction in RIP1K activation and restoration impaired autophagic flux.

As a member of the P2Y receptor family with a typical 7-transmembrane structure, P2Y6 purinergic receptor (P2Y6R) belongs to the G-protein-coupled nucleotide receptor activating the phospholipase-C signaling pathway. P2Y6R is widely involved in a range of human diseases, including atherosclerosis and other cardiovascular diseases, gradually attracting attention owing to its inappropriate or excessive activation. In addition, it was reported that P2Y6R might regulate inflammatory responses by governing the maturation and secretion of proinflammatory cytokines. Hence, several P2Y6R antagonists have been subjected to evaluation as new therapeutic strategies in recent years. This review was aimed at summarizing the role of P2Y6R in the pathogenesis of cardiovascular diseases, with an insight into the recent progress on discovery of P2Y6R antagonists.

Graphical abstract, Highlights • A reliable Glide docking-based virtual screening (VS) pipeline for P2Y14R was developed. • Several potent P2Y14R antagonists with novel scaffolds were identified utilizing the VS strategy. • P2Y14R inhibitory effect was evaluated by testing cAMP levels in HEK293 cells. • Anti-gout activity of screened compound was detected in MSU-treated THP-1 cells. • The mechanism of test compound in treating acute gouty arthritis was elucidated., P2Y14 nucleotide receptor is a Gi protein-coupled receptor, which is widely involved in physiological and pathologic events. Although several P2Y14R antagonists have been developed thus far, few have successfully been developed into a therapeutic drug. In this study, on the basis of two P2Y14R homology models, Glide docking-based virtual screening (VS) strategy was employed for finding potent P2Y14R antagonists with novel chemical architectures. A total of 19 structurally diverse compounds identified by VS and drug-like properties testing were set to experimental testing. 10 of them showed good inhibitory effects against the P2Y14R (IC50

Peptidomimetics are studied for medicinal application because of their ability to mimic hierarchical structures of peptides and proteins. To break the limitation and expand the peptidomimetics family, a new class of peptidomimetics based on peptide nucleic acids (PNAs) backbone - “γ-AApeptides” was developed. Compared with previous peptidomimetics, γ-AApeptides possess prominent advantages such as resistance to proteolytic degradation, enhanced chemodiversity, good selectivity and outstanding bioactivity. The synthesis of γ-AApeptides is carried out using a ‘‘monomer building block’’ strategy which is facile and efficient. : γ-AApeptides are able to mimic primary and secondary structures of therapeutic peptides, which make them promising candidates for molecular probes and potential drug leads. In the past decade, several interesting structures and applications of γ-AApeptides have been developed by different approaches such as structure-based design, combinatorial library screening, and peptides selfassembly and folding. By following the mechanism of host-defense peptides (HDPs), antibiotic γ- AApeptides showed broad-spectrum activity. At the same time, γ-AApeptides can be used for combinatorial library screening because of their structural stability and their chemodiversity. Anticancer agents, anti-T2DM (Type 2 diabetes mellitus) agents, anti-HIV (human immuno-deficiency virus) agents and anti-Alzheimer’s disease agents were developed by combinatorial screening and rational design. Furthermore, γ-AApeptides as biopolymers, nanomaterials, supramolecular structures and self-assembly architectures were studied due to their unique backbone structures. Therefore, γ-AApeptides may play an important role in the development of peptidomimetics.

Background and Purpose Clinical and experimental studies have shown that the sharp reduction of estrogen is one of the important reasons for the high incidence of Alzheimer’s disease (AD) in elderly women, but there is currently no such drug for treatment of AD. Our group first designed and synthesized a novel compound named FMDB. In this study, our aim is to investigate the neuroprotective effects and mechanism of FMDB in APP/PS1 transgenic mice. Experimental Approach 6 months old APP/PS1 transgenic mice were intragastrically administered with FMDB (1.25mg/kg, 2.5mg/kg and 5 mg/kg) every other day for 8 weeks. LV-ERβ-shRNA was injected bilaterally into the hippocampus of APP/PS1 mice to knockdown ERβ. Morris water maze test, novel object recognition test and open field test were used to evaluate the cognitive function. Immunofluorescence, TUNEL staining and Western Blot analysis were used for evaluating the hippocampal neurogenesis, apoptosis and signal transduction pathway related proteins. Key Results We found that FMDB ameliorate cognitive impairment in the Morris water maze and novel object recognition tests, increase hippocampal neurogenesis and prevent hippocampal apoptotic responses in APP/PS1 mice. Importantly, FMDB activated nuclear ERβ mediated CBP/p300, CREB and BDNF signaling, and membrane ERβ mediated PI3K/Akt, CREB and BDNF signaling in the hippocampus. Conclusion and Implications Our study demonstrates the contributions and mechanism of FMDB to cognition, neurogenesis and apoptosis in APP/PS1 mice. These lay the experimental foundation for the development of new anti-AD drugs.

