Compounds 4b Research Articles

Neurotoxicity, Neuroprotection, In Vitro MAOA/MAOB Inhibitory Activity Assessment, Molecular Docking, and Permeability Assay Studies of Newly Synthesized Hydrazones Containing a Pyrrole Ring.

Neurodegenerative diseases such as Parkinson's and Alzheimer's continue to be some of the most significant challenges in modern medicine. Recent research related to the molecular mechanisms of parkinsonism has opened up new approaches to antiparkinsonian therapy. In response to this, we present the evaluation of the potential neuroprotective and MAOA/MAOB inhibitory effects of newly synthesized hydrazones, containing a pyrrole moiety in the carboxyl fragment of the structure. The substances were studied on different brain subcellular fractions, including rat brain synaptosomes, mitochondria, and microsomes. The single application of 50 µM of each compound to the subcellular fractions showed that all substances exhibit a weak neurotoxic effect, with 7b, 7d, and 8d being the least neurotoxic representatives. The corresponding neuroprotective and antioxidant effects were also evaluated in different injury models on subcellular fractions, single out 7b, 7d, and 8d as the most prominent derivatives. A 1 µM concentration of each molecule from the series was also studied for potential hMAOA/hMAOB inhibitory effects. The results revealed a lack of hMAOA activity for all evaluated structures and the appearance of hMAOB effects, with compounds 7b, 7d, and 8d showing effects similar to those of selegiline. The best hMAOB selectivity index (>204) was determined for 7d and 8d, distinguishing these two representatives as the most promising molecules for further studies as potential selective MAOB inhibitors. The performed molecular docking simulations defined the appearance of selective MAOB inhibitory effects based on the interaction of the tested molecules with Tyr398, which is one of the components of the aromatic cage of MAOB and participated in π-π stabilization with the aromatic pyrrole ring. The preliminary PAMPA testing indicated that in relation to the blood-brain barrier (BBB) permeability, the tested pyrrole-based hydrazones may be considered as high permeable, except for 8a and 8e, which were established to be permeable in the medium range with -logP of 5.268 and 5.714, respectively, compared to the applied references.

Novel Pesticide Candidates Inspired by Natural Neolignan: Preparation and Insecticidal Investigation of Honokiol Analogs Containing 2-Aminobenzoxazole-Fused Core Scaffold.

As a continuation of our efforts to develop new agrochemicals with typical architecture and efficient bioactivity from plant natural products, natural neolignan honokiol was used as a lead compound to prepare novel analogs bearing the core 2-aminobenzoxazole scaffold. Their insecticidal potency against two representative agricultural pests, Plutella xylostella Linnaeus and Mythimna separata (Walker), were evaluated in vivo. The pesticide bioassay results revealed that compounds 7″a, 9, 10d, and 10j exhibited prominent larvicidal activity against the larvae of P. xylostella (LC50 = 7.95, 11.85, 15.51, and 12.06 μg/mL, respectively), superior to the precursor honokiol (LC50 = 43.35 μg/mL) and two botanical insecticides, toosendanin (LC50 = 26.20 μg/mL) and rotenone (LC50 = 23.65 μg/mL). Compounds 7d, 10d, and 10j displayed a more pronounced nonchoice antifeedant effect (AFC50 = 9.48, 9.14, and 12.41 μg/mL, respectively) than honokiol (AFC50 = 54.81 μg/mL) on P. xylostella. Moreover, compounds 7b, 7″a, 9, 10d, 10f, and 10j showed better growth inhibitory activity against M. separata (LC50 = 0.36, 0.34, 0.28, 0.16, 0.26, and 0.11 mg/mL, respectively) than honokiol, toosendanin, and rotenone (LC50 = 1.48, 0.53, and 0.46 mg/mL, respectively). A potted plant assay under greenhouse conditions illustrated that compounds 10d and 10j continued to provide good control efficacy against P. xylostella and an apparent protective effect on plants. Further cytotoxicity assay revealed that the aforementioned potent compounds showed relatively moderate toxicity and a good safety profile for non-target mammalian cells. Overall, the current work provides valuable insight into the agrochemical innovation of honokiol-derived analogs for use as natural-inspired pesticides in agricultural pest management.

