Compounds 4d Research Articles

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.

6-Substituted benzo[d]thiazole linked 2-(2-(bis (1H-benzo[d]imidazol-2-yl) methylene) hydrazineyl compounds: Synthesis, computational studies, and in-vitro anticancer assessment

In this study, four novel 6-substituted benzothiazole-linked bis-benzimidazoles (3a–d) were synthesized and characterized using 1H NMR, 13C NMR, FTIR, and HRMS techniques. The physicochemical properties of these compounds were examined, and experimental data validated the computed values. The absorption and emission properties were also investigated using carbonate, acetate, and phosphate buffers at various pH levels.In-silico studies revealed that methoxy derivative (3c) possesses the highest docking affinity for tyrosine kinase. Pharmacokinetic studies showed that, like the marketed drug erlotinib, none of the compounds act as substrates for p-glycoprotein, and all except compound 3d do not inhibit CYP-2C9. The gastrointestinal absorption profiles, including blood-brain barrier permeability, were also studied. Drug-likeness assessments based on Lipinski's rule of five and Ghose criteria suggested favourable properties, though some compounds showed deviations in molecular weight and logP values. In-vitro anticancer study via MTT assay includes its potency against MCF-7 and MDA-MB-231 breast cancer cell lines, including 3c as the most potent against MCF-7 cells, which coincides with the In-silico study.

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.

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.

Impurity affected transport properties of quantum well heterostructures with electronic and high-κ dielectric quantum screening

The effect of electronic and high-κ dielectric quantum screening (ES and DS) on the impurity-limited electron transport properties of quantum well/high-κ dielectric barrier type heterostructures with two-dimensional electron gas (2DEG) is studied theoretically. Characteristic of these heterosystems the 2D compound forms of screened impurity potential are employed for the first time. In the framework of 2D Debye-Hückel potential form an electron momentum relaxation time (τ) expression depending on the impurity 2D screening radius is obtained analytically. A numerical analysis of τ is carried out for the realistic HfO/InSb/HfO2QW heterostructure taking account both the finite mismatch of the energy bands at the heterointerface and the energy band non-parabolicity of InSb. The contributions of screened potential compound 2D forms to τ are established depending on QW width. A significant suppression of the scattering rate τ−1 (by an order of magnitude) is received with accounting of ES + DS combined effect.

Synthesis, biological evaluation and molecular modeling studies of methyl indole-isoxazole carbohydrazide derivatives as multi-target anti-Alzheimer’s agents

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that affects the elderly population globally and there is an urgent demand for developing novel anti-AD agents. In this study, a new series of indole-isoxazole carbohydrazides were designed and synthesized. The structure of all compounds was elucidated using spectroscopic methods including FTIR, 1H NMR, and 13C NMR as well as mass spectrometry and elemental analysis. All derivatives were screened for their acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activity. Out of all synthesized compounds, compound 5d exhibited the highest potency as AChE inhibitor with an IC50 value of 29.46 ± 0.31 µM. It showed significant selectivity towards AChE, with no notable inhibition against BuChE. A kinetic study on AChE for compound 5d indicated a competitive inhibition pattern. Also, 5d exhibited promising BACE1 inhibitory potential with an IC50 value of 2.85 ± 0.09 µM and in vitro metal chelating ability against Fe3+. The molecular dynamic studies of 5d against both AChE and BACE1 were executed to evaluate the behavior of this derivative in the binding site. The results showed that the new compounds deserve further chemical optimization to be considered potential anti-AD agents.

