Novel benzothiazole-pyrazoline-styrene hybrid for ultrasensitive detection of Hg(II) ions: Synthesis and chemosensor evaluation.

Water pollution has become a serious issue, and mercury(II) ion (Hg(II)) is highly toxic even at low concentrations. Therefore, Hg(II) concentration should be strictly monitored. This study evaluated pyrazoline compounds as fluorescence chemosensor agents for Hg(II) detection. These compounds were prepared from vanillin via etherification, Claisen-Schmidt, and cyclocondensation reactions, to yield benzothiazole-pyrazoline-styrene hybrid compounds. The hybrid compound without styrene was successfully synthesized in 97.70% yield with limit of detection (LoD) and limit of quantification (LoQ) values of 323.5 and 1078 µM, respectively. Conversely, the hybrid compound was produced in 97.29% yield with the LoD and LoQ values of 8.94 and 29.79 nM, respectively. Further spectroscopic investigations revealed that Hg(II) ions can either chelate with three nitrogen of pyridine, pyrazoline, and benzothiazole structures or two oxygen of vanillin and styrene. Furthermore, the hybrid compound was successfully applied in the direct quantification of Hg(II) ions in tap and underground water samples with a validity of 91.63% and 86.08%, respectively, compared with mercury analyzer measurement. The regeneration of pyrazoline was also easily achieved via the addition of an ethylenediaminetetraacetic acid solution. These findings show the promising application of the benzothiazole-pyrazoline-styrene hybrid compound for Hg(II) monitoring in real environmental samples.

N-phenyl pyrazoline derivative inhibits cell aggressiveness and enhances paclitaxel sensitivity of triple negative breast cancer cells.

Protein kinase dysregulation induces cancer cell aggressiveness leading to rapid tumor progression and poor prognosis in TNBC patients. Many small-molecule kinase inhibitors have been tested in clinical trials to treat TNBC patients. In the previous study, we found that N-phenylpyrazoline small molecule acts as a protein kinase inhibitor in cervical cancer cells. However, there remains unknown about N-phenyl pyrazoline potency as a kinase inhibitor and its anti-cancer activity in TNBC cells. In this study, we investigated the activity of N-phenyl pyrazoline against TNBC cells via tyrosine kinase inhibition. Based on the MTT assay, the IC50 values for the N-phenyl pyrazoline 2, 5, A, B, C, and D against Hs578T were 12.63 µM, 3.95 µM, not available, 18.62 µM, 30.13 µM, and 26.79 µM, respectively. While only P5 exhibited the IC50 against MDA MB 231 (21.55 µM). Further, N-phenyl pyrazoline 5 treatment significantly inhibited the cell proliferation rate of Hs578T and MDA MB 231 cells. The migration assay showed that treatment with the compound N-phenyl pyrazoline 5 with 4 µM concentration significantly reduced cell migration of Hs578T cells. N-phenyl pyrazoline 5 treatment at 1 µM and 2 µM was able to reduce the tumorsphere size of Hs578t cells. A combination treatment of P5 and paclitaxel showed a synergistic effect with a combination index score > 1 in both TNBC cells. Further, the P5 predictively targeted the protein kinases that significantly correlated to breast cancer prognosis. The GSEA analysis result shows that receptor tyrosine kinase, Notch3, Notch4, and Ephrin signaling pathways were targeted by P5. The P5 treatment reduced the EGFR expression level and activation in TNBC cells.

Pyrazoline B-Paclitaxel or Doxorubicin Combination Drugs Show Synergistic Activity Against Cancer Cells: In silico Study.

Background: Multidrug resistance in various cancer types is a major obstacle in cancer treatment. The concept of a single drug molecular target often causes treatment failure due to the complexity of the cellular processes. Therefore, combination chemotherapy, in which two or more anticancer drugs are co-administered, can overcome this problem because it potentially have synergistic efficacy besides reducing resistance, and drug doses. Previously, we reported that pyrazoline B had promising anticancer activity in both in silico and in vitro studies. To increase the efficacy of this drug, co-administration with established anticancer drugs such as doxorubicin and paclitaxel is necessary. Materials and Methods: In this study, we used an in silico approach to predict the synergistic effect of pyrazoline B with paclitaxel or doxorubicin using various computational frameworks and compared the results with those of an established study on the combination of doxorubicin-cyclophosphamide and paclitaxel-ascorbic acid. Results and Discussion: Drug interaction analysis showed the combination was safe with no contraindications or side effects. Furthermore, molecular docking studies revealed that doxorubicin-pyrazoline B and doxorubicin-cyclophosphamide may synergistically inhibit cancer cell proliferation by inhibiting the binding of topoisomerase I to the DNA chain. Moreover, the combination of pyrazoline B-paclitaxel may has synergistic activity to cause apoptosis by inhibiting Bcl2 binding to the Bax fragment or inhibiting cell division by inhibiting α-ß tubulin disintegration. Paclitaxel-ascorbic acid had a synergistic effect on the inhibition of α-ß tubulin disintegration. Conclusion: The results show that this combination is promising for further in vitro and in vivo studies.

