Novel Pyrazole-4-Carboxamide Derivatives Containing Oxime Ether Group as Potential SDHIs to Control Rhizoctonia solani.

In the search for novel succinate dehydrogenase inhibitor (SDHI) fungicides to control Rhizoctonia solani, thirty-five novel pyrazole-4-carboxamides bearing either an oxime ether or an oxime ester group were designed and prepared based on the strategy of molecular hybridization, and their antifungal activities against five plant pathogenic fungi were also investigated. The results indicated that the majority of the compounds containing oxime ether demonstrated outstanding in vitro antifungal activity against R. solani, and some compounds also displayed pronounced antifungal activities against Sclerotinia sclerotiorum and Botrytis cinerea. Particularly, compound 5e exhibited the most promising antifungal activity against R. solani with an EC50 value of 0.039 µg/mL, which was about 20-fold better than that of boscalid (EC50 = 0.799 µg/mL) and 4-fold more potent than fluxapyroxad (EC50 = 0.131 µg/mL). Moreover, the results of the detached leaf assay showed that compound 5e could suppress the growth of R. solani in rice leaves with significant protective efficacies (86.8%) at 100 µg/mL, superior to boscalid (68.1%) and fluxapyroxad (80.6%), indicating promising application prospects. In addition, the succinate dehydrogenase (SDH) enzymatic inhibition assay revealed that compound 5e generated remarkable SDH inhibition (IC50 = 2.04 µM), which was obviously more potent than those of boscalid (IC50 = 7.92 µM) and fluxapyroxad (IC50 = 6.15 µM). Furthermore, SEM analysis showed that compound 5e caused a remarkable disruption to the characteristic structure and morphology of R. solani hyphae, resulting in significant damage. The molecular docking analysis demonstrated that compound 5e could fit into the identical binding pocket of SDH through hydrogen bond interactions as well as fluxapyroxad, indicating that they had a similar antifungal mechanism. The density functional theory and electrostatic potential calculations provided useful information regarding electron distribution and electron transfer, which contributed to understanding the structural features and antifungal mechanism of the lead compound. These findings suggested that compound 5e could be a promising candidate for SDHI fungicides to control R. solani, warranting further investigation.

Stereoselective Synthesis of ß, γ-Fused Bicyclic γ-Ureasultams via an Intramolecular Mannich and aza-Michael Addition Cascade.

A novel approach has been developed for the synthesis of bicyclic ß, γ-fused bicyclic γ-ureasultams containing two consecutive chiral centers through an intramolecular Mannich and aza-Michael addition cascade of alkenyl sulfamides. The straightforward practical procedure and readily available starting materials enable the synthesis of variously substituted ureasultams. In addition, bicyclic γ-ureasultams is a class of potential biotin analogues.

Design, Synthesis, and Antifungal Activities of Novel Carboxamides Derivatives Bearing a Chalcone Scaffold as Potential SDHIs.

In search for SDHIs fungicides, twenty-five novel carboxamides containing a chalcone scaffold were designed, synthesized, and evaluated for antifungal activities against five pathogenic fungi. The results showed that compound 5 k exhibited outstanding antifungal activity against R. solani with an EC50 value of 0.20 µg/mL, which was much better than that of commercial SDHIs Boscalid (EC50 =0.74 µg/mL). Moreover, compound 5 k also displayed promising antifungal activities against S. sclerotiorum, B. cinerea, and A. alternate (IC50 =2.53-4.06 µg/mL), indicating that 5 k had broad-spectrum antifungal activity. Additionally, in vivo antifungal activities results showed that 5 k could significantly inhibit the growth of R. solani in rice leaves with good protective efficacy (57.78 %) and curative efficacy (58.45 %) at 100 µg/mL, both of which were much better than those of Boscalid, indicating a promising application prospect. Moreover, SEM analysis showed that compound 5 k could remarkably disrupt the typical structure and morphology of R. solani hyphae. Further SDH enzyme inhibition assay and molecular docking study revealed that lead compound 5 k had a similar mechanism of action as commercial SDHI Boscalid. These results indicated that compound 5 k showed potential as a SDHIs fungicide and deserved further investigation.

Design, Synthesis, and Antifungal Activities of Novel Pyrazole-4-carboxamide Derivatives Containing an Ether Group as Potential Succinate Dehydrogenase Inhibitors.