Design, synthesis, and evaluation of novel oxyacanthine derivatives for anti-SARS-CoV-2 activity

Here, we report the synthesis of a series of oxyacanthine derivatives and evaluation for their anti-SARS-CoV-2 activity in Vero E6 cells. In order to eliminate the potential metabolic activation caused by para-methylene phenol moiety in oxyacanthine, totally 29 derivatives were designed and synthesized, resulting in 23 compounds with antivirus IC50 below 5.00 μM and 9 compounds with antivirus IC50 below 1.00 μM. Among them, amides compound 4a and 4d exhibited potent anti-SARS-CoV-2 activity and the most favorable selectivity index (SI) in vitro with the SI values of 115 and 70, respectively. The pharmacokinetic properties of 4a and 4d were also assessed. Much more improved exposure in mice, longer half-life (T1/2), and increased oral bioavailability were observed for both compounds 4a and 4d compared with oxyacanthine.

One-Pot Total Synthesis of Natural Products Nitramarine, Nitraridine, and Analogues via a Cascade Oxidation/Pictet-Spengler Condensation/Annulation Process.

A cascade oxidation/Pictet-Spengler condensation/annulation process has been developed for the one-pot total synthesis of nitramarine, nitraridine, and their analogues. The procedure proceeded with easily available quinolines and tryptophan derivatives. A simple and metal-free approach, wide substrate scope, and functional group tolerance make it applicable for the synthesis of diverse bioactive nitramarine, nitraridine, and their derivatives. Furthermore, the bioactivity evaluation has identified two promising leading compounds 5d and 5e with potent antitumor proliferative activity against breast cancer cells.

Molecular hybridization, synthesis, in vitro α-glucosidase inhibition, in vivo antidiabetic activity and computational studies of isatin based compounds

In the pursuit of novel antidiabetic agents, a series of isatin-thiazole derivatives (7a-7j) were synthesized and characterized using a range of spectroscopic techniques. The enzyme inhibitory activities of the target analogues were assessed using both in vitro and in vivo assays. The tested compounds 7a-7j demonstrated In vitro inhibitory potential against α-glucosidase, as indicated by their IC50 values ranging from 28.47 to 46.61 µg/ml as compared to standard drug acarbose IC50 value of 27.22 ± 2.30 µg/ml. Additionally, compounds 7d and 7i were chosen for in vivo evaluation of their antidiabetic efficacy in streptozotocin-induced diabetic Wistar rats. These compounds exhibited significant antidiabetic activity both in vitro and in vivo, compound 7d produces therapeutic effects compared to standard pioglitazone by decreasing glycaemia and triglyceride levels in diabetic animals. Furthermore, a molecular docking study was conducted to elucidate the binding interactions of the compounds within the α-glucosidase enzyme binding pocket (PDB ID 3A47) and stability was confirmed by dynamics simulation trajectories. Thus, from the above findings, it may demonstrate that isatin-thiazole hybrids constitute promising candidates in the pursuit of developing newer oral antidiabetic agents.

Bioisosteric replacement of the carboxylic acid group in Hepatitis-C virus NS5B thumb site II inhibitors: phenylalanine derivatives

Hepatitis C virus (HCV) is a global health concern and the NS5B RNA-dependent RNA polymerase (RdRp) of HCV is an attractive target for drug discovery due to its role in viral replication. This study focuses on NS5B thumb site II inhibitors, specifically phenylalanine derivatives, and explores bioisosteric replacement and prodrug strategies to overcome limitations associated with carboxylic acid functionality. The synthesized compounds demonstrated antiviral activity, with compound 6d showing the most potent activity with an EC50 value of 3.717 μM. The hydroxamidine derivatives 7a-d showed EC50 values ranging from 3.9 μM to 11.3 μM. However, the acidic heterocyclic derivatives containing the oxadiazolone (8a-d) and oxadiazolethione (9a-d) rings did not exhibit measurable activity. A methylated heterocycle 10b showed a hint of activity at 8.09 μM. The pivaloyloxymethyl derivatives 11a and 11b did not show antiviral activity. Further studies are warranted to fully understand the effects of these modifications and to explore additional strategies for developing novel therapeutic options for HCV.

