Discovery, Optimization, and Biological Evaluation of Novel Pyrazol-5-yl-phenoxybenzamide Derivatives as Potent Succinate Dehydrogenase Inhibitors.

The diphenyl ether molecular pharmacophore has played a significant role in the development of fungicidal compounds. In this study, a variety of pyrazol-5-yl-phenoxybenzamide derivatives were synthesized and evaluated for their potential to act as succinate dehydrogenase inhibitors (SDHIs). The bioassay results indicate certain compounds to display a remarkable and broad-spectrum in their antifungal activities. Notably, compound 12x exhibited significant in vitro activities against Valsa mali, Gaeumannomyces graminis, and Botrytis cinerea, with EC50 values of 0.52, 1.46, and 3.42 mg/L, respectively. These values were lower or comparable to those of Fluxapyroxad (EC50 = 12.5, 1.93, and 8.33 mg/L, respectively). Additionally, compound 12x showed promising antifungal activities against Sclerotinia sclerotiorum (EC50 = 0.82 mg/L) and Rhizoctonia solani (EC50 = 1.86 mg/L), albeit lower than Fluxapyroxad (EC50 = 0.23 and 0.62 mg/L). Further in vivo experiments demonstrated compound 12x to possess effective protective antifungal activities against V. mali and S. sclerotiorum at a concentration of 100 mg/L, with inhibition rates of 66.7 and 89.3%, respectively. In comparison, Fluxapyroxad showed inhibition rates of 29.2 and 96.4% against V. mali and S. sclerotiorum, respectively. Molecular docking analysis revealed that compound 12x interacts with SDH through hydrogen bonding, π-cation, and π-π interactions, providing insights into the probable mechanism of action. Furthermore, compound 12x exhibited greater binding energy and SDH enzyme inhibitory activity than Fluxapyroxad (ΔGcal = -46.8 kcal/mol, IC50 = 1.22 mg/L, compared to ΔGcal = -41.1 kcal/mol, IC50 = 8.32 mg/L). Collectively, our results suggest that compound 12x could serve as a promising fungicidal lead compound for the development of more potent SDHIs for crop protection.

Efficacy and safety of targeted therapy plus immunotherapy combined with hepatic artery infusion chemotherapy (FOLFOX) for unresectable hepatocarcinoma.

BACKGROUND: The advent of cutting-edge systemic therapies has driven advances in the treatment of hepatocellular carcinoma (HCC), and therapeutic strategies with multiple modes of delivery have been shown to be more efficacious than monotherapy. However, the mechanisms underlying this innovative treatment modality have not been elucidated. AIM: To evaluate the clinical efficacy of targeted therapy plus immunotherapy combined with hepatic arterial infusion chemotherapy (HAIC) of FOLFOX in patients with unresectable HCC. METHODS: We enrolled 53 patients with unresectable HCC who received a combination of targeted therapy, immunotherapy, and HAIC of FOLFOX between December 2020 and June 2021 and assessed the efficacy and safety of the treatment regimen. RESULTS: The objective response rate was 60.4% (32/53), complete response was 24.5% (13/53), partial response was 35.9% (19/53), and stable disease was 39.6% (21/53). The median duration of response and median progression-free survival were 9.1 and 13.9 months, respectively. The surgical conversion rate was 34.0% (18/53), and 1-year overall survival was 83.0% without critical complicating diseases or adverse events (AEs). CONCLUSION: The regimen of HAIC of FOLFOX, targeted therapy, and immunotherapy was curative for patients with unresectable HCC, with no serious AEs and a high rate of surgical conversion.

Design, Synthesis, and Fungicidal Activities of Novel N-(Pyrazol-5-yl)benzamide Derivatives Containing a Diphenylamine Moiety.