A series of novel pyrazole-4-carboxamides bearing an ether group were designed and synthesized on the basis of the structure of commercial succinate dehydrogenase inhibitor (SDHI) fungicide flubeneteram via scaffold hopping and evaluated for their antifungal activities against five fungi. The bioassay results showed that most of the target compounds exhibited excellent in vitro antifungal activity against Rhizoctonia solani and some compounds exerted remarkable antifungal activities against Sclerotinia sclerotiorum, Botrytis cinerea, Fusarium graminearum, and Alternaria alternate. Particularly, compounds 7d and 12b displayed outstanding antifungal activity against R. solani, with an EC50 value of 0.046 µg/mL, far superior to that of boscalid (EC50 = 0.741 µg/mL) and fluxapyroxad (EC50 = 0.103 µg/mL). Meanwhile, compound 12b also presented a broader fungicidal spectrum than other compounds. Moreover, in vivo anti-R. solani results showed that compounds 7d and 12b could significantly inhibit the growth of R. solani in rice leaves with excellent protective and curative efficacies. In addition, the results of the succinate dehydrogenase (SDH) enzymatic inhibition assay showed that compound 7d generated significant SDH inhibition, with an IC50 value of 3.293 µM, which was about 2 times better than that of boscalid (IC50 = 7.507 µM) and fluxapyroxad (IC50 = 5.991 µM). Furthermore, scanning electron microscopy (SEM) analysis indicated that compounds 7d and 12b significantly destroyed the typical structure and morphology of R. solani hyphae. The molecular docking study revealed that compounds 7d and 12b could embed into the binding pocket of SDH and form hydrogen bond interactions with TRP173 and TRY58 at the activity site of SDH, which was in line with fluxapyroxad, indicating that they had a similar mechanism of action. These results demonstrated that compounds 7d and 12b could be promising candidates of SDHI fungicides, which deserved further investigation.

Histone Deacetylase and Enhancer of Zeste Homologue 2 Dual Inhibitors Presenting a Synergistic Effect for the Treatment of Hematological Malignancies.

Aberrance of epigenetic modification is one of the important factors leading to hematological malignancies. Histone deacetylase (HDAC) inhibitors and enhancers of zeste homologue 2 (EZH2) inhibitors are demonstrated to be significant epigenic modulators. Cocktail therapy of HDAC inhibitors and EZH2 inhibitors was demonstrated to be a promising strategy in hematological malignancies. We designed HDAC and EZH2 dual inhibitors based on the strong synergistic effect of SAHA and GSK126. Compound 20 exhibited excellent inhibitory activity against HDAC1 (IC50 = 0.12 µM) and EZH2 (IC50 = 0.059 µM), it also showed good antiproliferation activity against MV4-11 (IC50 = 0.17 µM), which has more potential than the cocktail therapy of SAHA and GSK126 (IC50 = 0.40 µM). 20 suppressed tumor growth in vivo, which was as good as the combination therapy. These results suggested that 20 may be a promising drug candidate for treating hematological malignancies.

Discovery of precision targeting EZH2 degraders for triple-negative breast cancer.

EZH2 is usually overexpressed in TNBC and other tumors, which has a great influence on the occurrence, development and prognosis of tumors. However, current EZH2 inhibitors, including Tazemetostat and GSK126, affect the methyl catalytic capacity of EZH2 and have little effect on the tumorigenic activity of EZH2 itself, resulting in poor efficacy against most solid tumors. Herein, we designed and optimized proteolytic targeting chimeras (PROTACs) precision targeting EZH2. The most active PROTAC molecule U3i has a high affinity for PRC2 complex (KD = 16.19 nM) and show good inhibitory effects on MDA-MB-231 (IC50 = 0.57 µM) and MDA-MB-468 (IC50 = 0.38 µM) cells. Compared with that of the GSK126, the growth inhibitory activities of U3i against these two TNBC cells increased by approximately 20- and 30-fold. Further studies showed that U3i can degrade PRC2 complex in TNBC cells, induce apoptosis, and cause little damage to normal cells. Therefore, U3i is a potential anticancer molecule for TNBC treatment.

Harmine-based dual inhibitors targeting histone deacetylase (HDAC) and DNA as a promising strategy for cancer therapy.