Design, Synthesis, molecular dynamic analysis, and In-Vivo anti-diabetic evaluation of novel hydrazine carboximidamide derivatives

Diabetes is one of the most rapidly growing health problems globally, and researchers working hard to develop novel efficient therapies against it. In this regard, hydrazine carboximidamide has a great deal of attention owing to its diverse biological activities. Herein, a new series of N, N-disubstituted hydrazine carboximidamide derivatives was designed, synthesized, and assessed for their antidiabetic activity. Docking studies were performed to initially evaluate the binding of the designed compounds to the target enzyme. It was found that all of the pivotal ligand-enzyme interactions, including the interactions with Glu205/Glu206 aminoacids were observed in docking studies. The molecular dynamic analysis showed that the antidiabetic activity of the newly developed compounds may be implemented through the inhibition of dipeptidyl peptidase 4 (DPP-4), an important target that involves enhancing insulin release and suppressing glucagon discharge from the pancreas. The target molecules were synthesized practically and all the newly-developed chemical structures were confirmed via spectrophotometric methods, including IR, LC-MS, 1H NMR, and 13C NMR techniques. Finally, the in-vivo studies were carried out to confirm the results obtained from the docking and molecular dynamics studies. Compounds 6b and 6d demonstrated improved glucose tolerance through oral glucose tolerance tests in NMRI mice (at a dose of 10 mg/kg). Furthermore, prolonged administration of compounds 6b and 6d to diabetic Wistar rats for 14 days led to a noteworthy reduction in blood levels of glucose, akin to the effects observed with sitagliptin, a standard diabetes medication.

Exploring the anticancer properties of indole pyrimidine derivatives: Synthesis, structural insights, docking analysis, and in vitro evaluation

The nitrogen containing heterocyclic and chalcones moiety widely recognized as favorable combination of diagnostic and therapeutic facilities in medicinal chemistry. In particular, indole analogs play a very important medicinal role in pharmacology activities, hence, drugs like pindolol, indomethacin, oxypertine, ellipticine, arbidol and ate viridine are well known in market. In this view, the title compounds 4(a-j) were synthesized in good yield. The purified compounds were explained by spectroscopic procedures (FT-IR, 1H NMR, 13CNMR, and LC-MS), and lastly, all synthetic compounds have in-vitro efficacy assessed against the HeLa human cervical cancer and MCF-7 human breast cancer cell lines, and their efficacy was compared to that of the well-known anticancer drug methotrexate (Methotrexate). Compounds 4a, 4b, 4c, and 4e from the series (4a-j) demonstrated the most notable inhibitory activity. The cytotoxicity evaluation of these newly synthesized compounds revealed that 4a, 4b, 4c, and 4e were the most toxic to HeLa cells, with IC50 values for growth inhibition of 20.41 ± 3.14, 23.54 ± 3.27, 24.77 ± 2.14, and 26.10 ± 1.58, respectively. These compounds exhibited an even stronger growth-inhibitory effect on MCF-7 cells, with IC50 values of 18.84 ± 2.69, 19.45 ± 3.14, 22.83 ± 2.68, and 21.80 ± 1.68, respectively. In comparison, methotrexate (Methotrexate) showed IC50 values of 28.29 ± 1.0 for HeLa cells and 45.08 ± 2.61 for MCF-7 cells. Additionally, compounds 4a, 4b, 4c, and 4e played a crucial role in interacting with the catalytic domain of PDE3, demonstrating IC50 values for PDE3A inhibition of 8.05 ± 1.27, 7.55 ± 2.14, 15.09 ± 1.54, and 17.12 ± 3.14, respectively. These results are compared with Cilostazol, a known PDE inhibitor, which exhibited an IC50 of 0.00368 ± 3.14. In-silico studies revealed that compounds (4a, 4b, and 4c) are comparatively very efficient in binding with PDE3A which was further validated with MMGBSA and MDSs.

Synthesis, DFT Calculations, and Biological Studies of New 2-Cyano-3-(Naphthalene-1-yl) Acryloyl Amide Analogues as Anticancer Agents.