Improved N-phenylpyrrolamide inhibitors of DNA gyrase as antibacterial agents for high-priority bacterial strains

In this work, we describe an improved series of N-phenylpyrrolamide inhibitors that exhibit potent activity against DNA gyrase and are highly effective against high-priority gram-positive bacteria. The most potent compounds show low nanomolar IC50 values against Escherichia coli DNA gyrase, and in addition, compound 7c also inhibits E. coli topoisomerase IV in the nanomolar concentration range, making it a promising candidate for the development of potent dual inhibitors for these enzymes. All tested compounds show high selectivity towards the human isoform DNA topoisomerase IIα. Compounds 6a, 6d, 6e and 6f show MIC values between 0.031 and 0.0625 μg/mL against vancomycin-intermediate S. aureus (VISA) and Enterococcus faecalis strains. Compound 6g shows an inhibitory effect against the methicillin-resistant S. aureus strain (MRSA) with a MIC of 0.0625 μg/mL and against the E. faecalis strain with a MIC of 0.125 μg/mL. In a time-kill assay, compound 6d showed a dose-dependent bactericidal effect on the MRSA strain and achieved bactericidal activity at 8 × MIC after 8 h. The duration of the post-antibiotic effect (PAE) on the MRSA strain for compound 6d was 2 h, which corresponds to the PAE duration for ciprofloxacin. The compounds were not cytotoxic at effective concentrations, as determined in an MTS assay on the MCF-7 breast cancer cell line.

Synthesis, antibacterial, anti-urease, DFT and molecular docking studies of novel bis-1,3,4-thiadiazoles

A series of 2-substitutedamino-1,3,4-thiadiazoles (4a-4j) were synthesized starting from various isothiocyanate derivatives. The newly synthesized compounds were characterized by 1H NMR, 13C NMR, and elemental analysis. All compounds were tested for antibacterial activity against Proteus vulgaris (ATCC 7829) via the microbroth dilution technique. Among them, compound 4h emerged as the most potent antibacterial agent with MIC value of 4.1 μM. All synthetic compounds were additionally evaluated for their urease inhibitory activity and exhibited good inhibitory potential against urease with IC50 values in the range of 1.732 ± 0.186 - 3.786 ± 0.300 μM as compared to the standard thiourea (IC50 = 11.008 ± 0.932 μM). Compounds 4d, 4h and 4i showed significant inhibitory effects with IC50 values of 1.981 ± 0.265, 1.732 ± 0.186 and 1.937 ± 0.173 μM, respectively. In silico molecular docking study showed the critical interactions of compound 4h with the active site of the urease. According to DFT, compounds 4j and 4d (with low ΔE=4.536 eV and 4.629 eV values, respectively) are more chemically reactive than the other molecules, in which consistent with their inhibitory potentials against the urease enzyme. Molecular Dynamics simulations also were performed to assess the energetic features of the urease in complex with compound 4h. Furthermore, the predicted ADMET characteristics of the compound 4h was calculated using QikProp to gain insights into its pharmacokinetic properties. These newly identified inhibitors of the urease enzyme can serve as leads for further antibacterial drug research and development.

Assessing β-Carboline Analogues As Antibiotic Agent Using In Vitro Studies

The mortality rate caused by bacterial diseases and bacterial antimicrobial resistance (AMR) is a significant concern in global public health. There is an urgent demand for new therapeutic agents that not only offer improved efficiency but also entail fewer secondary effects, addressing the challenges posed by the currently available drugs used in clinical practice. In this study, 40 analogues of β-carboline were subjected to solubility tests to determine their solubility. Among them, 22 analogues proved to be soluble and were subsequently tested for in vitro antibacterial activity using the agar disc diffusion method against S. aureus and E. coli to evaluate their effectiveness. The results of the in vitro antibacterial studies revealed that compounds 1h, 7d, and 1l displayed appreciable growth-inhibitory effects against E. coli, while compounds 1a, 1f, 1l, and 1j exhibited appreciable growth-inhibitory effects against S. aureus. Notably, compounds 1j and 1l displayed the highest growth-inhibitory potency against S. aureus and E. coli, respectively, out of the 22 compounds tested. Of all the analogues examined, 1l and 1j demonstrated the most substantial growth-inhibitory effects against E. coli and S. aureus, respectively, underscoring their potential as inhibitors.