Overexpression of histone deacetylases (HDACs) are observed in different types of cancers, but histone deacetylase inhibitors (HDACIs) have not shown significant efficacy as monotherapy against solid tumors. Recently, studies demonstrated that it is promising to combine HDACIs with DNA damage agents to improve DNA damage level to gain better effect on treating solid tumor. Harmine has been demonstrated to cause DNA damage by intercalating DNA. Therefore, we designed a series of harmine-based inhibitors targeting HDAC and DNA with multi-target strategy, the most potential compound 27 could bind to DNA and cause DNA damage. Furthermore 27 caused cells apoptosis through p53 signaling pathway, and exhibited significant anti-proliferation effects against HCT-116 cells (IC50 = 1.41 µM). As a DNA damage agent, 27 displayed low toxicity in normal cells. Compound 27 was demonstrated as a dual inhibitor targeting HDAC (HDAC1 IC50 = 0.022 µM and HDAC6 IC50 = 0.45 µM) and DNA, and had the potential in the treatment of solid tumor.

Novel insights into RIPK1 as a promising target for future Alzheimer's disease treatment.

Alzheimer's disease (AD) is an intractable neurodegenerative disease showing a clinical manifestation with memory loss, cognitive impairment and behavioral dysfunction. The predominant pathological characteristics of AD include neuronal loss, ß-amyloid (Aß) deposition and hyperphosphorylated Tau induced neurofibrillary tangles (NFTs), while considerable studies proved these could be triggered by neuronal death and neuroinflammation. Receptor-interacting protein kinase 1 (RIPK1) is a serine/threonine kinase existed at the cross-point of cell death and inflammatory signaling pathways. Emerging investigations have shed light on RIPK1 for its potential role in AD progression. The present review makes a bird's eye view on the functions of RIPK1 and mainly focus on the underlying linkages between RIPK1 and AD from comprehensive aspects including neuronal death, Aß and Tau, inflammasome activation, BBB rupture, AMPK/mTOR, mitochondrial dysfunction and O-glcNAcylation. Moreover, the discovery of RIPK1 inhibitors, ongoing clinical trials along with future RIPK1-targeted therapeutics are also reviewed.

Parthenolide Derivatives as PKM2 Activators Showing Potential in Colorectal Cancer.

As a vital kinase in the glycolysis system, PKM2 is extensively expressed in colorectal cancer (CRC) to support the energy and biosynthetic needs. In this study, we designed a series of parthenolide (PTL) derivatives through a stepwise structure optimization, and an excellent derivate 29e showed good activity on PKM2 (AC50 = 86.29 nM) and displayed significant antiproliferative activity against HT29 (IC50 = 0.66 µM) and SW480 (IC50 = 0.22 µM) cells. 29e decreased the expression of total PKM2, prevented nucleus translocation of PKM2 dimer, and inhibited PKM2/STAT3 signaling pathway. 29e remarkably increased OCR and decreased the extracellular acidification rate (ECAR). The antiproliferative effect of 29e depended on PKM2, and the Cys424 of PKM2 was the key binding site. Furthermore, 29e significantly suppressed tumor growth in the HT29 xenograft model without obvious toxicity. These outcomes demonstrate that 29e is a promising drug candidate for the treatment of CRC.

Discovery of PT-65 as a highly potent and selective Proteolysis-targeting chimera degrader of GSK3 for treating Alzheimer's disease.

GSK3 is a promising target for the treatment of Alzheimer's disease. Here, we describe the design and synthesize of a series of GSK3 degraders based on a click chemistry platform. A series of highly potent GSK3 degraders were obtained. Among them, PT-65 exhibited most potent degradation potency against GSK3α (DC50 = 28.3 nM) and GSK3ß (DC50 = 34.2 nM) in SH-SY5Y cells. SPR assay confirmed that PT-65 binds to GSK3ß with high affinity (KD = 12.41 nM). The proteomic study indicated that PT-65 could selectively induced GSK3 degradation. Moreover, PT-65 could effectively suppress GSK3ß and Aß mediated tau hyperphosphorylation in a dose-dependent manner and protect SH-SY5Y cells from Aß caused cell damage. We also confirmed that PT-65 could suppress OA induced tau hyperphosphorylation and ameliorate learning and memory impairments in vivo model of AD. In summary, PT-65 might be a promising candidate for the treatment of AD.

Discovery of First-in-Class Dual PARP and EZH2 Inhibitors for Triple-Negative Breast Cancer with Wild-Type BRCA.

