Discovery of Potent Indolyl-Hydrazones as Kinase Inhibitors for Breast Cancer: Synthesis, X-ray Single-Crystal Analysis, and In Vitro and In Vivo Anti-Cancer Activity Evaluation.

According to data provided by the World Health Organization (WHO), a total of 2.3 million women across the globe received a diagnosis of breast cancer in the year 2020, and among these cases, 685,000 resulted in fatalities. As the incidence of breast cancer statistics continues to rise, it is imperative to explore new avenues in the ongoing battle against this disease. Therefore, a number of new indolyl-hydrazones were synthesized by reacting the ethyl 3-formyl-1H-indole-2-carboxylate 1 with thiosemicarbazide, semicarbazide.HCl, 4-nitrophenyl hydrazine, 2,4-dinitrophenyl hydrazine, and 4-amino-5-(1H-indol-2-yl)-1,2,4-triazole-3-thione to afford the new hit compounds, which were assigned chemical structures as thiosemicarbazone 3, bis(hydrazine derivative) 5, semicarbzone 6, Schiff base 8, and the corresponding hydrazones 10 and 12 by NMR, elemental analysis, and X-ray single-crystal analysis. The MTT assay was employed to investigate the compounds' cytotoxicity against breast cancer cells (MCF-7). Cytotoxicity results disclosed potent IC50 values against MCF-7, especially compounds 5, 8, and 12, with IC50 values of 2.73 ± 0.14, 4.38 ± 0.23, and 7.03 ± 0.37 µM, respectively, compared to staurosproine (IC50 = 8.32 ± 0.43 µM). Consequently, the activities of compounds 5, 8, and 12 in relation to cell migration were investigated using the wound-healing test. The findings revealed notable wound-healing efficacy, with respective percentages of wound closure measured at 48.8%, 60.7%, and 51.8%. The impact of the hit compounds on cell proliferation was assessed by examining their apoptosis-inducing properties. Intriguingly, compound 5 exhibited a significant enhancement in cell death within MCF-7 cells, registering a notable increase of 39.26% in comparison to the untreated control group, which demonstrated only 1.27% cell death. Furthermore, the mechanism of action of compound 5 was scrutinized through testing against kinase receptors. The results revealed significant kinase inhibition, particularly against PI3K-α, PI3K-ß, PI3K-δ, CDK2, AKT-1, and EGFR, showcasing promising activity, compared to standard drugs targeting these receptors. In the conclusive phase, through in vivo assay, compound 5 demonstrated a substantial reduction in tumor volume, decreasing from 106 mm³ in the untreated control to 56.4 mm³. Moreover, it significantly attenuated tumor proliferation by 46.9%. In view of these findings, the identified leads exhibit promises for potential development into future medications for the treatment of breast cancer, as they effectively hinder both cell migration and proliferation.

Do corporate anti-bribery and corruption commitments enhance environmental management performance? The moderating role of corporate social responsibility accountability and executive compensation governance.

This study aims to examine the potential impact (substantive or symbolic) of firms' anti-bribery and corruption commitments (ABCC) on environmental management performance (ENVS). We also seek to explore whether this link is contingent on corporate social responsibility (CSR) accountability and executive compensation governance. To achieve these aims, we use a sample of 2151 firm-year observations representing 214 FTSE 350 non-financial companies from 2002 to 2016. Our findings support a positive association between firms' ABCC and ENVS. In addition, our evidence shows that CSR accountability and executive compensation governance are significant substitutes for ABCC to engender enhanced ENVS. Our study highlights practical implications for organisations, regulators and policymakers, and suggests several avenues for future environmental management research. Overall, our findings are unsensitive to alternative measures of ENVS, different types of multivariate regression methods, namely ordinary least squares (OLS) and two-step generalized method of moments (GMM) regressions, and controlling for industry environmental risk and the implementation of the UK Bribery Act 2010.

In-vitro viability of laser cladded Fe-based metallic glass as a promising bioactive material for improved osseointegration of orthopedic implants.

The commonly used metallic biomaterials fail to prove durability for orthopedics due to their lack of biocompatibility and poor bioactivity which weakens the bonding to bones. Metallic glasses (MGs) have attracted attention as an alternative biomaterial for orthopedics owing to their superior mechanical properties and acceptable biocompatibility. Nevertheless, their uses are limited due to geometrical constraints and brittleness. In this research, the in-vitro bioactivity of laser cladded FeCrMoCB MG on nickel-free stainless-steel was investigated. The proposed MG coating exhibited a remarkable in-vitro bioactivity behavior without prior treatment after immersion in simulated body fluid which is a key factor for better osseointegration. The surface morphology showed that apatite nucleated from the first day and completely covered the surface after 21 days. The energy dispersive spectroscopy spectra showed an increase in the Ca/P ratio from 0.51 at 3 days to 1.61 at 21 days, thus approaching the stoichiometric ratio of bone apatite. The infra-red examination revealed the existence of Ca+2, PO4-2 and OH- indicating the nucleation of brushite and B-type apatite. Additionally, the X-ray diffraction examination revealed the existence of amorphous and nanocrystalline calcium phosphates. These results show the potential of FeCrMoCB MGs as a promising bioactive coating for excellent osseointegration of metallic implants with bone tissue.