A set of novel naphthalene derivatives was synthesized via investment of the electrophilic reaction center of the easily obtainable starting substance, 2-cyano-3-(naphthalen-1-yl)acryloyl chloride (1), with various nitrogen nucleophiles and assessed as potential antitumor agents. The chemical structures of these derivatives were completely specified using several spectral and elemental analyses. The antiproliferative efficacy of the discovered compounds against the human cancer cell lines HepG2 and MCF-7 was investigated. Compounds 12b and 9 have more potent anticancer activity versus MCF-7 breast cancer. DFT calculations for the synthesized compounds were studied to determine molecular geometry, frontier orbital analysis, and molecular electrostatic potential. Compound 2 has the lowest energy gap, the highest softness, and the lowest hardness molecule. Also, the electrophilicity values of the studied molecules provide evidence for their biological effectiveness, as compound 9 had significant antiproliferative activity and a high value of electrophilicity (ω) (0.190 eV).

Synthesis, molecular docking, and anti-breast cancer study of 1-H-indol-3-Carbohydrazide and their derivatives

A prominent heterocyclic system found in medications and natural goods is indoles. Due to the significance of this important ring system, a fresh batch of unique indole derivatives was created using indole carbohydrazide. The triazole moiety of indole derivative (3) is produced by reacting carbohydrazide with carbon disulfide in alkaline conditions, followed by hydrazine treatment. In addition to synthesizing additional derivatives, indole-bearing triazole (3) was condensed with aromatic aldehydes to create the indole derivatives (4a–c). Mass spectra, 1HNMR, 13CNMR, and infrared spectroscopy were used to diagnose all produced derivatives. An MTT assay was employed to test the derivatives against MCF-7 cells. The findings demonstrated the inhibitory action of compounds 5a and 5b, with IC50 values of 42.6 ± 0.33 µM and 27.3 ± 0.28, respectively. Affinity energy and the interaction between the investigated chemicals and receptor (CDK4 ID: 2w96) were ascertained by studying molecular docking. The chemical structure-physicochemical-pharmacokinetic relationship provides useful insight for medicinal chemists to design indole-triazole derivatives with acceptable drug-like and pharmacokinetic properties.

Synthesis, cytotoxicity and 99mTc-MIBI tumor cell uptake evaluation of 2-phenylbenzothiazole tagged triazole derivatives.

Aim: The extensive utilization of 2-phenylbenzothiazole due to their wide array of biological activities, particularly in cancer therapy, has caused great attention to explore more potent derivatives.Materials & methods: We report the synthesis of 2-phenylbenzothiazole tagged 1,2,3-triaozle (8) through Cu(I)-catalyzed cycloaddition of alkyne side chain with aryl-substituted azides.Results: The in vitro experiments, using MTT and 99mTc-MIBI cell uptake methods, demonstrated the remarkable anticancer activity of these compounds against A549, SKOV3 and MCF7 cell lines.Conclusion: Compounds 8b, 8f and 8i possessed high cytotoxic activity as compared with doxorubicin. Compound 8g has a similar inhibitory effect on the proliferation of breast cancer cells as doxorubicin. In silico study indicated that compound 8 would be a good lead for the development of new potent anticancer agents.

Synthesis and Antifungal Evaluation of Cinnamic Acid-Geraniol Hybrids as Potential Fungicides.

Cinnamic acid and geraniol are two well-known antifungal natural products and widely applied in food and cosmetics industries. To discover novel natural product-based fungicide candidates with more potent activity and good ecological compatibility for the management of plant diseases, a series of cinnamic acid-geraniol hybrids were prepared by means of molecular hybridization and their chemical structures were well confirmed by spectral analysis. The antifungal activities of the target compounds against three phytopathogenic fungi Fusarium graminearum, Gaeumannomycesgraminis (Sacc.) Arx et Oliver var. tritici (Sacc.) Walker, and Valsa mali were evaluated. Among them, compounds 5e and 5f showed the remarkable antifungal activity against G. graminis with the EC50 values of 82.719 and 91.828 μg/mL, respectively; while compounds 5f and 6b exhibited the obvious antifungal activity against V. mali. It suggested that compound 5f can be further optimized for the design of novel broad-spectrum fungicide molecules as the secondary lead compound. In addition, some interesting structure-antifungal activity relationships were obtained. This work will provide some reference and guidance for the further discovery of novel fungicide candidates based on cinnamic acid and geraniol.