To accelerate the development of novel fungicides, a variety of N-(pyrazol-5-yl)benzamide derivatives with a diphenylamine moiety were designed and synthesized using a pharmacophore recombination strategy based on the structure of pyrazol-5-yl-aminophenyl-benzamides. The bioassay results demonstrated that most of the target compounds had excellent in vitro antifungal activities against Sclerotinia sclerotiorum, Valsa mali, and Botrytis cinerea. In particular, compound 5IIIh exhibited remarkable activity against S. sclerotiorum (EC50 = 0.37 mg/L), which was similar to that of fluxapyroxad (EC50 = 0.27 mg/L). In addition, compound 5IIIc (EC50 = 1.32 mg/L) was observed to be more effective against V. mali than fluxapyroxad (EC50 = 12.8 mg/L) and comparable to trifloxystrobin (EC50 = 1.62 mg/L). Furthermore, compound 5IIIh demonstrated remarkable in vivo protective antifungal properties against S. sclerotiorum, with an inhibition rate of 96.8% at 100 mg/L, which was close to that of fluxapyroxad (99.6%). Compounds 5IIIc (66.7%) and 5IIIh (62.9%) exhibited good in vivo antifungal effects against V. mali at 100 mg/L, which were superior to that of fluxapyroxad (11.1%) but lower than that of trifloxystrobin (88.9%). The succinate dehydrogenase (SDH) enzymatic inhibition assay was conducted to confirm the mechanism of action. Molecular docking analysis further revealed that compound 5IIIh has significant hydrogen-bonding, π-π, and p-π conjugation interactions with ARG 43, SER 39, TRP 173, and TYR 58 in the binding site of SDH, and the binding mode was similar to that of the commercial fungicide fluxapyroxad. All of the results suggest that compound 5IIIh could be a potential SDH inhibitor, offering a valuable reference for future studies.

C-arm CT guided percutaneous vertebroplasty for pain release in cancer patient with cervical 1 vertebral metastases: A case report.

OBJECTIVE: To evaluate the efficacy and treatment outcome of C-arm CT percutaneous vertebroplasty in the treatment of cervical 1 (C1) vertebral metastases. METHODS: This report recruited a male patient diagnosed with hepatocellular carcinoma and C1 vertebral metastases, who had suffered from severe neck pain symptoms and the analgesic showed little soothing effect. Under the guidance of C-arm CT, an 18G coaxial needle was used to puncture the left lateral mass of C1 vertebral metastases from lateral space between thyroid cartilage and the left carotid sheath, with 2 ml bone cement injected. RESULTS: Postoperative C-arm CT three-dimensional reconstruction scan showed that the bone cement was well filled and distributed in the left lateral mass of C1 vertebral body, and no leakage of bone cement was observed. The neck pain of the patients was significantly relieved one week after the operation. CONCLUSION: Under the guidance of C-arm CT, cement augmentation using percutaneous vertebroplasty in an anterior cervical direction could serve as a safe and effective pain relief approach for patients with C1 vertebral metastases.

Discovery of Novel Pyrazol-5-yl-benzamide Derivatives Containing a Thiocyanato Group as Broad-Spectrum Fungicidal Candidates.

In an effort to promote the development of new fungicides, a series of 48 novel N-(1-methyl-4-thiocyanato-1H-pyrazol-5-yl)-benzamide derivatives A1-A36 and B1-B12 were designed and synthesized by incorporating a thiocyanato group into the pyrazole ring, and their fungicidal activities were evaluated against Sclerotinia sclerotiorum, Valsa mali, Botrytis cinerea, Rhizoctonia solani, and Phytophthora capsici. In the in vitro antifungal/antioomycete assay, many of the target compounds exhibited good broad-spectrum fungicidal activities. Among them, compound A36 displayed the best antifungal activity against V. mali with an EC50 value of 0.37 mg/L, which was significantly higher than that of the positive controls fluxapyroxad (13.3 mg/L) and dimethomorph (10.3 mg/L). Meanwhile, compound B6 exhibited the best antioomycete activity against P. capsici with an EC50 value of 0.41 mg/L, which was higher than that of azoxystrobin (29.2 mg/L) but lower than that of dimethomorph (0.13 mg/L). Notably, compound A27 displayed broad-spectrum inhibitory activities against V. mali, B. cinerea, R. solani, S. sclerotiorum, and P. capsici with respective EC50 values of 0.71, 1.44, 1.78, 0.87, and 1.61 mg/L. The in vivo experiments revealed that compounds A27 and B6 presented excellent protective and curative efficacies against P. capsici, similar to that of the positive control dimethomorph. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) analyses showed that compound B6 could change the mycelial morphology and severely damage the ultrastructure of P. capsici. The results of the in vitro SDH enzymatic inhibition experiments indicated that compounds A27 and B6 could effectively inhibit the activity of P. capsici SDH (PcSDH). Furthermore, molecular docking analysis demonstrated significant hydrogen bonds and Pi-S bonding between the target compounds and the key amino acid residues of PcSDH, which could explain the probable mechanism of action. Collectively, these studies provide a valuable approach to expanding the fungicidal spectrum of pyrazol-5-yl-benzamide derivatives.

