Discovery of Novel Diamides Scaffold Containing Monofluoro-acrylamides Activating the Insect Ryanodine Receptor.

The research and development of organofluorine chemistry has flourished; in particular, monofluoroalkene has aroused considerable interest from medicinal and organic chemists. It is a significant attempt to introduce monofluoroalkene into agrochemicals. In this study, monofluoroalkene was introduced into diamide molecules and inserted between the aliphatic amide and benzene ring, and 44 compounds have been successfully synthesized. The bioassay results showed that compounds with monofluoro-acrylamide moiety (Z-isomers) had excellent larvicidal activity against lepidopteran pests at 5 mg·L-1. The LC50 values of compounds B16, B18, and B21 against Mythimna separata were 1.02, 1.32, and 0.78 mg·L-1, respectively. 3D-QSAR analysis including the CoMFA model and the CoMSIA model was conducted to illustrate the contributions of steric, electrostatic, hydrophobic, and hydrogen bond fields on the bioactivity. Moreover, typical symptoms caused by chlorantraniliprole including dehydration, shrinkage, and blackening were also observed on the test larvae treated with monofluoro-acrylamide diamide compounds. M. separata central neurons calcium imaging experiment of compound B18 indicated that the monofluoro-acrylamide diamide compounds were potential insect ryanodine receptor activators. The molecular docking was performed in the CHL binding domain of Plutella xylostella RyR and revealed that the predicted binding mode of compound B21 was slightly different from that of CHL. The MM|GBSA dG Bind values of B21 and CHL with P. xylostella RyR were respectively -85.797 and -95.641 kcal·mol-1. The present work explored the insecticidal properties of a new diamide scaffold containing a monofluoro-acrylamide fragment and extended the application of monofluoroalkene in the agrochemical field.

Anthranilic Diamides Containing Monofluoroalkene Amide Linkers as Potential Insect RyR Activators: Design, Synthesis, Bio-evaluation, and Computational Study.

In order to develop anthranilic diamides with novel chemotypes, a series of anthranilic diamides with acrylamide linkers were designed and synthesized. The results of preliminary bioassays indicated that compounds with a monofluoroalkene amide linker (Z-isomer) exhibited good larvicidal activity against lepidopteran pests. The LC50 values of compound A23 against Mythimna separata and Plutella xylostella were 1.44 and 3.48 mg·L-1, respectively, while those of chlorantraniliprole were 0.08 and 0.06 mg·L-1, respectively. Compound A23 also exhibited the same level of lethal potency against resistant and susceptible strains of Spodoptera frugiperda at 50 mg·L-1. Compound A23 exhibited similar symptoms as chlorantraniliprole in test larvae. Comparative molecular field analysis was conducted to demonstrate the structure-activity relationship. Central neuron calcium imaging experiments indicated that monofluoroalkene compounds were potential ryanodine receptor (RyR) activators and activated calcium channels in both the endoplasmic reticulum and the cell membrane. Molecular docking suggested that A23 had a better binding potency to P. xylostella RyR than chlorantraniliprole. The MM|GBSA dG bind value of A23 with P. xylostella RyR was 117.611 kcal·mol-1. Monofluoroalkene was introduced into anthranilic diamide insecticides for the first time and brought a novel chemotype for insect RyR activators. The feasibility of fluoroalkenes as insecticide fragments was explored.

[Testosterone replacement therapy improves metabolic indexes of the patients with hypogonadism: A meta-analysis].

OBJECTIVE: To systematically evaluate the effect of testosterone replacement therapy (TRT) on metabolic indexes in patients with hypogonadism. METHODS: We searched the databases of CNKI, CBM, Wanfang Data, VIP, PubMed, Medline, Embase and Cochrane Library from the establishment to May 2021 for clinical randomized controlled trials (RCT) on the improvement of metabolic indexes of the patients with hypogonadism treated by TRT. According to the inclusion and excretion criteria, we screened the literature, extracted the data and evaluated the quality of the included RCTs, followed by statistical analysis with the STATA15.1 software. RESULTS: Totally 19 RCTs with 1 553 cases were included. Compared with placebo, TRT effectively reduced the levels of fasting plasma glucose (FPG) and fasting insulin (FINS), improved Homeostatic Model Assessment-insulin resistance (HOMA-IR), decreased total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C), increased the body mass index (BMI), lowered the waist circumference (WC), but elevated the systolic blood pressure (SBP) and diastolic blood pressure (DBP) of the patients. No statistically significant differences were observed in the improvement of glycosylated hemoglobin (HbA1c) and triglyceride (TG) between the TRT-treated patients and placebo controls. The results of Egger's and Begg's tests showed no significant publication bias among the studies. CONCLUSION: TRT can significantly improve metabolic indexes in patients with hypogonadism, though further studies are needed to confirm its long-term efficacy and safety in patients with metabolic disorders.