Exploring The Antimicrobial Potential of Novel 1,2,4‒Triazole Conjugates with Pyrazole: Synthesis, Biological Activity and In Silico Docking.

In the present study, a new series of 1,2,4‒triazole linked pyrazole hybrids (5a‒5l) were synthesized from dimethyl amino pyrazole (1) in good yield by three-step reaction. The chemical structures of the resulted compounds were thoroughly elucidated using spectral analyses such as IR, 1H-NMR, 13C-NMR, mass spectra and elemental analysis. The target compounds were screened for their antimicrobial activities against the various standard pathogen strains, Gram‒(‒ve) (E. coli, P. aeruginosa, K. pneumoniae, A. baumannii), and Gram‒(+ve) (S. aureus,S. faecalis) microorganisms. According to the results obtained, in particular, compounds 5b, 5f, 5h and 5j was effective at inhibiting the antibacterial growth of all the bacteria's, having MIC values ranging 0.983‒14.862 mg/mL and compared to moxifloxacin (1.391‒22.01 mg mL-1). The most active compounds were chosen to interact with the DNA gyrase and topoisomerase-IV targets via molecular docking. These selected ligands interacted with PDB targets 2XCO, 1S16 and docked into the active site of amino acids Ala-269, Gly-413, Asn-405, Ser-1182, Thr-1185, His-1186, His-1186, Lys-1189, and Trp-1213.The pharmacokinetic properties, stability, and drug-likeness parameters of all target molecules were estimated using SwissADME and PkCSM protocols. The current study used in silico approaches combining e-pharmacophore modeling and structure-based molecular docking of targets to identify antimicrobial agents.

Synthesis and in silico studies of some new pyrrolylbenzamide derivatives as antitubercular and antimicrobial agents

Eighteen new pyrrolylbenzamide derivatives (6a-6r) were synthesized by reacting N-(2,5-dimethyl- 1H-pyrrol-1-yl)-4-(2-hydrazineyl-2-oxoethoxy)benzamide (4) with substituted benzoic acids (5a-5r) in the presence of 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, diisopropyl ethylamine and dimethyl formamide. The produced compounds were subjected to molecular docking studies against the dihydrofolate reductase (DHFR) and InhA mycobacterial enzymes. The compounds were biologically screened for antimycobacterial, and antibacterial activities along with InhA and DHFR enzyme inhibition studies. The compounds were also analyzed for ADMET parameters. The compounds 6j, 6l, 6q, and 6r exhibited good antitubercular activity, and compounds 6j, 6l, 6q, and 6r were effective against the Gram-negative Escherichia coli strain. The compounds 6b, 6f, 6j, 6l, and 6q showed good InhA inhibition and compounds 6b, 6c, 6j, 6l, and 6q were effective against DHFR enzyme. Among the synthesized compounds 6j and 6l exhibited promising antitubercular, antibacterial, and effective InhA and DHFR enzyme inhibition values.. KEYWORDS :Benzamide, Dimethylpyrrole, Antimycobacterial activity, Antibacterial activity.

Synthesis and Molecular Docking Study of Some New Thiazole-coumarin Molecular Hybrids as Antibacterial Agents.

The emergence of drug-resistant bacteria and multidrug-resistant diseases, both of which are associated with high mortality, has posed a serious global health issue. Thiazoles and coumarins were reported as antimicrobial agents. This research paper aims to describe the synthesis of some novel thiazole derivatives bear-ing a coumarin residue as antibacterial agents Methods: The thiazole - coumarin hybrids were synthesized starting from the condensation of 3-acetyl coumarin (1) hydrazine carbothioamide (2) or thisemicarbazide then reacting the resulting products with different p-substituted phenacyl bromides (4a-e), hydrazonoyl chlorides (8a-e), and (11). In vitro antibacterial activity was studied in this work. In addition, molecular docking studies for the new compounds have also been carried out to investigate the binding mode of actions against the target DNA gyrase B. Some of the newly synthesized compounds such as compounds 10b, 7, and 6b showed pronounced activities against Gram (+ve) and Gram (-ve) bacteria compared to a reference antibacterial agent. Compounds 10b, 7, and 6b exhibited the best binding affinity against the target. We could obtain a series of precious hitherto unknown thiazole derivatives with varied antibacterial activities from cheap laboratory-available starting material following rather simple environmentally friendly techniques avoiding the use of hazardous or heavy metal-containing catalysts.