Both the inhibition of inflammatory flares and the treatment of hyperuricemia itself are included in the management of gout. Extending our efforts to development of gout therapy, two series of benzoxazole deoxybenzoin oxime derivatives as inhibitors of innate immune sensors and xanthine oxidase (XOD) were discovered in improving hyperuricemia and acute gouty arthritis. In vitro studies revealed that most compounds not only suppressed XOD activity, but blocked activations of NOD-like receptor (NLRP3) inflammasome and Toll-like receptor 4 (TLR4) signaling pathway. More importantly, (E)-1-(6-methoxybenzo[d]oxazol-2-yl)-2-(4-methoxyphenyl)ethanone oxime (5d) exhibited anti-hyperuricemic and anti-acute gouty arthritis activities through regulating XOD, NLRP3 and TLR4. Compound 5d may serve as a tool compound for further design of anti-gout drugs targeting both innate immune sensors and XOD.

The P2Y14 nucleotide receptor, a subtype of P2Y receptors, is implicated in many human inflammatory diseases. Based on the identification of favorable residues of two screening hits in the almost symmetrical P2Y14 binding domain, we describe the structural optimization of previously identified virtual screening hits 6 and 7 that result in the development of P2Y14R antagonists with a novel 2-phenyl-benzoxazole acetamide chemical scaffold. Notably, compound 52 showed potent P2Y14R antagonistic activity (IC50 = 2 nM), and a stronger inhibitory effect on MSU-induced inflammatory in vitro, better than a previously described P2Y14R antagonist PPTN. In vivo evaluation demonstrated that compound 52 also had satisfactory inhibitory activity on the inflammatory response of gout flares in mice. Moreover, P2Y14R antagonist 52 decreased paw swelling and inflammatory cell infiltration through cAMP/NLRP3/GSDMD signaling pathways in MSU-induced acute gouty arthritis mice. The discussions on the binding mechanism that employ MM/GBSA free energy calculations/decompositions also provide some useful clues for further structural designing of compound 52. Taken together, 2-phenyl-benzoxazole acetamide derivative 52 with potent P2Y14R antagonistic activity and in vivo potency could be a promising strategy for gout therapy and deserves further optimization.

Herein we disclose SAR studies of a series of dimethylamino pyrrolidines which we recently reported as novel inhibitors of the PRC2 complex through disruption of EED/H3K27me3 binding. Modification of the indole and benzyl moieties of screening hit 1 provided analogs with substantially improved binding and cellular activities. This work culminated in the identification of compound 2, our nanomolar proof-of-concept (PoC) inhibitor which provided on-target tumor growth inhibition in a mouse xenograft model. X-ray crystal structures of several inhibitors bound in the EED active-site are also discussed.

Hyperuricemia is a kind of metabolic disease resulted from imbalance between urate production and excretion. Xanthine oxidase (XOD) or renal urate transporter 1 (URAT1) inhibitors have been applied for hyperuricemia treatment in clinic, but available drugs could not simultaneously target XOD and URAT1 and had various adverse effects. (E)-2-(4-bromophenyl)-1-(2, 4-dihydroxyphenyl)ethanone oxime (BDEO), as a deoxybenzoins oxime analog, was obtained from a cluster of deoxybenzoins derivatives synthesized by our research group with potent anti-hyperuricemic activity, which was expected to be dual inhibitor of XOD and URAT1. This study aimed to investigate effects of BDEO on XOD and URAT1 in vitro, as well as the possible mechanism by which BDEO attenuated hyperuricemia in vivo. In vitro, BDEO obviously inhibited XOD activity with an IC50 value of 3.33μM, moreover, in Human embryonic kidney (HEK)293 cells expressing URAT1, BDEO and benzbromarone blocked uptake of uric acid with a Ki value of 0.145μM. On the other hand, mice were orally administrated by oxonate for seven consecutive days to induce hyperuricemia, BDEO at various doses were administered intragastrically to hyperuricemic and normal mice daily. BDEO dose-dependently decreased serum urate level and uric acid excretion in 24h in hyperuricemic mice. More importantly, BDEO significantly suppressed hepatic XOD activity and down-regulated renal URAT1 protein level in hyperuricemic mice. Notably, BDEO exhibited no effects on all these detected biochemical indicators in normal mice, predicting its safety. Taken together, the data suggested that BDEO may serve as a dual XOD and URAT1 inhibitor for treatment of hyperuricemia.

Since the first pan-HDAC inhibitor SAHA was approved by U.S. FDA 10 years ago, HDACs including SIRT1-7 have received significant attention due to the fact that aberrant histone deacetylase activtiy has been implicated in a variety of human diseases, such as cancers, virus infection, and neurodegenerative diseases. During the past years, a considerable achievement of development of isoform- or class-selective HDAC inhibitors has been made, yielding many drug candidates for further clinical studies, which represents a state-of-the-art technology in the drug discovery arena. Areas covered: This review covers new patents and articles about isoform- or class-selective HDAC inhibitors during the last four years, as well as the therapeutic potential of these compounds. Expert opinion: HDACs represent one of the most promising therapeutic targets, particularly for tumor therapy though their roles in cancer are still blurry. From 2012 to present, along with the advances of structural biology and homology models, lots of isoform- or class-selective HDAC inhibitors, such as hydroxamic acids and benzamides with various capping groups were found, providing a promising way to circumvent drug toxicity and side-effect issues, as well as providing chemical probes for further better understanding of the biological process related to specific isoform.

