Design, Synthesis and Cytotoxicity Evalufation of Substituted Benzimidazole Conjugated 1,3,4-Oxadiazoles.

Two series of 2-substituted benzimidazole conjugated 1,3,4-oxadiazole derivatives were designed, synthesized and evaluated for their cytotoxic activities against the three human cancer cell lines (cervical cancer (HeLa), breast cancer (MCF-7) and lung cancer (A549)). As the results 14 compounds demonstrated consistent to stronger cytotoxicities compared to the control 5-fluorouracil (5-FU) towards the tested cell lines including 4c (HeLa); 4b, 4e, 4h, 7i-j, 7m-n, 7s (MCF-7); 7b (MCF-7, A549); 7h (HeLa, MCF-7); and 4d, 4i, 7c (HeLa, MCF-7, A549), with the IC50 ranging from 2.7 to 38 µM. Notably, compound 4b illustrated almost 5-fold activity against the MCF-7 while 4d, 4i were 9- and 8-fold (HeLa), 4.5- and 13-fold (MCF-7), 4.7- and 4-fold (A549) increase in activity compared to 5-FU, respectively, and were found as lead compounds. These findings suggest that compounds 4b, 4d and 4i merit further characterization and can serve as promising scaffolds in the discovery of new potent anticancer agents.

Synthesis of (3S,4S)-4-aminopyrrolidine-3-ol derivatives and biological evaluation for their BACE1 inhibitory activities.

Synthesis, SAR study and BACE1 inhibitory activity of (3S,4S)-4-aminopyrrolidine-3-ol derivatives (2) were described. The compound 7c exhibited more inhibition activity than 11a (IC50: 0.05µM vs 0.12µM, respectively), but the latter was more effective in cell-based assay (IC50: 1.7µM vs 40% inhibition by 7c @ 10µM) due to the relatively higher cell permeability. Most of the compounds showed high selectivity over BACE2 and cathepsin D. This work will provide useful information for further structural modifications to develop potent BACE1 inhibitors in cell.

Extracting lignin from sugarcane bagasse for methylene blue and hexavalent chromium adsorption in textile wastewater: a facile, green, and sustainable approach.

This study presents the process of extracting lignin from sugarcane bagasse collected in the Mekong Delta, Vietnam by the alkali method. NaOH has been used as an effective, environmentally friendly chemical to enhance the extraction process. The obtained lignin was applied for methylene blue (MB) and hexavalent chromium (Cr(vi)) removal. Factors influencing lignin extraction and adsorption processes of MB and Cr(vi) were investigated, showcasing the sustainable reusability of lignin extracted from sugarcane bagasse. Lignin characterization was also carried out by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR) and thermogravimetric analysis (TGA) techniques. The results showed that the extracted lignin content reached 38.61% under optimal conditions (NaOH concentration of 10%, reaction temperature of 90 °C and reaction time of 90 min). The adsorption efficiency and capacity of lignin reached 90.90% and 9.09 mg g-1 for MB and 80.10% and 28.04 mg g-1 for Cr(vi), respectively, under optimum adsorption conditions (pH, adsorption time, initial methylene blue concentration, and used lignin content). The adsorption process obeyed Langmuir adsorption and was principally physical adsorption. These findings prove sugarcane bagasse based lignin as a cheap and efficient adsorbent for MB and Cr(vi) removal, which contributes to the utilization of the abundant agricultural by-product for wastewater treatment.

Protective effect of TPP-Niacin on microgravity-induced oxidative stress and mitochondrial dysfunction of retinal epithelial cells.

Adverse effects of spaceflight on the human body are attritubuted to microgravity and space radiation. One of the most sensitive organs affected by them is the eye, particularly the retina. The conditions that astronauts suffer, such as visual acuity, is collectively called a spaceflight-associated neuro-ocular syndrome (SANS); however, the underlying molecular mechanism of the microgravity-induced ocular pathogenesis is not clearly understood. The current study explored how microgravity affects the retina function in ARPE19 cells in vitro under time-averaged simulated microgravity (µG) generated by clinostat. We found multicellular spheroid (MCS) formation and a significantly decreased cell migration potency under µG conditions compared to 1G in ARPE19 cells. We also observed that µG increases intracellular reactive oxygen species (ROS) and causes mitochondrial dysfunction in ARPE19 cells. Subsequently, we showed that µG activates autophagic pathways and ciliogenesis. Furthermore, we demonstrated that mitophagy activation is triggered via the mTOR-ULK1-BNIP3 signaling axis. Finally, we validated the effectiveness of TPP-Niacin in mitigating µG-induced oxidative stress and mitochondrial dysfunction in vitro, which provides the first experimental evidence for TPP-Niacin as a potential therapeutic agent to ameliorate the cellular phenotypes caused by µG in ARPE19 cells. Further investigations are, however, required to determine its physiological functions and biological efficacies in primary human retinal cells, in vivo models, and target identification.