Synthesis and Molecular Dynamic Simulation of Novel Cationic and Non-cationic Pyrimidine Derivatives as Potential G-quadruplex-ligands.

Drug resistance has been a problem in cancer chemotherapy, which often causes shortterm effectiveness. Further, the literature indicates that telomere G-quadruplex could be a promising anti-cancer target. We synthesized and characterized two new pyrimidine derivatives as ligands for G-quadruplex DNA. The interaction of novel non-cationic and cationic pyrimidine derivatives (3a, b) with G-quadruplex DNA (1k8p and 3qsc) was explored by circular dichroism (CD) and ultraviolet-visible spectroscopy and polyacrylamide gel electrophoresis (PAGE) methods. The antiproliferative activity of desired compounds was evaluated by the MTT assay. Apoptosis induction was assessed by Propidium iodide (P.I.) staining and flow cytometry. Computational molecular modeling (CMM) and molecular dynamics simulation (MD) were studied on the complexes of 1k8p and 3qsc with the compounds. The van der Waals, electrostatic, polar solvation, solventaccessible surface area (SASA), and binding energies were calculated and analyzed. The experimental results confirmed that both compounds 3a and 3b interacted with 1k8p and 3qsc and exerted cytotoxic and proapoptotic effects on cancer cells. The number of hydrogen bonds and the RMSD values increased in the presence of the ligands, indicating stronger binding and suggesting increased structural dynamics. The electrostatic contribution to binding energy was higher for the cationic pyrimidine 3b, indicating more negative binding energies. Both experimental and MD results confirmed that 3b was more prone to form a complex with DNA G-quadruplex (1k8p and 3qsc), inhibit cell growth, and induce apoptosis, compared to the non-cationic pyrimidine 3a.

Rational design, synthesis and biological evaluation 1,2,3-triazole aryl attached (4,6-dimethoxy-1,3,5-triazin-2-yl)thiazole derivatives as anticancer agents

A new library of 1,2,3-triazole aryl-attached (4,6-dimethoxy-1,3,5-triazin-2-yl) thiazoles (11a–j) has been designed and synthesized and its structures were characterized by 1H NMR 13C NMR and mass spectral data. Further, these derivatives (11a-j) were evaluated for their anticancer activity against four human cancer cell lines, including PC3 (prostate cancer), A549 (lung cancer), MCF-7 (breast cancer) and A2780 (ovarian cancer) by employing the MTT method, and the obtained results were compared with etoposide. Among all the examined compounds, 11a, 11b, 11c, 11i and 11j displayed the most promising activity. Particularly, two compounds 11a and 11b possessed good activity.

Molecular hybridization of pyridine-thiophene clubbed isoxazole heterocycle in a single entity: Synthesis, antimicrobial, antitubercular, molecular docking and ADMET analysis

In the present study, 10 new hybrid pyridine-thiophene clubbed isoxazole derivatives (8a-j) were synthesized from the reaction of benzylideneacetophenones (7a-j) with hydroxylamine hydrochloride in alkaline medium. The synthesized compounds were tested for in vitro antimicrobial and antitubercular properties. Four promising new lead compounds such as 8c, 8d, 8f, and 8h endowed with excellent antimicrobial and antitubercular activity. In addition, the docking score for the most active compounds 8b, 8e, 8g, and 8h was found to be -8.6 to -8.8 kcal/mol demonstrating its favorable accommodation within the active site of the PknB enzyme.. KEYWORDS :ADMET analysis, Antimicrobial, Antitubercular, Molecular docking, Molecular hybridization, Pyridine-thiophene clubbed isoxazole.

Unveiling the antibacterial efficacy of thiazolo [3,2-a] pyrimidine: Synthesis, molecular docking, and molecular dynamic simulation.