Kelch-like ECH-associated protein (Keap1)-nuclear factor erythroid-2-related factor 2 (Nrf2) protein-protein interaction has become an important drug target for the treatment of Alzheimer's disease. In this study, we found a novel piperine derivative (HJ22) synthesized by our group with great ability to bind to Keap-1 and activate Keap1-Nrf2-ARE signaling pathway in vitro, driving us to investigate the beneficial effects of HJ22 on ibotenic acid (IBO)-induced neurological disorders in rats and underlying mechanisms. Interestingly, HJ22 significantly ameliorated IBO-induced cognitive impairment in Morris water maze, Y-maze and passive avoidance tests. Moreover, HJ22 significantly attenuated cholinergic dysfunction and neuronal morphological changes via inhibiting apoptotic cell death induced by IBO. Notably, HJ22 inhibited the interaction between Keap1 and Nrf2, and subsequently up-regulated nuclear Nrf2 expression, thereby inhibiting oxidative stress and Thioredoxin-interacting protein (TXNIP)-mediated Nod-like receptor protein 3 (NLRP3) inflammasome activation. These findings demonstrated that HJ22 exhibited potent therapeutic effects against IBO-induced cognitive impairment by alleviating cholinergic damage, oxidative stress, apoptosis and neuroinflammation, which might be partly attributed to its inhibitory activity on Keap1-Nrf2 protein-protein interaction.

The glycine transporter 1 (GlyT1) has emerged as a key novel target for the treatment of schizophrenia. Herein, we report the synthesis and biological evaluation of aminotetralines and aminochromanes as novel classes of competitive GlyT1 inhibitors. Starting from a high-throughput screening hit, structure–activity relationship studies led first to the discovery of aminotetralines displaying high GlyT1 potency and selectivity, with favorable pharmacokinetic properties. Systematic investigations of various parameters (e.g., topological polar surface area, number of hydrogen bond donors) guided by ex vivo target occupancy evaluation resulted in lead compounds possessing favorable brain penetration properties as for (7S,8R)-27a. Further optimization revealed compounds with reduced efflux liabilities as for aminochromane 51b. In an in vivo efficacy model (7S,8R)-27a, dose-dependently reversed L-687,414 induced hyperlocomotion in mice with an ED50 of 0.8 mg/kg. All these results suggest (7S,8R)-27a and 51b as n...

The development of glycine transporter 1 (GlyT1) inhibitors may offer putative treatments for schizophrenia and other disorders associated with hypofunction of the glutaminergic N-methyl-d-aspartate (NMDA) receptor. Herein, we describe the synthesis and biological evaluation of a series of 3,4-disubstituted pyrrolidine sulfonamides as competitive GlyT1 inhibitors that arose from de novo scaffold design. Relationship of chemical structure to drug–drug interaction (DDI) and bioactivation was mechanistically investigated. Murine studies were strategically incorporated into the screening funnel to provide early assessments of in vivo target occupancy (TO) by ex vivo binding studies. Advanced compounds derived from iterative structure–activity relationship (SAR) studies possessed high potency in ex vivo binding studies and good brain penetration, promising preliminary in vivo efficacy, acceptable preclinical pharmacokinetics, and manageable DDI and bioactivation liabilities.

Receptor-interacting protein 1 kinase (RIP1K) plays a key role in necroptosis. Necrostatin-1 (Nec-1), a specific inhibitor of RIP1K, provides neuroprotection against ischemic brain injury, associating with inhibition of inflammation. Recently, our group synthesized a novel analog of Nec-1, 5-(3',5'-dimethoxybenzal)-2-thio-imidazole-4-ketone (DTIO). The present study investigated the effect of DTIO on ischemic stroke-induced brain injury in both acute and chronic phase and its underlying mechanism. In vivo, DTIO treatment reduced infarct volume and improved neurological deficits in the acute phase after permanent middle cerebral artery occlusion (pMCAO) and it also attenuated brain atrophy and promoted brain functional recovery in the chronic phase post-cerebral ischemia/reperfusion (I/R). In vitro, DTIO treatment decreased lactate dehydrogenase (LDH) leakage and necrotic cell death in the oxygen and glucose deprivation (OGD) or oxygen and glucose deprivation and reoxygenation (OGD/R)-induced neuronal or astrocytic cell injury. Simultaneously, DTIO suppressed the production and release of inflammatory cytokines, and reduced the formation of glial scar. Homology modeling analysis illustrated that DTIO had an ability of binding to RIP1K. Furthermore, immunoprecipitation analysis showed that DTIO inhibited the phosphorylation of RIP1K and decreased the interaction between the RIP1K and RIP3K. In addition, knockdown of RIP1K had neuroprotective effects and inhibited the release of proinflammatory cytokines, but didn't have a significant effect on DTIO-mediated neuroprotection. In conclusion, DTIO has protective effects on acute ischemic stroke and promotes functional recovery during chronic phase, associating with protecting ischemic neurons and astrocytes, inhibiting inflammation, and lessening the glial scar formation via inhibiting of the RIP1K.