Discovery of novel salicylaldehyde derivatives incorporating an α-methylene-γ-butyrolactone moiety as fungicidal agents.

BACKGROUND: Plant diseases caused by phytopathogenic fungi and oomycetes pose a serious threat to ensuring crop yield and quality. Finding novel fungicidal candidates based on natural products is one of the critical methods for developing effective and environmentally friendly pesticides. In this study, a series of salicylaldehyde derivatives containing an α-methylene-γ-butyrolactone moiety were designed, synthesized, and their fungicidal activities were evaluated. RESULTS: The bioassay studies indicated that compound C3 displayed an excellent in vitro activity against Rhizoctonia solani with a half-maximal effective concentration (EC50 ) value of 0.65 µg/mL, higher than that of pyraclostrobin (EC50 = 1.44 µg/mL) and comparable to that of carbendazim (EC50 = 0.33 µg/mL). For Valsa mali and Phytophthora capsici, compound C3 also showed good fungicidal activities with EC50 values of 0.91 and 1.33 µg/mL, respectively. In addition, compound C3 exhibited promising protective in vivo activity against R. solani (84.1%) at 100 µg/mL, which was better than that of pyraclostrobin (78.4%). The pot experiment displayed that compound C3 had 74.8% protective efficacy against R. solani at 200 µg/mL, which was comparable to that of validamycin (78.2%). The antifungal mode of action research indicated that compound C3 could change the mycelial morphology and ultrastructure, increase cell membrane permeability, affect respiratory metabolism by binding to complex III, and inhibit the germination and formation of sclerotia, thereby effectively controlling the disease. CONCLUSION: The present study provides support for the application of these salicylaldehyde derivatives as promising potential pesticides with remarkable and broad-spectrum fungicidal activities against phytopathogenic fungi and oomycetes in crop protection. © 2023 Society of Chemical Industry.

Furofuran Lignans for Plant Protection: Discovery of Sesamolin and Its Derivatives as Novel Anti-Tobacco Mosaic Virus and Antibacterial Agents.

Natural products have been a valuable source of efficient and low-risk pesticides. In this work, a series of novel sesamolin derivatives A0-A31 and B0-B4 were designed and synthesized via structural simplification of furofuran lignan phrymarolin II, and their antiviral and antibacterial activities were systematically evaluated. The bioassay results showed that compound A24 displayed remarkable inactivation activity against tobacco mosaic virus (TMV) with an EC50 value of 130.4 µg/mL, which was superior to that of commercial ningnanmycin (EC50 = 202.0 µg/mL). The antiviral mode of action assays suggested that compound A24 may obstruct self-assembly by binding to TMV coat protein (CP), thus resisting the TMV infection. In addition, compound A25 possessed prominent antibacterial activities, especially against Ralstonia solanacearum with an EC50 value of 43.8 µg/mL, which is better than those of commercial bismerthiazol and thiodiazole copper. This research lays a solid foundation for the utilization of furofuran lignans in crop protection.

[Effects of total ginsenosides from Panax ginseng stems and leaves on gut microbiota and short-chain fatty acids metabolism in acute lung injury mice].