Two series of C-Mannich base derivatives were synthesized and evaluated through the reaction of formaldehyde, two thiazolo-pyrimidine compounds, and various 2°-amines. The chemical structures and inherent properties of the synthesized compounds were authenticated using a variety of spectroscopic techniques. The aseptic bactericidal potential of the compounds was assessed alongside five common bacterial microbes, with Ampicillin employed as the reference drug. Compounds 9b and 9d demonstrated comparable antibacterial activity to ampicillin against Bacillus subtilis and Bacillus megaterium, respectively, at 100 μg/mL. Furthermore, compounds 9f and 10f exhibited noteworthy action against Staphylococcus aureus (MIC: 250 μg/mL). Compounds 10b and 10f displayed excellent efficacy versus Escherichia coli, boasting (MIC: 50 μg/mL). Molecular docking studies elucidated the necessary connections and energies of molecular entities with the E. coli DNA gyrase B enzyme, a pivotal target in bacterial DNA replication. Further thermodynamic stability of the ligand-receptor complex of 10b and 10f were further validated though 200 ns molecular dynamics simulation. The findings highlight the potential of these synthesized derivatives as effective antibacterial agents and provide valuable insights into their mechanism of action.

Unveiling the anticancer potential of novel spirooxindole-tethered pyrazolopyridine derivatives

In the current medical era, human health is confronted with various challenges, with cancer being a prominent concern. Therefore, enhancing the therapeutic arsenal for cancer with a constant influx of novel molecules that selectively target tumor cells while displaying minimal toxicity toward normal cells is imperative. This study delves into the antiproliferative and EGFR kinase inhibitory activities of newly reported spirooxindole-pyrazolo[3,4-b]pyridine derivatives 8a-h and 10a-h. The inhibitory effects on the growth of human cancer cell lines A-549 (lung carcinoma), Panc-1 (pancreatic carcinoma), and A-431 (skin epidermoid carcinoma) were evaluated, and the SAR has been clarified through analysis. With IC50 values in the single-digit micromolar range, compounds 8b, 8d, 10a-b, and 10d were shown to be the most effective antiproliferative candidates against the studied cancer cell lines. They also exerted negligible cytotoxicity (with selectivity scores between 8.63 and 30.02) against the human lung MRC5 cell line. Additionally, we investigated the potential inhibitory action of compounds 8b, 8d, 10a-b, and 10d on EGFR and VEGFR-2. 10a was this investigation’s most effective EGFR inhibitor, with an IC50 value of 0.54 μM. Ultimately, the molecular docking analysis of congener 10a highlighted its effective suppression of EGFR by examining its binding mode and docking score compared to Erlotinib. These findings underscore the potential of spirooxindole-pyrazolo[3,4-b]pyridine derivatives as promising anticancer agents targeting EGFR kinase.

Synthesis and biological evaluation of sulfonamide derivatives containing imidazole moiety as ALK5 inhibitors.

Four series of sulfonamide derivatives (13a-b, 14a-d, 15a-b, and 16a-d) were synthesized and evaluated for their activin receptor-like kinase 5 (ALK5) inhibitory activities. Of these, compounds 13b (IC50 = 0.130μM) and 15a (IC50 = 0.130μM) showed the highest inhibitory activities against ALK5 kinase, with activities similar to the positive control LY-2157299. Notably, we discovered that introduction of sulfonamide group at the 2-position of the central imidazole ring significantly increased ALK5 inhibitory activity. Compounds 13b and 15a did not show toxicity in A549 cells up to the maximum concentration of 50μM, and effectively inhibited TGF-β1-induced Smad-signaling and cell motility in A549 cells. The results indicate that compounds 13b and 15a are worth of further development as anticancer agents.