Towards targeting EGFR and COX-2 inhibitors: comprehensive computational studies on the role of chlorine group in novel thienyl-pyrazoline derivative.

To enhance the effectiveness of chemotherapy and overcome resistance, scientists must develop novel drugs or scaffolds that have a combined effect, such as the inhibition of EGFR and COX-2. This research employed virtual screening techniques, such as docking, and dynamics simulation, to predict chlorinated thienyl-pyrazoline derivatives that inhibit these proteins. The study proposed eleven (11) ligands with binding energies ranging from -7.8 kcal/mol to -8.7 kcal/mol for EGFR and -6.4 kcal/mol to -8.4 kcal/mol for COX-2. Ligands P1 and P11 exhibited the highest binding affinity for both proteins. The results of RMSD, RMSF, RoG, SASA the number of hydrogen bonds, and BAR free binding energy demonstrated the good stability of ligands P1 and P11 when binding to both proteins over 180 ns simulations. In addition, the absorption, distribution, metabolism, excretion, and toxicity properties of the selected ligands were assessed to predict their toxicity and drug likeliness. Based on the results, these compounds can be proposed for further synthesis and in vitro studies.Communicated by Ramaswamy H. Sarma.

Chalcone-3 Inhibits the Proliferation of Human Breast Cancer MDA-MB-231 Cell Line.

OBJECTIVE: Chalcone-3 has been shown to be cytotoxic and selective against luminal subtype breast cancer cell lines, which are suspected to occur through the mechanism of epidermal growth factor receptors (EGFR) inhibition. However, the cytotoxic effect has never been tested on cell strains from patients with triple negative breast cancer (TNBC), where EGFR expression is known to increase. This study aimed to identify the role of chalcone-3 in one of the downstream targets of EGFR as an antiproliferative agent. METHODS: Chalcone-3 was examined for its effect on proliferation in human breast cancer MDA-MB-231 cell lines. The percentage of proliferation inhibition was analyzed using methyl-thiazol tetrazolium assay. Flow cytometry was used to analyze the population of cell cycle distribution and the expression of cyclin-D1 and pEGFR. RESULTS: Chalcone-3 inhibited the proliferation of MDA-MB-231 cells in a dose and time-dependent manner with an IC50 value of 17.98±6.36 µg/mL by inducing cell cycle arrest at the G2/M phase. Flow cytometry assays showed that chalcone-3 significantly reduced the expression of pEGFR and cyclin-D1, contributing to cell cycle arrest. CONCLUSION: Chalcone-3 might have potential as an anti-proliferative drug to treat TNBC.

Synthesis, biological evaluation and molecular docking of methoxy n-phenylpyrazoline derivatives as anticancer agents.

This research aims to synthesize some N-phenylpyrazoline derivatives with methoxy substituents and study their activity as potent anticancer agents as well as their interaction with the EGFR receptor on cancer cells. The synthesis of N-phenylpyrazolines was carried out via cyclocondensation reaction of chalcones and phenylhydrazine. All products were elucidated using GC-MS, FT-IR, 1H- and 13C-NMR spectrometers. The cytotoxicity evaluation was performed against cancer cell lines (HeLa, MCF-7, T47D, WiDr) and normal cell lines (Vero) using MTT assays. A molecular docking study of pyrazolines was conducted toward EGFR protein as a receptor. Cyclocondensation reactions yielded N-phenylpyrazolines in 63-91%. The presence of methoxy substituents on synthesized pyrazolines enhanced their potency as an anticancer agent. The best pyrazolines with high cytotoxicity and selectivity are compound 2e against HeLa cell line, 2d against WiDr cell line and 2f against MCF-7 cell line. Compound 2g is the most promising anticancer agent with a broad spectrum activity toward several cancer cell lines. A molecular docking study showed that the binding energy value of compound 2g with EGFR receptor is -8.4 kcal/mol and has interaction with Met769 residue. This study presented a convenient method for preparing N-phenylpyrazoline derivatives as promising anticancer candidates.

A Potent EGFR Inhibitor, N-Phenyl Pyrazoline Derivative Suppresses Aggressiveness and Cancer Stem Cell-Like Phenotype of Cervical Cancer Cells.