PARP inhibitors have highly significant effects on BRCA mutant cells, allowing targeted therapy of triple-negative breast cancer (TNBC). However, some TBNC patients lack BRCA mutations. Recent studies have shown that EZH2 inhibitors can increase the sensitivity of wild-type BRCA cells to PARP inhibitors. We designed a series of dual PARP and EZH2 inhibitors, and the most promising compound, 5a, showed good inhibitory activity against PARP-1 and EZH2 and good inhibitory effects on MDA-MB-231 (IC50 = 2.63 µM) and MDA-MB-468 (IC50 = 0.41 µM) cells with wild-type BRCA. Compared with that of olaparib, the growth inhibitory activities against these two cell types increased by approximately 15- and 80-fold, respectively, which was even more effective than the combination of olaparib and tazemetostat/GSK126. 5a can induce autophagy death of tumor cells and cause less damage to normal cells. Therefore, 5a, as a first-in-class dual PARP and EZH2 inhibitor, is a potential anticancer drug candidate for the treatment of TNBC.

Synthesis and evaluation of multi-target-directed ligands with BACE-1 inhibitory and Nrf2 agonist activities as potential agents against Alzheimer's disease.

Cumulative evidence suggests that ß-amyloid and oxidative stress are closely related with each other and play key roles in the process of Alzheimer's disease (AD). Multitarget regulation of both pathways might represent a promising therapeutic strategy. Here, a series of selenium-containing compounds based on ebselen and verubecestat were designed and synthesized. Biological evaluation showed that 13f exhibited good BACE-1 inhibitory activity (IC50 = 1.06 µΜ) and potent GPx-like activity (ν0 = 183.0 µM min-1). Aß production experiment indicated that 13f could reduce the secretion of Aß1-40 in HEK APPswe 293T cells. Moreover, 13f exerted a cytoprotective effect against the H2O2 or 6-OHDA caused cell damage via alleviation of intracellular ROS, mitochondrial dysfunction, Ca2+ overload and cell apoptosis. The mechanism studies indicated that 13f exhibited cytoprotective effect by activating the Keap1-Nrf2-ARE pathway and stimulating downstream anti-oxidant protein including HO-1, NQO1, TrxR1, GCLC, and GCLM. In addition, 13f significantly reduced the production of NO and IL-6 induced by LPS in BV2 cells, which confirmed its anti-inflammatory activity as a Nrf2 activator. The BBB permeation assay predicted that 13f was able to cross the BBB. In summary, 13f might be a promising multi-target-directed ligand for the treatment of AD.

Rhodium(iii) catalyzed olefination and deuteration of tetrahydrocarbazole.

The rhodium-catalyzed olefination and deuteration of tetrahydrocarbazoles in water with the aid of an N,N-dimethylcarbamoyl-protected group is presented. This olefination method features a broad substrate scope, good functional-group tolerance, and high efficiency in water. Practical applications of the protocol are illustrated by the synthesis of various evodiamine derivatives. As such, this environmentally friendly approach to directly modify natural products will attract much attention in academic and industrial research.

Optimization of WZ4003 as NUAK inhibitors against human colorectal cancer.

NUAK, the member of AMPK (AMP-activated protein kinase) family of protein kinases, is phosphorylated and activated by the LKB1 (liver kinase B1) tumor suppressor protein kinase. Recent work has indicated that NUAK1 is a key component of the antioxidant stress response pathway, and the inhibition of NUAK1 will suppress the growth and survival of colorectal tumors. As a promising target for anticancer drugs, few inhibitors of NUAK were developed. With this goal in mind, based on NUAK inhibitor WZ4003, a series of derivatives has been synthesized and evaluated for anticancer activity. Compound 9q, a derivative of WZ4003 by removing a methoxy group, was found to be the most potential one with stronger inhibitory against NUAK1/2 enzyme activity, tumor cell proliferation and inducing apoptosis of tumor cells. By in vivo efficacy evaluations of colorectal SW480 xenografts, 9q suppresses tumor growth more effectively with an excellent safety profile in vivo and is therefore seen as a suitable candidate for further investigation.

Identification and optimization of piperlongumine analogues as potential antioxidant and anti-inflammatory agents via activation of Nrf2.

Oxidative stress and inflammation are significant risk factors for neurodegenerative disease. The Keap1-Nrf2-ARE pathway is one of the most promising defensive systems against oxidative stress. Here, dozens of piperlongumine analogues were designed, synthesized, and tested on PC12 cells to examine neuroprotective effects against H2O2 and 6-OHDA induced damage. Among them, 6d was found to be able to alleviate the accumulation of ROS, inhibit the production of NO and downregulate the level of IL-6, which indicated its potential antioxidant and anti-inflammatory activity. Further studies proved that 6d could activate Nrf2 signaling pathway, induce the translocation of Nrf2 from cell cytosol to nucleus and upregulate the related phase II antioxidant enzymes including NQO1, HO-1, GCLC, GCLM and TrxR1. These results confirmed that 6d exerted antioxidant and anti-inflammatory activities by activating Nrf2 signaling pathway. Moreover, the parallel artificial membrane permeability assay indicated that 6d can cross the blood-brain barrier. In general, 6d is promising for further development as a therapeutic drug against oxidative stress and inflammation related neurodegenerative disorders.