This study aimed to investigate the biological effects and underlying mechanisms of the total ginsenosides from Panax ginseng stems and leaves on lipopolysaccharide(LPS)-induced acute lung injury(ALI) in mice. Sixty male C57BL/6J mice were randomly divided into a control group, a model group, the total ginsenosides from P. ginseng stems and leaves normal administration group(61.65 mg·kg~(-1)), and low-, medium-, and high-dose total ginsenosides from P. ginseng stems and leaves groups(15.412 5, 30.825, and 61.65 mg·kg~(-1)). Mice were administered for seven continuous days before modeling. Twenty-four hours after modeling, mice were sacrificed to obtain lung tissues and calculate lung wet/dry ratio. The number of inflammatory cells in bronchoalveolar lavage fluid(BALF) was detected. The levels of interleukin-1ß(IL-1ß), interleukin-6(IL-6), and tumor necrosis factor-α(TNF-α) in BALF were detected. The mRNA expression levels of IL-1ß, IL-6, and TNF-α, and the levels of myeloperoxidase(MPO), glutathione peroxidase(GSH-Px), superoxide dismutase(SOD), and malondialdehyde(MDA) in lung tissues were determined. Hematoxylin-eosin(HE) staining was used to observe the pathological changes in lung tissues. The gut microbiota was detected by 16S rRNA sequencing, and gas chromatography-mass spectrometry(GC-MS) was applied to detect the content of short-chain fatty acids(SCFAs) in se-rum. The results showed that the total ginsenosides from P. ginseng stems and leaves could reduce lung index, lung wet/dry ratio, and lung damage in LPS-induced ALI mice, decrease the number of inflammatory cells and levels of inflammatory factors in BALF, inhibit the mRNA expression levels of inflammatory factors and levels of MPO and MDA in lung tissues, and potentiate the activity of GSH-Px and SOD in lung tissues. Furthermore, they could also reverse the gut microbiota disorder, restore the diversity of gut microbiota, increase the relative abundance of Lachnospiraceae and Muribaculaceae, decrease the relative abundance of Prevotellaceae, and enhance the content of SCFAs(acetic acid, propionic acid, and butyric acid) in serum. This study suggested that the total ginsenosides from P. ginseng stems and leaves could improve lung edema, inflammatory response, and oxidative stress in ALI mice by regulating gut microbiota and SCFAs metabolism.

Tricrilactones A-H, Potent Antiosteoporosis Macrolides with Distinctive Ring Skeletons from Trichocladium crispatum, an Alpine Moss-Associated Fungus.

Tricrilactones A-H (1-8), a new family of oligomeric 10-membered macrolides featuring collectively five unique ring skeletons, were isolated from a hitherto unexplored fungus, Trichocladium crispatum. Compounds 1 and 7 contain two unconventional bridged (aza)tricyclic core skeletons, 2, 3, 5, and 6 share an undescribed tetracyclic 9/5/6/6 ring system, 4 bears an uncommon 9/5/6/10/3-fused pentacyclic architecture, and 8 is a dimer bridged by an unexpected C-C linkage. Their structures, including absolute configurations, were elucidated by spectroscopic analysis, quantum chemical calculations, and X-ray diffraction analysis. Importantly, the absolute configuration of the highly flexible side chain of 1 was resolved by the asymmetric synthesis of its four stereoisomers. The intermediate-trapping and isotope labeling experiments facilitated the proposal of the biosynthetic pathway for these macrolides. In addition, their antiosteoporosis effects were evaluated in vivo (zebrafish).

Percutaneous microwave ablation and transcatheter arterial chemoembolization for serum tumor markers and prognostics of middle-late primary hepatic carcinoma.

BACKGROUND: Primary hepatic carcinoma (PHC) has an insidious onset and is usually diagnosed in the middle and late stages. Although transcatheter arterial chemoembolization (TACE) is the preferred option for treating middle- and advanced-stage PHC, it has limited efficacy in killing tumor cells and poor long-term efficacy. TACE plus percutaneous microwave coagulation therapy (PMCT) is more effective than interventional therapy alone and can improve survival time. However, there are few reports on the effects of TACE and PMCT on serum marker levels and the prognosis of patients with advanced PHC. AIM: To investigate the effect of PMCT + TACE on serum tumor markers and the prognosis of middle-late PHC. METHODS: This retrospective study included 150 patients with middle-late PHC admitted to Zhongshan People's Hospital between March 2018 and February 2021. Patients were divided into a single group (treated with TACE, n = 75) and a combined group (treated with TACE + PMCT, n = 75). Before and after treatment, the clinical efficacy and serum tumor marker levels [carbohydrate antigen 19-9 (CA19-9), alpha-fetoprotein (AFP), and carcinoembryonic antigen (CEA)] of both groups were observed. The 1-year survival rates and prognostic factors of the two groups were analyzed. RESULTS: The combined group had 21 and 35 cases of complete remission (CR) and partial remission (PR), respectively. The single group had 13 and 25 cases of CR and PR, respectively. After 4 wk of treatment, the serum CA19-9, CEA, and AFP levels in the single and combined groups decreased, with the decrease in the combined group being more significant (P < 0.05). The 1-year survival rate of the combined group (80.00%) was higher than that of the single group (60.00%) (P < 0.05). The average survival time within 1 year in the combined group was 299.38 ± 61.13 d, longer than that in the single group (214.41 ± 72.97 d, P < 0.05). COX analysis revealed that tumor diameter, tumor number, and the treatment method were prognostic factors for patients with middle-late PHC (P < 0.05). CONCLUSION: TACE + PMCT is effective in treating patients with mid-late PHC. It reduces the levels of tumor markers, prolongs survival, and improves prognosis.