Expeditious Green Synthesis of Novel 4-Methyl-1,2,5,6-tetraazafluoranthen-3(2H)-one Analogue from Ninhydrin: N/S-Alkylation and Aza-Michael Addition.

A straightforward green synthesis of 4-methyl-1,2,5,6-tetraazafluoranthen-3(2H)-one 6 is reported from ninhydrin 1 via condensation with ethyl acetoacetate, followed by cyclization with hydrazine hydrate in water as a benign solvent. Tetraazafluoranthen-3-thione 7 was obtained using Lawesson's reagent. N-alkylated tetraazafluoranthen-3-one 8-12 and S-alkylated analogues 13-15 were synthesized via alkylation. The investigation of the unique reactivity of 4-methyl-1,2,5,6-tetraazafluoranthen-3(2H)-one/thione toward the alkylation and aza-Michael additions was explored.

Synthesis of a New Series of Nitrogen/Sulfur Heterocycles by Linking Four Rings: Indole; 1,2,4-Triazole; Pyridazine; and Quinoxaline.

A new series of nitrogen and sulfur heterocyclic systems were efficiently synthesized by linking the following four rings: indole; 1,2,4-triazole; pyridazine; and quinoxaline hybrids. The strength of the acid that catalyzes the condensation of 4-amino-5-(1H-indol-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione 1 with aromatic aldehydes controlled the final product. Reflux in glacial acetic acid yielded Schiff bases 2-6, whereas concentrated HCl in ethanol resulted in a cyclization product at C-3 of the indole ring to create indolo-triazolo-pyridazinethiones 7-16. This fascinating cyclization approach was applicable with a wide range of aromatic aldehydes to create the target cyclized compounds in excellent yield. Additionally, the coupling of the new indolo-triazolo-pyridazinethiones 7-13 with 2,3-bis(bromomethyl)quinoxaline, as a linker in acetone and K2CO3, yielded 2,3-bis((5,6-dihydro-14H-indolo[2,3-d]-6-aryl-[1,2,4-triazolo][4,3-b]pyridazin-3 ylsulfanyl)methyl)quinoxalines 19-25 in a high yield. The formation of this new class of heterocyclic compounds in high yields warrants their use for further research. The new compounds were characterized using nuclear magnetic resonance (NMR) and mass spectral analysis. Compound 6 was further confirmed by the single crystal X-ray diffraction technique.

Discovery of hydrazide-based pyridazino[4,5-b]indole scaffold as a new phosphoinositide 3-kinase (PI3K) inhibitor for breast cancer therapy.

Herein, the mono and dialkylation of pyridazino[4,5-b]indole were achieved with a set of alkylating agents, including amyl bromide, allyl bromide, benzyl bromide and ethyl chloroacetate in the presence of K2CO3/acetone or KOH/DMSO. The hydrazinolysis of mono and di-esters 10 and 11 gave the target hydrazides 12 and 13, which displayed promising, potent, and significant cytotoxic activity against the MCF-7 cell line with IC50 values of 4.25 and 5.35 µm compared to that of the standard drug 5-FU (IC50 6.98 µm), respectively. RT-PCR analysis of the most active compound 12 was performed to determine its mode of action through the up-regulation of pro-apoptotic genes and inhibition of anti-apoptotic and PI3K/AKT/mTOR genes. The findings were consistent with the proposed mechanism illustrated in the in silico study. Further, the in vivo analysis exhibited its potent anti-cancer activity through the prolongation of survival parameters, and inhibition of ascetic fluid parameters in EAC-bearing mice.

Fabrication and deformation behaviour of multilayer Al2O3/Ti/TiO2 nanotube arrays.

In this study, titanium thin films were deposited on alumina substrates by radio frequency (RF) magnetron sputtering. The mechanical properties of the Ti coatings were evaluated in terms of adhesion strength at various RF powers, temperatures, and substrate bias voltages. The coating conditions of 400W of RF power, 250°C, and a 75V substrate bias voltage produced the strongest coating adhesion, as obtained by the Taguchi optimisation method. TiO2 nanotube arrays were grown as a second layer on the Ti substrates using electrochemical anodisation at a constant potential of 20V and anodisation times of 15min, 45min, and 75min in a NH4F electrolyte solution (75 ethylene glycol: 25 water). The anodised titanium was annealed at 450°C and 650°C in a N2 gas furnace to obtain different phases of titania, anatase and rutile, respectively. The mechanical properties of the anodised layer were investigated by nanoindentation. The results indicate that Young's modulus and hardness increased with annealing temperature to 650°C.