A type of novel rhodanine-based 4-anilinoquinazoline, which designed the combination between quinazoline as the backbone and various substituted biological rhodanine groups as the side chain, have been synthesized, and their antiproliferative activities were also evaluated firstly. These compounds displayed good antiproliferative activity and EGFR-TK inhibitory activity. Among them, compound 8d showed good inhibitory activity (IC50 = 2.7 μM for Hep G2, IC50 = 3.1 μM for A549) and molecular docking of 8d into EGFR TK active site was also performed, this inhibitor well fitting the active site might well explain its excellent inhibitory activity.

Gout is a crystalline-related arthropathy caused by the deposition of monosodium urate (MSU). Acute gouty arthritis is the most common first symptom of gout. Studies have shown that NOD-like receptor protein 3 (NLRP3) inflammasome as pattern recognition receptors can be activated by uric acid crystallization, triggering immune inflammation and causing acute gouty arthritis symptoms. Currently, the treatment of gout mainly includes two basic methods: reducing uric acid and alleviating inflammation. In this paper, 22 novel benzoxazole and benzimidazole derivatives were synthesized from deoxybenzoin oxime derivatives. These compounds have good inhibitory effects on NLRP3 and XOD screened by our research group in the early stage. The inhibitory activities of XOD and NLRP3 and their derivatives were also screened. Notably, compound 9b is a multi-targeting inhibitor of NLRP3 and XOD with excellent potency in treating hyperuricemia and acute gouty arthritis.

Cyclopamine is a naturally occurring steroidal alkaloid that attenuates the Hedgehog signaling pathway by inhibiting the Smoothened receptor. The Hedgehog pathway plays an important role in many human cancers. Cyclopamine has served as a pivotal tool compound in elucidating the pharmacological effect of the Hedgehog signaling pathway, however, due to its poor solubility, stability, and moderate activity, its clinical development has been impeded. Significant efforts were made to overcome the shortcomings of cyclopamine, giving which results cultivated in the identification of IPI- 926, a derivative of cyclopamine, which proceeded to clinical trials.

A series of curcumin derivatives as potent dual inhibitors of xanthine oxidase (XOD) and urate transporter 1 (URAT1) was discovered as anti-hyperuricemic agents. These compounds proved efficient effects on anti-hyperuricemic activity and uricosuric activity in vivo. More importantly, some of them exhibited proved efficient effects on inhibiting XOD activity and suppressing uptake of uric acid via URAT1 in vitro. Especially, the treatment of 4d was demonstrated to improve uric acid over-production and under-excretion in oxonate-induced hyperuricemic mice through regulating XOD activity and URAT1 expression. Docking study was performed to elucidate the potent XOD inhibition of 4d. Compound 4d may serve as a tool compound for further design of anti-hyperuricemic drugs targeting both XOD and URAT1.

Polycomb repressive complex 2 (PRC2) is a regulator of epigenetic states required for development and homeostasis. PRC2 trimethylates histone H3 at lysine 27 (H3K27me3), which leads to gene silencing, and is dysregulated in many cancers. The embryonic ectoderm development (EED) protein is an essential subunit of PRC2 that has both a scaffolding function and an H3K27me3-binding function. Here we report the identification of A-395, a potent antagonist of the H3K27me3 binding functions of EED. Structural studies demonstrate that A-395 binds to EED in the H3K27me3-binding pocket, thereby preventing allosteric activation of the catalytic activity of PRC2. Phenotypic effects observed in vitro and in vivo are similar to those of known PRC2 enzymatic inhibitors; however, A-395 retains potent activity against cell lines resistant to the catalytic inhibitors. A-395 represents a first-in-class antagonist of PRC2 protein-protein interactions (PPI) for use as a chemical probe to investigate the roles of EED-containing protein complexes.

A series of novel rhodanine-based acylsulfonamide derivatives were designed, synthesized, and evaluated as small-molecule inhibitors of anti-apoptotic Bcl-2 protein. These compounds exhibit potent antiproliferative activity in three human tumor cell lines (Hep G2, PC-3 and B16-F10). Among them, the most potent compounds 10 and 11 bind to Bcl-2 with a K(i) of 20 and 25 nM, respectively. Docking studies demonstrated that these two compounds orient similarly at the binding site of Bcl-2, and the calculated binding affinities (Glide XP score) of compound 10 is more negative than that of compound 11. The binding interactions of compounds with high binding affinity to Bcl-2 protein were analyzed.

Genistein is the most abundant isoflavone in soybeans. It has exhibited diverse biological activities, among these, its anticancer effects is most noteworthy. Through regulating critical cell cycle genes, genistein can inhibit cancer cell growth in vivo and in vitro. It has been reported that genistein can inhibit activation of NF-κB and Akt signaling pathways to induce cell apopt1osis, both pathways are well known for their function to maintain a balance between cell survival and apoptosis. In order to find out more outstanding anticancer isoflavone agents, against cancers extended synthesis of genistein derivatives has been carried out. Some of these synthetic compounds demonstrated higher anticancer activity with lower doses. Based on these results, genistein and its synthetic derivatives may be an emerging new type of anticancer agents.