Usnic acid derivatives as tau-aggregation and neuroinflammation inhibitors.

Accumulation of tau protein aggregation plays a crucial role in neurodegenerative diseases, such as Alzheimer's disease (AD). Uncontrollable neuroinflammation and tau pathology form a vicious circle that further aggravates AD progression. Herein, we reported the synthesis of usnic acid derivatives and evaluation of their inhibitory activities against tau-aggregation and neuroinflammation. The inhibitory activity of the derivatives against the self-fibrillation of the hexapeptide AcPHF6 was initially screened by ThT fluorescence assay. Using circular dichroism and transmission electron microscopy, compound 30 showed the most potent inhibitory activity against AcPHF6 self-fibrillation. Compound 30 was further confirmed to inhibit the aggregation of full-length 2N4R tau protein by a heparin-induced mechanism. In addition, we investigated the anti-inflammatory activity of compound 30, and showed that compared with sodium usnate, it reduced NO release in LPS-stimulated mouse microglia BV2 cells. More importantly, 30 showed significant protective effects against okadaic acid-induced memory impairment in rats. Thus, 30 was a novel tau-aggregation and neuroinflammation inhibitor that represented a potential therapeutic candidate for AD.

A hemicyanine derivative for near-infrared imaging of ß-amyloid plaques in Alzheimer's disease.

The formation of amyloid-ß (Aß) plaques in the brain is one of the main pathological features of Alzheimer's disease (AD). The imaging probes, capable of detecting Aß deposition, are important tools for early diagnosis of AD. In this article, we designed, synthesized and evaluated a cyanine-based near-infrared fluorescence (NIRF) probe ZT-1 for the detection of Aß deposits in the brain. The probe had excellent fluorescent properties with an emission maximum above 720 nm upon binding to Aß aggregates with affinity of 445.0 nM (Kd). Furthermore, ZT-1 exhibited good biostability, photostability, and binding selectivity toward Aß1-42 aggregates by in vitro fluorescence staining experiments. In vivo NIRF imaging result also revealed that our probe could efficiently differentiate transgenic and wild-type mice. All these studies indicated that ZT-1 is a promising fluorescent probe for Aß plaques in the AD brains.

Design, synthesis, and antibacterial activity of novel 8-methoxyquinoline-2-carboxamide compounds containing 1,3,4-thiadiazole moiety.

A series of novel 8-methoxyquinoline-2-carboxamide compounds containing 1,3,4-thiadiazole moiety was designed and synthesized by using an active substructure combination method. Then, the antibacterial activities of all the target compounds were evaluated in vitro against three Gram-positive bacteria and three Gram-negative bacteria. The antibacterial assay showed that some target compounds displayed moderate to good antibacterial efficacy in comparison with the reference drug Chloromycin. Some interesting results of structure-activity relationships were also discussed.

Application of Sustainable Natural Bioresources in Agriculture: Iodine-Mediated Oxidative Cyclization for Metal-Free One-Pot Synthesis of N-Phenylpyrazole Sarisan Analogues as Insecticidal Agents.

In view of potential agricultural activity of sarisan (isolated from many plants or easily synthesized from sesamol, another biorenewable natural product) analogues, many research studies on the application of these biorenewable and abundant natural resources have been proceeded. A series of novel sarisan analogues containing N-phenylpyrazole were synthesized and evaluated for their insecticidal activity against a crop-threatening insect pest, Mythimna separata Walker. Meanwhile, an iodine-mediated oxidative intramolecular C-N bond formation methodology has been established for the one-pot synthesis of these N-phenylpyrazole-containing sarisan analogues. This practical one-pot methodology is metal-free and requires no separation of the less stable intermediate hydrazones. In addition, it was found that compounds 8l-r exhibited more promising insecticidal activity with the final mortality rates (FMRs) >62.1%, when compared with the positive control toosendanin. Especially, compound 8r with 2-fluoro-4-bromophenyl showed the most potent insecticidal activity, the FMR of which was 79.3%. On the basis of this, some interesting results of structure-activity relationships were also discussed.