Design, synthesis, molecular modeling, and biological evaluation of acrylamide derivatives as potent inhibitors of human dihydroorotate dehydrogenase for the treatment of rheumatoid arthritis.

Human dihydroorotate dehydrogenase (DHODH) is a viable target for the development of therapeutics to treat cancer and immunological diseases, such as rheumatoid arthritis (RA), psoriasis and multiple sclerosis (MS). Herein, a series of acrylamide-based novel DHODH inhibitors as potential RA treatment agents were designed and synthesized. 2-Acrylamidobenzoic acid analog 11 was identified as the lead compound for structure-activity relationship (SAR) studies. The replacement of the phenyl group with naphthyl moieties improved inhibitory activity significantly to double-digit nanomolar range. Further structure optimization revealed that an acrylamide with small hydrophobic groups (Me, Cl or Br) at the 2-position was preferred. Moreover, adding a fluoro atom at the 5-position of the benzoic acid enhanced the potency. The optimization efforts led to potent compounds 42 and 53‒55 with IC50 values of 41, 44, 32, and 42 nmol/L, respectively. The most potent compound 54 also displayed favorable pharmacokinetic (PK) profiles and encouraging in vivo anti-arthritic effects in a dose-dependent manner.

Structural Optimization and Structure-Activity Relationship of 4-Thiazolidinone Derivatives as Novel Inhibitors of Human Dihydroorotate Dehydrogenase.

Human dihydroorotate dehydrogenase (hDHODH), one of the attractive targets for the development of immunosuppressive drugs, is also a potential target of anticancer drugs and anti-leukemic drugs. The development of promising hDHODH inhibitors is in high demand. Based on the unique binding mode of our previous reported 4-thiazolidinone derivatives, via molecular docking method, three new series 4-thiazolidinone derivatives were designed and synthesized as hDHODH inhibitors. The preliminary structure-activity relationship was investigated. Compound 9 of biphenyl series and compound 37 of amide series displayed IC50 values of 1.32 µM and 1.45 µM, respectively. This research will provide valuable reference for the research of new structures of hDHODH inhibitors.

[Transurethral holmium laser enucleation of the prostate combined with Jisheng Shenqi Decoction for benign prostatic hyperplasia].

OBJECTIVE: To assess the clinical effects of transurethral holmium laser enucleation of the prostate (HoLEP) combined with Jisheng Shenqi Decoction (HoLEP + JSSD) on BPH. METHODS: This study included 110 BPH patients treated in our hospital from August 2017 to April 2018, who were randomly assigned to receive HoLEP (n = 55) or HoLEP + JSSD (n = 55). We compared the pre- and post-operative IPSS, quality of life (QOL) score, prostate volume, postvoid residual urine volume (PVR), maximum urinary flow rate (Qmax), average urinary flow rate (Qavg) and levels of serum T, E2 and T/E2 as well as postoperative complications between the two groups of patients. RESULTS: After treatment, both IPSS and QOL score were significantly lower in the HoLEP + JSSD than in the HoLEP group (P < 0.05), and so were the prostate volume and PVR (P < 0.05). The Qmax, Qavg and serum T level were significantly higher (P < 0.05) while T/E2 markedly lower in the former than in the latter group (P < 0.05). There were no statistically significant differences between the HoLEP + JSSD and HoLEP groups in the E2 level (P > 0.05) or the total incidence rate of complications postoperatively (21.82% vs 29.09%, P > 0.05). CONCLUSIONS: HoLEP + JSSD can significantly alleviate the lower urinary tract symptoms as well as improve the QOL and bladder and urinary tract functions of BPH patients.

Fabrication and characterization of ß-cypermethrin-loaded PLA microcapsules prepared by emulsion-solvent evaporation: loading and release properties.