Transition-Metal-Catalyzed Asymmetric Reductive Amination and Amidation Cascade Reaction for the Synthesis of Piperazinones.

An efficient enantioselective reductive amination and amidation cascade reaction has been developed. Catalyzed by iridium or rhodium complexes and with the help of sets of additives, the coupling of simple alkyl diamines and α-ketoesters occurs smoothly to afford the chiral cyclic piperazinone products. For disubstituted and monosubstituted alkyl diamine substrates, the corresponding reactions proceed through distinctive types of intermediates and thus require different transition metals to achieve high enantioselectivity, namely, iridium for the former and rhodium for the latter. In this transformation, the applied highly modular phosphoramidite-phosphine hybrid ligands displayed preeminent versatility and tunability.

Discovery of Novel α-Methylene-γ-Butyrolactone Derivatives Containing Vanillin Moieties as Antiviral and Antifungal Agents.

On the basis of the structure of nicotlactone A (L1), a series of novel α-methylene-γ-butyrolactone derivatives B1-B43 were designed and synthesized by structure simplification and active fragment replacement strategies, and their antiviral and antifungal activities were evaluated. The bioassay studies indicated that many target compounds possessed good to excellent antiviral activity against tobacco mosaic virus (TMV) and some of these compounds exhibited specific antifungal activities against Valsa mali and Fusarium graminearum. Compound B32 exhibited the best anti-TMV activity (inactivation effect, 88.9%; protection effect, 65.8%; curative effect, 52.8%) in vivo at 500 mg/L, which is significantly higher than that of commercial virucides ribavirin and ningnanmycin. The inhibition effect of compound B32 was also visualized by the inoculation test using green fluorescent protein (GFP)-labeled TMV. The preliminary antiviral mechanism of compound B32 was investigated. Transmission electron microscopy (TEM) showed that compound B32 could destroy the integrity of virus particles. Then, molecular docking and isothermal titration calorimetry (ITC) analysis further demonstrated that compound B32 exhibited a strong binding affinity to the TMV coat protein with a dissociation constant (Kd) of 3.06 µM, superior to ribavirin. Thus, we deduced that compound B32 may interfere with the self-assembly of TMV particles by binding TMV coat protein (CP). In addition, compound B28 showed good in vitro activity against F. graminearum with an inhibition rate of 90.9% at 50 mg/L, which was greater than that of fluxapyroxad (59.1%) but lower than that of the commercial fungicide carbendazim (96.8%). The present study provides support for the application of these α-methylene-γ-butyrolactone derivatives as novel antiviral and antifungal agents in crop protection.

Rational Design, Synthesis, and Biological Evaluation of Fluorine- and Chlorine-Substituted Pyrazol-5-yl-benzamide Derivatives as Potential Succinate Dehydrogenase Inhibitors.