Objective: Metastasis causes approximately 90% of cancer-related deaths, including in cervical cancer patients. Uncontrolled cell proliferation, migration, and cancer stemness act as critical events in primary tumor growth and cancer metastasis progression in cervical cancer. Here, we investigated the anti-proliferative, anti-migration, and cancer stemness inhibition activity of N-phenyl pyrazoline derivatives against cervical cancer cells. Methods: The chalcone and phenylhydrazine were used to synthesize the N-phenyl pyrazoline 2/5 (P2 and P5). The MTT, colony formation, and wound healing assays were performed to evaluate the N-phenyl pyrazoline effect in HeLa cells. The N-phenyl pyrazoline's protein target was predicted using SwissTargetPrediction and AutoDock Vina software. The Western blotting assay was performed to evaluate the target proteins. The public dataset analysis was used to confirm the clinical relevance of target protein in cervical cancer patients. Results: N-phenyl pyrazoline 2 and 5 were successfully synthesized. The N-phenyl pyrazolines 2 and 5 exhibit cytotoxic effect in HeLa cell line with 20.26 µM, 4.708 µM of IC50, respectively. Further study shows that the N-phenyl pyrazoline 5 suppresses the cell proliferation and migration ability of HeLa cell line in a dose-dependent manner. Target prediction and molecular docking reveal that EGFR and ERBB2 protein as the main target of the N-phenyl pyrazoline 5 compound. The N-phenyl pyrazoline 5 suppresses the EGFR expression level but not the total ERK1/2. Public data and GSEA analysis found that the EGFR high expression level is positively associated with poor survival, cancer metastasis-related signaling pathways, and cancer stem cell markers in cervical cancer patients. In addition, the N-phenyl pyrazoline 5 reduces the HeLa's tumorsphere size and cancer stem cell marker, CD133. Conclusion: N-phenyl pyrazoline 5 suppresses the cell viability, proliferation, migration, and cancer stem cell-like phenotype of cervical cancer cells via EGFR inhibition.

Metabologenomics approach to the discovery of novel compounds from Streptomyces sp. GMR22 as anti-SARS-CoV-2 drugs.

COVID-19 is spreading rapidly yet there is no clinically proven drug available now. Soil-derived Streptomyces sp. GMR22 has a large genome size (11.4 Mbp) and a huge BGCs (Biosynthetic Gene Clusters) encoding secondary metabolites. This bacterium is a potential source for producing a wide variety of compounds which are able to block SARS-CoV-2, the causative agent of COVID-19. This study aimed to predict the secondary metabolites of Streptomyces sp. GMR22 and to evaluate the ability as SARS-CoV-2 inhibitor. The AntiSMASH 5.0 was used for genome mining analysis and targeted liquid chromatography-high resolution mass spectrometry (LC-HRMS) was used for metabolite analysis. In silico molecular docking was performed on important target proteins of SARS-CoV-2 i.e., spike protein (PDB ID: 6LXT), Receptor Binding Domain (RBD)-ACE2 (Angiotensin-Converting Enzyme 2) (PDB ID: 6VW1), 3CLpro (3-chymotrypsin-like protease) (PDB ID: 6M2N), and RdRp (RNA-dependent RNA polymerase) (PDB ID: 6M71). Two compounds from GMR22 extract, echoside A and echoside B were confirmed by targeted LC-HRMS and potential as SARS-CoV-2 inhibitor. Echoside A and echoside B showed higher docking score than remdesivir as COVID-19 drug on four target proteins, i.e., spike protein (-7.9 kcal/mol and -7.8 kcal/mol), RBD-ACE2 (-7.5 kcal/mol and -8.2 kcal/mol), 3CLpro (-8.4 kcal/mol and -9.4 kcal/mol) and RdRp (-7.3 kcal/mol and -8.0 kcal/mol). A combination of genome mining and metabolomic approaches can be used as integrated strategy to elucidate the potential of GMR22 as a resource in the discovery of anti-COVID -19 compound.

Novel luminescent Schiff's base derivative with an azo moiety for ultraselective and sensitive chemosensor of Fe3+ ions.

Chemosensors with ultrasensing capabilities for detection of metal ions have received particular attention when using luminescent organic compounds. Even though hundreds of chemosensor agents have been reported for Fe3+ ion sensing, the designs of those molecules have been complicated and time consuming, in addition to having limited application for aquatic samples due to their poor hydrophilicity. Here, we synthesized a novel azo-imine derivative (L2) that showed ultrasensitive and selective sensing for Fe3+ ions. L2 exhibited ultraselective detection of Fe3+ ions with a turn-off of its emission intensity at 341 nm in H2 O:MeOH (4:1 v/v) aqueous medium. This quenching phenomenon was in good agreement with its colour change from orange-yellowish to colourless. Its capability was shown due to its very low limit of detection and limit of quantification values of 0.31 and 1.04 µM, respectively. The interference study showed that L2 is ultraselective for the detection of Fe3+ ions without a significant reduction in its sensing capability even in competitive metal mixtures. Furthermore, direct Fe3+ quantification of tap and drinking water showed that L2 gave good recovery percentages. These findings demonstrated that the Schiff's base with an azo fluorophore derivative is a potential chemosensor agent for Fe3+ ions sensing applications in aqueous media.