The genus Chaetomium fungi are considered to be a rich source of novel and bioactive secondary metabolites of great importance. Up till now, a variety of more than 200 secondary metabolites belonging to diverse structural types of chaetoglobosins, epipolythiodioxopiperazines, azaphilones, xanthones, anthraquinones, chromones, depsidones, terpenoids, and steroids have been discovered. Most of these fungal metabolites exhibited antitumor, cytotoxic, antimalarial, enzyme inhibitory, antibiotic, and other activities. This review covers the extraction, structure elucidation, structural diversity, and biological activities of natural products isolated from about 30 fungi associated with marine- and terrestrial- origins, and highlights some bioactive compounds as well as their mechanisms of action and structure-activity relationships.

A type of novel 4,6-substituted-(diaphenylamino)quinazolines, which designed based on the 4-(phenylamino)quinazoline moiety, have been discovered as potential EGFR inhibitors. These compounds displayed good antiproliferative activity and EGFR-TK inhibitory activity. Especially, 4-((4-(3-bromophenylamino)quinazolin-6-ylamino)methyl)phenol ( 5b ) , showed the most potent inhibitory activity (IC 50 = 0.28 μM for Hep G2, IC 50 = 0.59 μM for A16-F10 and IC 50 = 0.87 μM for EGFR) and effectively induces apoptosis in a dose-dependent manner in the Hep G2 cell line. Molecular docking of 5b into EGFR TK active site was also performed. This inhibitor nicely fitting the active site might well explain its excellent inhibitory activity.

Design, synthesis and structure–activity relationship of a series of biphenylsulfonamido-3-methylbutanoic acid based aggrecanase-1 inhibitors are described. In addition to robust aggrecanase-1 inhibition, these compounds also exhibit potent MMP-13 activity. In cell-based cartilage explants assay compound 48 produced 87% inhibition of proteoglycan degradation at 10 μg/mL. Good pharmacokinetic properties were demonstrated by 46 with a half-life of 6 h and bioavailability of 23%.

β-Ketoacyl-acyl carrier protein synthase III (FabH) catalyzes the initial step of fatty acid biosynthesis via a type II fatty acid synthase in most bacteria. The important role of this essential enzyme combined with its unique structural features and ubiquitous occurrence in bacteria has made it an attractive new target for the development of new FabH inhibitors. We first used a structure-based approach to develop 24 new vinylogous carbamates (4a–15a, 4b–15b) that target FabH for the development of new antibiotics in this paper. Potent FabH inhibitory and selective anti- Gram-negative bacteria activities were observed in most of these vinylogous carbamates. Especially, compound 6a and 7a showed the most potent FabH inhibitory activity with IC50 of 2.6 and 3.3 μM, respectively. Docking simulation was performed to position compound 6a into the Escherichia coli FabH active site and the possible binding conformation of compounds has been proposed. The biological data and molecular docking indicated that compounds 6a and 7a were potent inhibitors of E. coli FabH as antibiotics deserving further research.

Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a crucial role in the process of cancer angiogenesis. A series of quinoline amide derivatives were prepared and found to be good inhibitors of VEGFR-2. The inhibitory activities were investigated against VEGFR-2 kinase and human umbilical vein endothelial cells (HUVEC) in vitro. Compound 6 (5-chloro-2-hydroxy-N-(quinolin-8-yl)benzamide) exhibited the most potent inhibitory activity (IC50 = 3.8 and 5.5 nM for VEGFR-2 kinase and HUVEC, respectively). Docking simulation supported the initial pharmacophoric hypothesis and suggested a common mode of interaction at the ATP-binding site of VEGFR-2, which demonstrates that compound 6 is a potential agent for cancer therapy deserving further researching.

In the search for potential immunosuppressive agents with high efficacy and low toxicity, a series of new deoxybenzoins were synthesized and evaluated for their cytotoxicity and immunosuppressive activity. Among the synthesized compounds, four deoxybenzoin oximes (compounds 31, 32, 37, and 38) exhibited lower cytotoxicity and higher inhibitory activity toward anti-CD3/anti-CD28 co-stimulated T-cell proliferation than other compounds. More significantly, compound 31 is > 100-fold less cytotoxic than cyclosporine A (CsA) and is also more potent (31: SI>684.64, CsA: SI=235.44). The preliminary inhibition mechanism of compound 31 was also identified by flow cytometry, and this compound exerts immunosuppressive activity by inducing apoptosis in activated lymph node cells in a dose-dependent manner. In addition, the mechanism of apoptosis was detected by western blot analysis.