Eco-friendly Synthesis of Indole Conjugated Chromeno[d]Pyrimidines as Anti-cancer Agents and their Molecular Modelling Studies

Introduction: Many medicinally active new chemical entities depend on indole conjugated chromeno[d]pyrimidine derivatives as a building block. The synthesis of 4-(1H-indol-3-yl)-3,4- dihydro-1H-chromeno[4,3-d]pyrimidine-2,5-dione 4 were achieved in the current study by treating 4- hydroxy-2H-chromen-2-one 1, indole aldehydes 2, and urea/thiourea 3 in the presence of L-proline. Methods: By adopting the above protocol, we were able to synthesize eight compounds, i.e. 4-(1Hindol- 3-yl)-3,4-dihydro-1H-chromeno[4,3-d]pyrimidine-2,5-diones (4a-4h), in the presence of Lproline as a catalyst in ethanol as solvent for 2-3 hours at 70-75°C with decent yields of 80-85%, and their structures were ascertained by various spectral techniques. They were further screened for their potentiality to inhibit cancer growth in HepG2 and MDA-MD-231 cells. Results: The scope of the synthesis of biological relevant Indole conjugated Chromeno[ d]Pyrimidines by three-component reaction (MCRs) process was investigated. The most optimised conditions obtained were 0.3 eq of L-proline for 2 hours at 70-75°C which gave the best yield (85%). The few advantages of this newly developed method are excellent yields, no metal catalyst, less toxic solvents, simple workup no chromatographic column purifications. On further screening for their anticancer activities, out of all, the compound 4b displayed noteworthy cytotoxicity with IC50 values of 8.1 and 9.2 μM against HepG2 and MDA-MD-231, respectively. Additionally, in silico studies also supported that compound 4b had favourable binding energy (-7.8 kcal/mol) when compared to the co-crystal ligand (LS5) in inhibiting the human cyclin-dependent kinase 2 (CDK2) protein. Conclusion: In conclusion, we have developed a simple, convenient, and efficient method for the synthesis of structurally diverse indole conjugated chromeno[d]pyrimidine analogues in the presence of L-proline as catalyst in ethanol as solvent with good yields. Further, the in vitro cytotoxic studies against HepG2 and MDA-MD-231 cells demonstrated that the synthesized compounds had good to reasonable activity, except for compound 4d.

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 comparative anticancer studies of Novel amide functoinalised thienopyridine and pyridothienopyrimidinone derivatives

Amide functionalized trifluoromethyl thieno[2,3-b] pyridine derivatives as a series were prepared starting from reaction between 1,3 di-ketone and thiocyanoacetamide. Compound 3 reacts with bromoethyl acetate to give compound 4. Compound 4 on reaction with diverse substituted aromatic and aliphatic amines gives amide derivatives 5a-f and these amide derivatives on reaction with triethylorthoformate give pyridothienopyrimidinone derivatives 6a-f. All the final compounds were evaluated for anti cancer activity against four human cancer cell lines such as A549—Lung cancer (CCL-185), MCF7—Breast cancer (HTB-22), DU145—Prostate cancer (HTB-81) and HeLa—Cervical cancer (CCL-2) by using MTT assay. Promising compound 5d was identified.