Desmodinosides A-E: New Flavonoid C-glycosides from Desmodium heterocarpon var. stigosum with hepatoprotective and antifungal activity.

Five new flavonoid C-glycosides named desmodinosides A-E (1-5) and one known compound, apigenin 6-C-ß-d-xylopyranosyl-2''-O-ß-D-glucopyranoside (6) have been isolated from the methanol extract of the aerial parts of Desmodium heterocarpon var. stigosum. These compounds were determined by 1D and 2D-NMR and HR-MS spectroscopies. The methanol extract of this plant, in particular, demonstrated hepatoprotection and antifungal inhibition. This extract has a remarkable hepatoprotection and activity-dose response with an EC50 of 43.07 µg/mL. The hepatoprotective effect on human liver hepatoma cells (HepG2) of the isolated flavonoid C-glycosides 1-6 was observed. Desmodinosides A-C (1-3) were found to exhibit moderate hepatoprotective activity on HepG2 cells. Of these, compound 2 showed the best hepatoprotective activity with an EC50 value of 74.12 µg/mL. While compounds 1 and 3 displayed EC50 values of 271.21 and 211.99 µg/mL, respectively. Quercetin, a positive control, also caused an EC50 value of 36.42 µg/mL. In addition to having hepatoprotective effect, the methanol extract had an inhibitory effect on the growth of oomycete; it inhibited Phytophthora infestans with IC50 of 13.3 µg/mL and IC90 of 78.7 µg/mL. The oomycete inhibition was directly attributed to compounds 5 and 6, which significantly inhibited P. infestans with IC50 values of 27.4 and 24.7 µg/mL, respectively. Both 5 and 6 and methanol extract were active against P. infestanse in a dose-dependent manner. Our study demonstrated for the first time the new flavonoid C-glycosides from D. heterocarpon var. stigosum and their novel pharmacological properties. The study findings also suggest the plant extract and its metabolites could be used as a new botanical source of bioactive compounds.

A novel IRAK4/PIM1 inhibitor ameliorates rheumatoid arthritis and lymphoid malignancy by blocking the TLR/MYD88-mediated NF-κB pathway.

Interleukin-1 receptor-associated kinase 4 (IRAK4) is a pivotal enzyme in the Toll-like receptor (TLR)/MYD88 dependent signaling pathway, which is highly activated in rheumatoid arthritis tissues and activated B cell-like diffuse large B-cell lymphoma (ABC-DLBCL). Inflammatory responses followed by IRAK4 activation promote B-cell proliferation and aggressiveness of lymphoma. Moreover, proviral integration site for Moloney murine leukemia virus 1 (PIM1) functions as an anti-apoptotic kinase in propagation of ABC-DLBCL with ibrutinib resistance. We developed a dual IRAK4/PIM1 inhibitor KIC-0101 that potently suppresses the NF-κB pathway and proinflammatory cytokine induction in vitro and in vivo. In rheumatoid arthritis mouse models, treatment with KIC-0101 significantly ameliorated cartilage damage and inflammation. KIC-0101 inhibited the nuclear translocation of NF-κB and activation of JAK/STAT pathway in ABC-DLBCLs. In addition, KIC-0101 exhibited an anti-tumor effect on ibrutinib-resistant cells by synergistic dual suppression of TLR/MYD88-mediated NF-κB pathway and PIM1 kinase. Our results suggest that KIC-0101 is a promising drug candidate for autoimmune diseases and ibrutinib-resistant B-cell lymphomas.