Two series of novel N -benzyl- N -(X-2-hydroxybenzyl)- N ′-phenylureas and thioureas ( 1a – 18a ; 1b – 18b ) as potential EGFR and HER-2 kinase inhibitors have been discovered. These compounds displayed good EGFR and HER-2 inhibitory activity and the SARs are also been studied. Especially compound 7b demonstrated significant EGFR and HER-2 inhibitory activity (IC 50 = 0.08 μM for EGFR and IC 50 = 0.35 μM for HER-2). Docking simulation was performed to position compound 7b into the EGFR active site to determine the probable binding conformation and antiproliferative assay results indicating that these series of urea and thioureas own high antiproliferative activity against MCF-7. Above all, thiourea 7b would be a potential anticancer agent deserves further research.

Nine 2-arylthiazolidine-4-carboxylic acid derivatives and nine 3-tert-butoxycarbonyl-2-arylthiazolidine-4-carboxylic acid derivatives were synthesized to screen for their antibacterial activities. Compounds 5, 14–18 were first reported. Their chemical structures were clearly determined by 1H NMR, 13C NMR, ESI mass spectra and elemental analyses, coupled with one selected single-crystal structure. All the compounds were assayed for antibacterial activities against two Gram-positive bacterial strains (Bacillus subtilis ATCC 6633 and Staphylococcus aureus ATCC 6538) and two Gram-negative bacterial strains (Escherichia coli ATCC 35218 and Pseudomonas aeruginosa ATCC 13525) by MTT method. Most of the 3-tert-butoxycarbonyl-2-arylthiazolidine-4-carboxylic acid derivatives exhibited better antibacterial activities against the four bacterial strains than relative 2-arylthiazolidine-4-carboxylic acid derivatives. Compound (2RS,4R)-3-(tert-butoxycarbonyl)-2-(5-fluoro-2-hydroxyphenyl)thiazolidine-4-carboxylic acid (14) showed powerful antibacterial activities against P. aeruginosa with IC50 value of 0.195 μg/mL, which was superior to the positive controls Penicillin G and Kanamycin B, respectively. On the basis of the biological results, structure–activity relationships were discussed.

As a naturally wide distributed flavone, chrysin exhibits numerous biological activities including anticancer, anti-inflammatory, and antimicrobials activities. Beta-ketoacyl-acyl carrier protein synthase III (FabH) catalyzes the initial step of fatty acid biosynthesis via a type II fatty acid synthase in most bacteria. The important role of this essential enzyme combined with its unique structural features and ubiquitous occurrence in bacteria has made it an attractive new target for the development of antibacterial agents. We first used a structure-based approach to develop 18 novel chrysin analogues that target FabH for the development of new antibiotics. Structure-based design methods were used for the expansion of the chrysin derivatives including molecular docking and SAR research. Based on the results, 5-hydroxy-2-phenyl-7-(2-(piperazin-1-yl)ethoxy)-4H-chromen-4-one (3g) showed the most potent antibacterial activity with MIC of 1.56-6.25 microg/mL against the test bacterial stains, and docking simulation was performed to position compound 3g into the Escherichia coli FabH active site to determine the probable binding conformation. The biological assays indicated that compound 3g is a potent inhibitor of E.coli FabH as antibiotics.

Cortisol and the glucocorticoid receptor signaling pathway have been implicated in the development of diabetes and obesity. The reduction of cortisone to cortisol is catalyzed by 11beta-hydroxysteroid dehydrogenase type I (11beta-HSD1). 2,4-Disubsituted benzenesulfonamides were identified as potent inhibitors of both the human and mouse enzymes. The lead compounds displayed good pharmacokinetics and ex vivo inhibition of the target in mice. Cocrystal structures of compounds 1 and 20 bound to human 11beta-HSD1 were obtained. Compound 20 was found to achieve high concentrations in target tissues, resulting in 95% inhibition in the ex vivo assay when dosed with a food mix (0.5 mg of drug per g of food) after 4 days. Compound 20 was efficacious in a mouse diet-induced obesity model and significantly reduced fed glucose and fasted insulin levels. Our findings suggest that 11beta-HSD1 inhibition may be a valid target for the treatment of diabetes.

Tpl2 (cot/MAP3K8) is an upstream kinase of MEK in the ERK pathway. It plays an important role in Tumor Necrosis Factor-alpha (TNF-alpha) production and signaling. We have discovered that 8-halo-4-(3-chloro-4-fluoro-phenylamino)-6-[(1H-[1,2,3]triazol-4-ylmethyl)-amino]-quinoline-3-carbonitriles (4) are potent inhibitors of this enzyme. In order to improve the inhibition of TNF-alpha production in LPS-stimulated human blood, a series of analogs with a variety of substitutions around the triazole moiety were studied. We found that a cyclic amine group appended to the triazole ring could considerably enhance potency, aqueous solubility, and cell membrane permeability. Optimization of these cyclic amine groups led to the identification of 8-chloro-4-(3-chloro-4-fluorophenylamino)-6-((1-(1-ethylpiperidin-4-yl)-1H-1,2,3-triazol-4-yl)methylamino)quinoline-3-carbonitrile (34). In a LPS-stimulated rat inflammation model, compound 34 showed good efficacy in inhibiting TNF-alpha production.