To develop novel succinate dehydrogenase inhibitors (SDHIs), two series of novel N-4-fluoro-pyrazol-5-yl-benzamide and N-4-chloro-pyrazol-5-yl-benzamide derivatives were designed and synthesized, and their antifungal activities were evaluated against Valsa mali, Sclerotinia sclerotiorum, FusaHum graminearum Sehw, Physalospora piricola, and Botrytis cinerea. The bioassay results showed that some of the target compounds exhibited good antifungal activities in vitro against V. mali and S. sclerotiorum. Remarkably, compound 9Ip displayed good in vitro activity against V. mali with an EC50 value of 0.58 mg/L. This outcome was 21-fold greater than that of fluxapyroxad (12.45 mg/L) and close to that of the commercial fungicide tebuconazole (EC50 = 0.36 mg/L). In addition, in vivo experiments proved that compound 9Ip has good protective fungicidal activity with an inhibitory rate of 93.2% against V. mali at 50 mg/L, which was equivalent to that of the positive control tebuconazole (95.5%). The results of molecular docking indicated that there were obvious hydrogen bonds and p-π interactions between compound 9Ip and succinate dehydrogenase (SDH), which could explain the probable action mechanism. In addition, the SDH enzymatic inhibition assay was carried out to further prove its mode of action. Our studies suggest that compound 9Ip could be a fungicidal lead to discover more potent SDHIs for crop protection.

Novel N-(1H-Pyrazol-5-yl)nicotinamide Derivatives: Design, Synthesis and Antifungal Activity.

To discover more effective antifungal agents, twenty N-(1H-pyrazol-5-yl)nicotinamide derivatives were designed, synthesized, and structurally confirmed by 1 H-NMR, 13 C-NMR, and ESI-MS. All target compounds were evaluated for their antifungal activities by mycelia growth inhibition. Preliminary screening results displayed that many of these compounds had good fungicidal activity to S. sclerotiorum and V. mali. Compound B4 exhibited antifungal activity against S. sclerotiorum and V. mali with EC50 values of 10.35 and 17.01 mg/L, respectively. The experiment in vivo identified that compound B4 was effective for suppressing rape sclerotinia rot caused by S. sclerotiorum at 50 mg/L. The molecular docking study and scanning electron microscopy preliminary clarified the possible antifungal mechanism of compound B4.

Total Synthesis and Anti-Tobacco Mosaic Virus Activity of the Furofuran Lignan (±)-Phrymarolin II and Its Analogues.

Phrymarolin II, a furofuran lignan isolated from Phryma leptostachya L., features a 3,7-dioxabicyclo[3.3.0]octane skeleton. Herein, we report an alternative total synthesis of (±)-phrymarolin II (2), which was performed in 9 steps from commercially available sesamol. The key steps of the synthesis included a zinc-mediated Barbier-type allylation and a copper-catalyzed anomeric O-arylation. Our total synthesis allowed the synthesis of analogues of (±)-phrymarolin II. Most derivatives displayed good to excellent in vivo activity against tobacco mosaic virus (TMV). (±)-Phrymarolin II (2) and compounds (±)-31d and (±)-31g exhibited similar or higher activity than commercial ningnanmycin, which indicated that phrymarolin lignans are a promising new class of plant virus inhibitors.

Divergent Entry to Walsucochin Nortriterpenoids: Total Syntheses of (±)-Walsucochin A and (±)-Walsucochinoids C-F.

Nortriterpenoids isolated from Walsura cochinchinensis have attracted much attention from both synthetic and medicinal chemists, yet only recently have efficient synthetic approaches to any members appeared. Shown here is that the common intermediate with a 6/6/5/6-fused tetracyclic ring nucleus can be converted to walsucochin family members. The first total syntheses of (±)-walsucochin A, (±)-walsucochinoids C-F, and their analogues were achieved in this work.

Synthesis and Biological Activity of Novel Pyrazol-5-yl-benzamide Derivatives as Potential Succinate Dehydrogenase Inhibitors.

To promote the discovery and development of new fungicides, a series of novel pyrazol-5-yl-benzamide derivatives were designed, synthesized by hopping and inversion of amide groups of pyrazole-4-carboxamides, and evaluated for their antifungal activities. The bioassay data revealed that compound 5IIc exhibited an excellent in vitro activity against Sclerotinia sclerotiorum with an EC50 value of 0.20 mg/L, close to that of commercial fungicide Fluxapyroxad (EC50 = 0.12 mg/L) and Boscalid (EC50 = 0.11 mg/L). For Valsa mali, compound 5IIc (EC50 = 3.68 mg/L) showed a significantly higher activity than Fluxapyroxad (EC50 = 12.67 mg/L) and Boscalid (EC50 = 14.83 mg/L). In addition, in vivo experiments proved that compound 5IIc has an excellent protective fungicidal activity with an inhibitory rate of 97.1% against S. sclerotiorum at 50 mg/L, while the positive control Fluxapyroxad showed a 98.6% inhibitory effect. The molecular docking simulation revealed that compound 5IIc interact with TRP173, SER39, and ARG43 of succinate dehydrogenase (SDH) through a hydrogen bond and p-π interaction, which could explain the probable mechanism of the action between compound 5IIc and target protein. Also, the SDH enzymatic inhibition assay was carried out to further validate its mode of action. These results demonstrate that compound 5IIc could be a promising fungicide candidate and provide a valuable reference for further investigation.