ZIKV Inhibitors Based on Pyrazolo[3,4-d]pyridazine-7-one Core: Rational Design, In Vitro Evaluation, and Theoretical Studies.

The Zika virus (ZIKV) is believed to cause birth defects, and no anti-ZIKV drugs have been approved by medical organizations to date. Starting from antimicrobial lead compounds with a pyrazolo[3,4-d]pyridazine-7-one scaffold, we synthesized 16 derivatives and screened their ability to interfere with ZIKV infection utilizing a cell-based phenotypic assay. Of these, five compounds showed significant inhibition of ZIKV with a selective index value greater than 4.6. In particular, compound 9b showed the best anti-ZIKV activity with a selectivity index of 22.4 (half-maximal effective concentration = 25.6 µM and 50% cytotoxic concentration = 572.4 µM). Through the brine shrimp lethality bioassay, 9b, 10b, 12, 17a, and 19a showed median lethal dose values in a range of 87.2-100.3 µg/mL. Compound 9b was also targeted to the NS2B-NS3 protease of ZIKV using molecular docking protocols, in which it acted as a noncompetitive inhibitor and strongly bound to five key amino acids (His51, Asp75, Ser135, Ala132, Tyr161). Utilizing the pharmacophore model of 9b, the top 20 hits were identified as prospective inhibitors of NS2B-NS3 protease, and six of them were confirmed for their stability with the protease via redocking and molecular dynamics simulations.

Benzimidazole Derivatives as Novel Zika Virus Inhibitors.

We have synthesized 50 benzimidazole (BMZ) derivatives with 1,2-phenylenediamines and aromatic aldehydes under mild oxidation conditions by using inexpensive, nontoxic inorganic salt sodium metabisulfite in a one-pot condensation reaction and screened their ability to interfere with Zika virus (ZIKV) infection utilizing a cell-based phenotypic assay. Seven BMZs inhibited an African ZIKV strain with a selectivity index (SI=CC50 /EC50 ) of 9-37. Structure-activity relationship analysis demonstrated that substitution at the C-2, N-1, and C-5 positions of the BMZ ring were important for anti-ZIKV activity. The hybrid structure of BMZ and naphthalene rings was a structural feature responsible for the high anti-ZIKV activity. Importantly, BMZs inhibited ZIKV in human neural stem cells, a physiologically relevant system considering the severe congenital anomalies, like microcephaly, caused by ZIKV infection. Compound 39 displayed the highest antiviral efficacy against the African ZIKV strain in Huh-7 (SI>37) and neural stem cells (SI=12). Compound 35 possessed the highest activity in Vero cells (SI=115). Together, our data indicate that BMZs derivatives have to be considered for the development of ZIKV therapeutic interventions.

Suppression of NFAT5-mediated Inflammation and Chronic Arthritis by Novel κB-binding Inhibitors.

Nuclear factor of activated T cells 5 (NFAT5) has been implicated in the pathogenesis of various human diseases, including cancer and arthritis. However, therapeutic agents inhibiting NFAT5 activity are currently unavailable. To discover NFAT5 inhibitors, a library of >40,000 chemicals was screened for the suppression of nitric oxide, a direct target regulated by NFAT5 activity, through high-throughput screening. We validated the anti-NFAT5 activity of 198 primary hit compounds using an NFAT5-dependent reporter assay and identified the novel NFAT5 suppressor KRN2, 13-(2-fluoro)-benzylberberine, and its derivative KRN5. KRN2 inhibited NFAT5 upregulation in macrophages stimulated with lipopolysaccharide and repressed the formation of NF-κB p65-DNA complexes in the NFAT5 promoter region. Interestingly, KRN2 selectively suppressed the expression of pro-inflammatory genes, including Nos2 and Il6, without hampering high-salt-induced NFAT5 and its target gene expressions. Moreover, KRN2 and KRN5, the latter of which exhibits high oral bioavailability and metabolic stability, ameliorated experimentally induced arthritis in mice without serious adverse effects, decreasing pro-inflammatory cytokine production. Particularly, orally administered KRN5 was stronger in suppressing arthritis than methotrexate, a commonly used anti-rheumatic drug, displaying better potency and safety than its original compound, berberine. Therefore, KRN2 and KRN5 can be potential therapeutic agents in the treatment of chronic arthritis.