Twenty amines and oximes from deoxybenzoins were prepared and evaluated for their inhibitory activity against Helicobacter pylori urease. Among these compounds, high inhibitory activities were observed in amines and oximes, especially amines 1b (IC 50 = 0.011 mM) and 6b (IC 50 = 0.047 mM) exhibited good in vitro activities, and were comparable to acetohydroxamic acid (AHA). The hydroxyl groups on deoxybenzoin skeleton may be responsible for the inhibitory activity and coordinate with the nickel (active site) on enzyme. A direct interaction may exist between the OH group of hydroxylamines or NH group of amines and His α323 of H. pylori urease, which is on the flap of the enzyme active site.

Within the past ten years, a huge volume of research on the synthesis, structure-activity relationships (SAR), and anticancer activities of the urea derivatives was reported. Many aromatic urea derivatives such as N-phenyl-N-(2-chloroethyl)ureas (CEUs) and benzoylureas (BUs) show good anticancer activity, and these compounds have mainly been proved to be tubulin ligands that inhibit the polymerization of tubulin. Heterocyclic urea derivatives play an important role in anticancer agents because of their good inhibitory activity against receptor tyrosine kinases (RTKs), raf kinases, protein tyrosine kinases (PTKs), and NADH oxidase, which play critical roles in many aspects of tumorigenesis. Thiourea derivatives are also of wide interest because of their diverse anticancer activity against various leukemias and solid tumors. In this review, the anticancer activity of the urea derivatives mentioned above is summarized in detail. It is hoped that increasing knowledge of the SAR and cellular processes underlying the antitumor-activity of urea derivatives will be beneficial to the rational design of new generation of urea anticancer drugs.

A series of luteolin derivatives 2-20 were prepared, 3-20 of which were first reported. The chemical structures of these compounds were confirmed by means of 1H NMR, ESI-MS and elemental analyses. The compounds were assayed for antibacterial (Bacillus subtilis, Staphylococcus aureus, Pseudomonas fluorescens and Escherichia coli) activities by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl trtrazolium bromide) method. Among the compounds tested, most of them displayed significant activity against the tested strains, and 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-hydroxy-7-(2-(3-morpholinopropylamino)ethoxy)-4H-chromen-4-one (17) showed the most favorable antibacterial activity in vitro with MICs of 1.562, 3.125, 3.125, and 6.25 microg/mL against B. subtilis, S. aureus, P. fluorescens and E. coli, respectively. Structure-activity relationships (SAR) were also discussed based on the obtained experimental data.

Three series of novel formononetin derivatives were synthesized, in which formononetin and heterocyclic moieties were separated by 2-carbon, 3-carbon, and 4-carbon spacers. The chemical structures of these compounds were confirmed. All the derivatives were screened for antiproliferative activities against Jurkat cell line and HepG-2 cell line. In this paper, compounds prepared were also screened for their antibacterial activity of six bacterial strains. Compound 3b exihibited promising antibacterial activity against B. subtilis with minimal inhibitory concentration (MIC) value of 0.78 μg/mL, and compound 5e showed significant antiproliferative activities against Jurkat cell growth with IC50 of 1.35×10−4 μg/mL. The preliminary investigation of structure-activity relationships (SARs) was also discussed based on the obtained experimental data.

11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) is the enzyme that converts cortisone to cortisol. Evidence suggests that selective inhibition of 11beta-HSD1 could treat diabetes and metabolic syndrome. Presented herein are the synthesis, structure-activity relationship, and in vivo evaluation of piperazine sulfonamides as 11beta-HSD1 inhibitors. Through modification of our initial lead 5a, we have identified potent and selective 11beta-HSD1 inhibitors such as 13q and 13u with good pharmacokinetic properties.

Metronidazole (MET-OH), widely used as an antibacterial agent, is found to have some side effects on human bodies. Due to these disadvantages, people have been looking for its modification compounds for substituents. In this article, four MET-OH derivatives were designed, prepared, and structurally characterized by single crystal X-ray diffraction. These compounds are MET-OTs (1), MET-Br (2), MET-Cl (3), and MET-I (4). X-ray structure analyses revealed that, 1 crystallized in the monoclinic system with space group P2 1 /c, with a = 16.1178, b = 7.5473, c = 13.4161 A, V = 1520.3 A3, β = 111.3210o and Z = 4. 2 crystallized in the monoclinic system with space group P2 1 /c, with a = 12.079, b = 11.089, c = 6.380 A, V = 847.1 A3, β = 97.57o and Z = 4. 3 crystallized in the monoclinic system with space group P2 1 /c, with a = 12.098, b = 11.007, c = 6.295 A, V = 830.3 A3, β = 97.886o and Z = 4. 4 crystallized in the triclinic system with space group P1, with a = 6.192, b = 7.740, c = 10.001 A, V = 457.9 A3, α = 89.073, β = 86.903, γ = 73.097o and Z = 2. In this article, metronidazole-derived compounds were prepared and structurally characterized by single crystal X-ray diffraction