Bioactivity-Guided Synthesis Accelerates the Discovery of 3-(Iso)quinolinyl-4-chromenones as Potent Fungicide Candidates.

Fungal infections could cause tremendous decreases in crop yield and quality. Natural products, including flavonoids and (iso)quinolines, have always been an important source for lead discovery in medicinal and agricultural chemistry. To promote the discovery and development of new fungicides, a series of 3-(iso)quinolinyl-4-chromenone derivatives was designed and synthesized by the active substructure splicing principle and evaluated for their antifungal activities. The lead optimization was guided by bioactivity. The bioassay data revealed that the 3-quinolinyl-4-chromenone 13 showed significant in vitro activities against S. sclerotiorum, V. mali, and B. cinerea with EC50 values of 3.65, 2.61, and 2.32 mg/L, respectively. The 3-isoquinolinyl-4-chromenone 25 exhibited excellent in vitro activity against S. sclerotiorum with an EC50 value of 1.94 mg/L, close to that of commercial fungicide chlorothalonil (EC50 = 1.57 mg/L) but lower than that of boscalid (EC50 = 0.67 mg/L). For V. mali and B. cinerea, 3-isoquinolinyl-4-chromenone 25 (EC50 = 1.56, 1.54 mg/L) showed significantly higher activities than chlorothalonil (EC50 = 11.24, 2.92 mg/L). In addition, in vivo experiments proved that compounds 13 and 25 have excellent protective fungicidal activities with inhibitory rates of 88.24 and 94.12%, respectively, against B. cinerea at 50 mg/L, while the positive controls chlorothalonil and boscalid showed inhibitory rates of 76.47 and 97.06%, respectively. Physiological and biochemical studies showed that the primary action of mechanism of compounds 13 and 25 on S. sclerotiorum and B. cinerea may involve changing mycelial morphology and increasing cell membrane permeability. In addition, compound 13 may also affect the respiratory metabolism of B. cinerea. This study revealed that compounds 13 and 25 could be promising candidates for the development of novel fungicides in crop protection.

Remote C-H Activation Strategy Enables Total Syntheses of Nortriterpenoids (±)-Walsucochin B and (±)-Walsucochinoids M and N.

Total syntheses of (±)-walsucochin B and (±)-walsucochinoids M and N have been achieved from farnesyl bromide. The key steps of the synthetic sequence are the titanocene-mediated radical cyclization and base-induced cycloaromatization for the rapid construction of the 6/6/5/6-fused tetracyclic skeleton. Importantly, a Cu-mediated remote C-H hydroxylation reaction has been developed to site-selectively install the oxygen function at the C-7 position of the target molecules, thus solving the biggest challenge for the synthesis of the compounds.

Programmable meroterpene synthesis.

The bicyclo[3.3.1]nonane architecture is a privileged structural motif found in over 1000 natural products with relevance to neurodegenerative disease, bacterial and parasitic infection, and cancer among others. Despite disparate biosynthetic machinery, alkaloid, terpene, and polyketide-producing organisms have all evolved pathways to incorporate this carbocyclic ring system. Natural products of mixed polyketide/terpenoid origins (meroterpenes) are a particularly rich and important source of biologically active bicyclo[3.3.1]nonane-containing molecules. Herein we detail a fully synthetic strategy toward this broad family of targets based on an abiotic annulation/rearrangement strategy resulting in a 10-step total synthesis of garsubellin A, an enhancer of choline acetyltransferase and member of the large family of polycyclic polyprenylated acylphloroglucinols. This work solidifies a strategy for making multiple, diverse meroterpene chemotypes in a programmable assembly process involving a minimal number of chemical transformations.