Microcapsulses can be designed to effectively encapsulate, protect, and control the release of pesticides. In this study, emulsion-solvent evaporation method was used to fabricate microcapsules using dichloromethane as the solvent, polylactic acid (PLA) as the carrier materials, poly(vinyl alcohol) as the emulsifier, and ß-cypermethrin as the entrapped pesticide. The effects of process parameters on the microcapsules characteristics (size, loading content, and encapsulation efficiency) were investigated. Also, the release behavior of the ß-cypermethrin was measured experimentally and modeled mathematically. Kinetic analysis indicated that release mechanism of ß-cypermethrin was compatible to Fickian diffusion. By optimizing the process parameters, ß-cypermethrin-loaded microcapsules were successfully produced with spherical shape, smooth surface, high encapsulation efficiency (> 80%), and a range of pesticide contents. These parameters could be adjusted to achieve delivery systems with desirable release profiles. The results are beneficial to develop delivery systems for rational and effective usage of pesticides.

[Anticancer activity of Luteolin and its synergism effect with BCG on human bladder cancer cell line BIU-87].

OBJECTIVE: To investigate the anticancer activity of Luteolin (Lu) and its synergism effect with bacillus calmette-guerin (BCG) on human bladder cancer cell line BIU-87. METHODS: Cultured BIU-87 cells were treated with different concentrations of Lu alone or the combination of Lu with BCG. MTT assay was used to measure the cell proliferation inhibition, and IC50 was calculated. Cell cycle and apoptosis were analyzed by flow cytometry with propidium iodide (PI) staining and Annexin-V FITC/PI dual parameter markers to clarify the mechanism of inhibiting cell proliferation and inducing apoptosis. Caspase-3 and phosphorylated c-Jun N-terminal kinases (P-JNK) expression were measured to detect the apoptosis signal pathways of Lu in cancer cells. RESULTS: Both Lu and BCG apparently inhibited the cell proliferation and induced the apoptosis dose-dependently, and microscope observation showed morphological changes in the apoptosis. Flow cytometry indicated that Lu arrested the cell cycle at G2 phase (P<0.05). It sensitized BCG-induced cytotoxicity and cell apoptosis, and upregulated expression of caspase-3 and activation of JNK (P<0.05). CONCLUSION: As an effective anticancer agent, Lu can sensitize the effect of BCG by inducing the cell cycle arrest and apoptosis. This synergism effect is achieved by activation of caspase-3 and JNK. Combination of Lu with BCG may be one of the potential treatment for bladder cancer.

[Combined use of TUVP and TURP for prostate cancer with bladder outlet obstruction].

OBJECTIVE: To investigate a new surgical method for the treatment of prostate cancer with bladder outlet obstruction. METHODS: Forty-seven patients with prostate cancer complicated with bladder outlet obstruction were treated by combined use of transurethral electrovaporization ablation of the prostate (TUVP) and transurethral resection of the prostate (TURP). RESULTS: The operations were successful, with satisfactory results and no serious complication. IPSS decreased from (26.5 +/- 4.8) pre-operatively to (8.5 +/- 2.2) post-operatively (P < 0.05); Qmax increased from (4.6 +/- 1.5) ml/s to (14.5 +/- 3.6) ml/s (P < 0.05); and PSA decreased from (58.1 +/- 7.2) microg/L to (3.6 +/- 1.8) microg/L (P < 0.01). CONCLUSION: The combined use of TUVP and TURP is a safe and ideal method for the treatment of prostate cancer with bladder outlet obstruction.

[Combined use of TUVP and TURP for treating BPH (report of 179 cases)].

OBJECTIVE: To investigate a new operation method for the treatment of benign prostate hyperplasia(BPH). METHODS: One hundred and seventy-nine patients with BPH were treated by the combined use of transurethral electrovaporization ablation of the prostate(TUVP) and transurethral resection of the prostate(TURP). RESULTS: The procedure was successful and the results were satisfactory, with little bleeding and no serious complication. IPSS decreased from 29.0 preoperatively to 7.6 postoperatively (P < 0.05) and Qmax increased from 5.8 ml/s preoperatively to 14.8 ml/s postoperatively(P < 0.05). CONCLUSIONS: The combined use of TUVP and TURP is a safe, effective and ideal method for the treatment of BPH.