Synthesis, structural modification, and biological activity of a novel bisindole alkaloid iheyamine A

Diseases caused by plant viruses and pathogens pose a serious threat to crop yield and quality. Traditional pesticides have gradually developed drug resistance and brought certain environmental safety issues during long-term overuse. There is an urgent need to discover new candidate compounds to address these issues. In this study, we achieved the efficient synthesis of iheyamine A and its derivatives, and discovered their excellent antiviral activities against tobacco mosaic virus (TMV). Most compounds displayed higher antiviral activities against TMV than commercial ribavirin at 500 μg/mL, with compounds 3a (Inactive effect IC50: 162 µg/mL), 3d (Inactive effect IC50: 249 µg/mL), 6p (Inactive effect IC50: 254 µg/mL), and 7a (Inactive effect IC50: 234 µg/mL) exhibiting better antiviral activities than ningnanmycin at 500 μg/mL (Inactive effect IC50: 269 µg/mL). Meanwhile, the structure–activity relationships of this type of compounds were systematically studied. We chose 3a for further antiviral mechanism research and found that it can directly act on viral coat protein (CP). The interaction of 3a and CP was further verified via molecular docking. These compounds also showed broad-spectrum fungicidal activities against 8 plant pathogenic fungi, especially for P. piricola. This study provides a reference for the role of iheyamine alkaloids in combating plant pathogenic diseases.

Synthesis, crystal structure, Hirshfeld surface, computational and biological studies of spiro-oxindole derivatives as MDM2-p53 inhibitors.

The spiro-oxindole derivatives were synthesized via a 1,3-dipolar cycloaddition approach and characterized by FT-IR, 1H, 13C NMR and mass spectral techniques. The single crystal XRD of 6d further validates the formation of compounds. DFT calculations indicated the reactive nature of compound 6d. Docking studies with 5LAW disclosed the minimum binding energy of - 10.83kcal/mol for 6d. Furthermore, safe oral bioavailability was ensured by the physicochemical, pharmacokinetic, and toxicity predictions. The anticancer analysis of synthesized compounds showed substantial activity against A549 cells, notably with an IC50 value of 8.13 ± 0.66µM for 6d compared to standard doxorubicin. 6d was also evaluated for cytotoxicity against L929 healthy cells and A549, showing selectivity towards A549 than healthy cells. AO/EB staining method showed early apoptotic cellular death in the A549 cell line in a dose-dependent manner.

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.

Thiophene-Linked 1,2,4-Triazoles: Synthesis, Structural Insights and Antimicrobial and Chemotherapeutic Profiles.

The reaction of thiophene-2-carbohydrazide 1 or 5-bromothiophene-2-carbohydrazide 2 with various haloaryl isothiocyanates and subsequent cyclization by heating in aqueous sodium hydroxide yielded the corresponding 4-haloaryl-5-(thiophen-2-yl or 5-bromothiophen-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione 5a-e. The triazole derivatives 5a and 5b were reacted with different secondary amines and formaldehyde solution to yield the corresponding 2-aminomethyl-4-haloaryl-2,4-dihydro-3H-1,2,4-triazole-3-thiones 6a-e, 7a-e, 8, 9, 10a and 10b in good yields. The in vitro antimicrobial activity of compounds 5a-e, 6a-e, 7a-d, 8, 9, 10a and 10b was evaluated against a panel of standard pathogenic bacterial and fungal strains. Compounds 5a, 5b, 5e, 5f, 6a-e, 7a-d, 8, 9, 10a and 10b showed marked activity, particularly against the tested Gram-positive bacteria and the Gram-negative bacteria Escherichia coli, and all the tested compounds were almost inactive against all the tested fungal strains. In addition, compounds 5e, 6a-e, 7a-d and 10a exhibited potent anti-proliferative activity, particularly against HepG-2 and MCF-7 cancer cell lines (IC50 < 25 μM). A detailed structural insight study based on the single crystals of compounds 5a, 5b, 6a, 6d and 10a is also reported. Molecular docking studies of the highly active antibacterial compounds 5e, 6b, 6d, 7a and 7d showed a high affinity for DNA gyrase. Meanwhile, the potent anti-proliferative activity of compounds 6d, 6e and 7d may be attributed to their high affinity for cyclin-dependent kinase 2 (CDK2).