Discovery of the potent covalent inhibitor with an acrylate warhead for SARS-CoV-2 3CL protease

COVID-19 has caused severe consequences in terms of public health and economy worldwide since its outbreak in December 2019. SARS-CoV-2 3C-like protease (3CLpro), crucial for the viral replications, is an attractive target for the development of antiviral drugs. In this study, several kinds of Michael acceptor warheads were utilized to hunt for potent covalent inhibitors against 3CLpro. Meanwhile, novel 3CLpro inhibitors with the P3-3,5-dichloro-4-(2-(dimethylamino)ethoxy)phenyl moiety were designed and synthesized which may form salt bridge with residue Glu166. Among them, two compounds 12b and 12c exhibited high inhibitory activities against SARS-CoV-2 3CLpro. Further investigations suggested that 12b with an acrylate warhead displayed potent activity against HCoV-OC43 (EC50 = 97 nM) and SARS-CoV-2 replicon (EC50 = 45 nM) and low cytotoxicity (CC50 > 10 μM) in Huh7 cells. Taken together, this study devised two series of 3CLpro inhibitors and provided the potent SARS-CoV-2 3CLpro inhibitor (12b) which may be used for treating coronavirus infections.

Therapeutic Effect of 1,3‐Thiazin‐6‐One for the Treatment of Brain Cancer Through Increased Accumulation in the Brain Glioblastoma Cells

AbstractIn the present study a library of five (2‐(amino)‐1,3‐thiazin‐6‐one) compounds was synthesized and investigated as against glioblastoma cells in vitro and in vivo in the mice model. The results revealed that all of the five 1,3‐thiazin‐6‐one compounds (4a, 4b, 4c, 4d and 4e) exhibited cytotoxicity against U87MG and 9 L brain cancer cell lines. Moreover, it was found that 9 L cells showed slightly higher sensitivity towards the compounds 4a, 4b, 4c, 4d and 4e compared to U87MG cells. It was observed that the compounds 4a, 4b, 4c, 4d and 4e showed a time‐dependent increase in uptake efficiency by U87MG and 9 L cells. Furthermore, the data revealed that uptake of the compounds and therefore internalization was maximum during initial 1 h of the treatment. Among the synthesized compounds, compound 4c containing trifluoromethyl moiety showed higher uptake efficiency compared to the compound 4a, 4b, 4d and 4e. Treatment of U87MG and 9 L cell tumor spheroids with compound 4c significantly (P<0.05) inhibited the tumor growth compared to the control spheroids. In vivo data revealed that treatment with compound 4c led to a significant (P<0.05) decrease in glioblastoma growth in mice in dose‐dependent manner. Growth of glioblastoma in mice was almost completely inhibited after 28 days of treatment with 2 mg/kg dose of compound 4c. Pharmacokinetic studies showed that compound 4c remained in circulation for longer duration in mice and its terminal half‐life was found to be 6.5 h. Treatment of U87MG and 9 L cells with compound 4c led to a prominent decrease in expression of CYR61 protein. In conclusion, findings of the present study suggest that compound 4c acts as a potential therapeutic agent for the treatment of advanced brain cancer through activation of Hippo pathway. Therefore, more studies need to be performed to investigate the detailed mechanism underlying the inhibitory effect of compound 4c against the glioblastoma.

Design, synthesis, pharmacophore modeling, and molecular docking of some novel chloroacetamide derivatives as herbicidal agents

BackgroundThe discovery of new lead compounds with desired properties and biological activity is an excellent challenge in pesticide chemistry. Chloroacetamide are an important class of synthetic herbicides.ResultsTo explore the herbicidal activity of chloroacetamides, several new chloroacetamide derivatives have been designed, and synthesized. The compounds have been described by forming Schiff bases followed by chloroacetylation of imines. The herbicidal activity as a chlorophyll inhibition was evaluated against two broadleaf weeds (Chenopodium album and Anagallis arvensis) and two grass weeds (Lolium temulentum and Echinochloa crus-galli) in comparison with acetochlor as a standard herbicide. 1H-NMR, 13C-NMR and mass spectroscopic analyses confirmed the chemical structures of the synthesized compounds. Several compounds have demonstrated highly potent herbicidal activity compared to the standard herbicide acetochlor. Some of them have been described as the most effective against weeds tested, such as compounds 5b and 18b. Molecular docking to the active sites of Very Long Chain Fatty Acid Synthase (VLCFAS) has indicated that most compounds are low-energy binding agents and show high affinity for the active pocket.ConclusionNovel herbicides may be discovered by combining chloroacetamide derivatives with these existing lead structures.Graphical