Tectorigenin, isolated from the rhizomes of Belamcanda chinensis, shows a wide variety of biological activities. The interest in its biological activities has been matched by a corresponding interest in its synthesis. We herein reported a convenient synthesis of tectorigenin in good yield. The starting material, 2,4,6‐trihydroxyanisole, gave the intermediate 2,4,4′,6‐tetrahydroxy‐3‐methoxydeoxybenzoin by a Hoesch reaction with 4‐hydroxyphenylacetonitrile. The intermediate was then reacted with methanesulfonyl chloride to produce a mixture of tectorigenin and Ψ‐tectorigenin. Purification of tectorigenin was unnecessary at this stage as Ψ‐tectorigenin in the mixture was isomerized to tectorigenin by refluxing in n‐BuOH in the presence of K2CO3.

We have previously reported the discovery and initial SAR of the [1,7]naphthyridine-3-carbonitriles and quinoline-3-carbonitriles as Tumor Progression Loci-2 (Tpl2) kinase inhibitors. In this paper, we report new SAR efforts which have led to the identification of 4-alkylamino-[1,7]naphthyridine-3-carbonitriles. These compounds show good in vitro and in vivo activity against Tpl2 and improved pharmacokinetic properties. In addition they are highly selective for Tpl2 kinase over other kinases, for example, EGFR, MEK, MK2, and p38. Lead compound 4-cycloheptylamino-6-[(pyridin-3-ylmethyl)-amino]-[1,7]naphthyridine-3-carbonitrile (30) was efficacious in a rat model of LPS-induced TNF-alpha production.

The title compound, 3, 6-dihydroxy-2-[2-(4-hydroxy-phenyl)-vinyl]- benzene-1,3-dicarbaldehyde was synthesized by Vilslmeier reaction from resveratrol (trans-3,4′,5-trihydroxystilbene). Its structure was determined by X-ray single crystal diffraction. The crystal belongs to monoclinic, space group P21/n with crystallographic parameters: a = 7.2950(15) A, b = 14.781(3) A, c = 12.202(2) A, β = 96.57(3)°, μ = 0.108 mm−1, V = 1307.1(5) A, Z = 4, Dx = 1.445 g/cm3, F(000) = 592, T = 293(2) K, 2.17°≤ θ ≤ 26.00°. The X-ray results demonstrated that the Vilslmeier reaction of resveratrol with DMF, POCl3 and CH3CN yielded 4,6-dhydroxy-2-[2-(4-hydroxy-phenyl)-vinyl]-benzene-1,3-dicarbaldehyde. In this article, a resveratrol derivative was prepared and structurally characterized by single crystal X-ray diffraction.

Three series of metronidazole-flavonoid derivatives were generated and evaluated for antimicrobial activity against H. pylori. Among these compounds, high anti-H. pylori activities were observed in isoflavones derivatives 4-7, 19, and 20 but exhibited no inhibitory activity against other sorts of bacteria and fungi, for example, Streptococcus pneumoniae, Bacillus subtilis, Escherichia coli, Pseudomonas fluorescence, and Aspergillus niger. Genistein derivative 6 with the potent activity (MIC=0.39 microg mL(-1)) was >50-fold more than metronidazole, and comparable to the positive control amoxicillin. Additionally, compound 6 can significantly attenuate the increase in interleukin-8 (IL-8) levels in the AGS cells stimulated by H. pylori water extract (HPE) at concentrations of 15, 30, and 60 micromol L(-1), which did not show any effects on the cell viability.

Tumor progression loci-2 (Tpl2) (Cot/MAP3K8) is a serine/threonine kinase in the MAP3K family directly upstream of MEK. Recent studies using Tpl2 knockout mice have indicated an important role for Tpl2 in the lipopolysaccharide (LPS) induced production of tumor necrosis factor alpha (TNF-alpha) and other proinflammatory cytokines involved in diseases such as rheumatoid arthritis. Initial 4-anilino-6-aminoquinoline-3-carbonitrile leads showed poor selectivity for Tpl2 over epidermal growth factor receptor (EGFR) kinase. Using molecular modeling and crystallographic data of the EGFR kinase domain with and without an EGFR kinase-specific 4-anilinoquinazoline inhibitor (erlotinib, Tarceva), we hypothesized that we could diminish the inhibition of EGFR kinase by substitution at the C-8 position of our 4-anilino-6-aminoquinoline-3-carbonitrile leads. The 8-substituted-4-anilino-6-aminoquinoline-3-carbonitriles were prepared from the appropriate 2-substituted 4-nitroanilines. Modifications to the C-6 and C-8 positions led to the identification of compounds with increased inhibition of TNF-alpha release from LPS-stimulated rat and human blood, and these analogues were also highly selective for Tpl2 kinase over EGFR kinase. Further structure-activity based modifications led to the identification of 8-bromo-4-(3-chloro-4-fluorophenylamino)-6-[(1-methyl-1H-imidazol-4-yl)methylamino]quinoline-3-carbonitrile, which demonstrated in vitro as well as in vivo efficacy in inhibition of LPS-induced TNF-alpha production.