Synthesis and Anti-Breast Cancer Potency of Mono- and Bis-(pyrazolyl[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine) Derivatives as EGFR/CDK-2 Target Inhibitors.

The target mono- and bis-(6-pyrazolyltriazolo-thiadiazine) derivatives 4a-c and 6a-d were synthesized using a straightforward protocol via reaction of 3-bromoacetylpyrazole 2 with 4-amino-s-triazole-3-thiols 3a-c and bis(4-amino-5-mercapto-s-triazol-3-yl)alkanes 5a-d, respectively. The bis(6-pyrazolyl-s-triazolo[3,4-b][1,3,4]thiadiazine) derivatives 8a,b and 10 were also constructed by reaction of the triazolo[3,4-b][1,3,4]thiadiazine-3-thiol 4c with the proper dibromo compounds 7a,b and 9, respectively. Structures of the new substances were determined by spectroscopic and analytical data. Compounds 4b, 4c, and 6a showed potent cytotoxicity against MCF-7 (IC50 = 3.16, 2.74, and 0.39 µM, respectively) and were safe against the MCF-10A cells. Compounds 4b, 4c, and 6a also showed promising dual EGFR and CDK-2 inhibition activities, particularly 6a was the most effective (IC50 = 19.6 and 87.9 nM, respectively), better than Erlotinib and Roscovitine. Compound 6a treatment induced EGFR and CDK-2 enzyme inhibition by 97.18% and 94.11%, respectively, at 10 µM (the highest concentration). Compound 6a notably induced cell apoptosis in MCF-7 cells, increasing the cell population by total apoptosis 43.3% compared to 1.29% for the untreated control group, increasing the cell population at the S-phase by 39.2% compared to 18.6% (control).

Synthesis of novel mono- and bis-pyrazolylthiazole derivatives as anti-liver cancer agents through EGFR/HER2 target inhibition.

3-Bromoacetyl-4-(2-naphthoyl)-1-phenyl-1H-pyrazole (6) was synthesized from 2-acetylnaphthalene and was used as a new key building block for constructing the title targets. Thus, the reaction of 6 with the thiosemicarbazones 7a-d and 9-11 afforded the corresponding simple naphthoyl-(3-pyrazolyl)thiazole hybrids 8a-d and 12 ~ 14. The symmetric bis-(2-naphthoyl-pyrazol-3-yl)thiazol-2-yl)hydrazono)methyl)phenoxy)alkanes 18a-c and 21a-c were similarly synthesized from reaction of 6 with the appropriate bis-thiosemicarbazones 17a-c and 19a-c, respectively. The synthesized two series of simple and symmetrical bis-molecular hybrid merging naphthalene, thiazole, and pyrazole were evaluated for their cytotoxicity. Compounds 18b,c and 21a showed the most potent cytotoxicity (IC50 = 0.97-3.57 µM) compared to Lapatinib (IC50 = 7.45 µM). Additionally, they were safe (non-cytotoxic) against the THLE2 cells with higher IC50 values. Compounds 18c exhibited promising EGFR and HER-2 inhibitory activities with IC50 = 4.98 and 9.85 nM, respectively, compared to Lapatinib (IC50 = 6.1 and 17.2 nM). Apoptosis investigation revealed that 18c significantly activated apoptotic cell death in HepG2 cells, increasing the death rate by 63.6-fold and arresting cell proliferation at the S-phase. Compound 18c upregulated P53 by 8.6-fold, Bax by 8.9-fold, caspase-3,8,9 by 9, 2.3, and 7.6-fold, while it inhibited the Bcl-2 expression by 0.34-fold. Thereby, compound 18c exhibited promising cytotoxicity against EGFR/HER2 inhibition against liver cancer.

Synthesis and Evaluation of Thioamide and Bromo Derivatives of 1,3-Diphenylpropane-1,3-dione as 5α-Reductase Inhibitors.

BACKGROUND: 1,3-Diphenylpropane-1,3-dione (1) is an acetylacetone ß-diketone in which both of the methyl groups have been replaced with phenyl groups. It is a component of licorice root extract (Glycyrrhiza glabra) and has anti-mutagenic and anti-cancer properties. It functions as a metabolite, an anti-mutagen, and an anti-neoplastic agent. It is an aromatic ketone and a ß-diketone. 1,3-Diphenylpropane-1,3-dione (1) is primarily used in PVC hard and soft materials, including plates, films, profiles, pipes, and fittings. OBJECTIVES: This research aims to examine the utility of 1,3-diphenylpropane-1,3-dione (1) for the synthesis of a variety of new heterocyclic compounds, such as thioamide, thiazolidine, thiophene-2-carbonitrile, phenylthiazole, thiadiazole-2-carboxylate, 1,3,4-thiadiazole derivatives, 2-bromo-1,3-diphenylpropane-1,3-dione, new substituted benzo[1,4]thiazines, phenylquinoxalines, and imidazo[1,2-b][1,2,4]triazole derivatives of potential biological activity Methods: 1,3-Diphenylpropane-1,3-dione (1) was used as a starting compound for the synthesis of 3-oxo-N,3-diphenyl-2-(phenylcarbonyl)propanethioamide (3) and 2-bromo-1,3-diphenylpropane-1,3-dione (25), which can be used for further preparations. The 5α-reductase inhibitor activity of some of the synthesized compounds was also tested in vivo; the ED50 and LD50 data were established, Results: Using IR, 1H-NMR, mass spectroscopy, and elemental analysis, the structures of all produced compounds were elucidated. Some of these prepared compounds were reported as 5α-reductase inhibitors. CONCLUSION: New heterocyclic compounds can be formed via 1,3-diphenylpropane-1,3-dione (1), and some of these compounds can act as 5α-reductase inhibitors.

Design and synthesis of new bis(1,2,4-triazolo[3,4-b][1,3,4]thiadiazines) and bis((quinoxalin-2-yl)phenoxy)alkanes as anti-breast cancer agents through dual PARP-1 and EGFR targets inhibition.

A number of new 1,ω-bis((acetylphenoxy)acetamide)alkanes 5a-f were prepared then their bromination using NBS furnished the novel bis(2-bromoacetyl)phenoxy)acetamides 6a-f. Reaction of 6a-f with 4-amino-5-substituted-4H-1,2,4-triazole-3-thiol 7a-d and with o-phenylenediamine derivatives 9a and b afforded the corresponding bis(1,2,4-triazolo[3,4-b][1,3,4]thiadiazine) derivatives 8a-l and bis(quinoxaline) derivatives 10a-e in good yields. The cytotoxicity of the synthesized compounds as well as apoptosis induction through PARP-1 and EGFR as molecular targets was evaluated. Three compounds, 8d, 8i and 8l, exhibited much better cytotoxic activities against MDA-MB-231 than the drug Erlotinib. Interestingly, compound 8i induced apoptosis in MDA-MB-231 cells by 38-fold compared to the control arresting the cell cycle at the G2/M phase, and its treatment upregulated P53, Bax, caspase-3, caspase-8, and caspase-9 gene levels, while it downregulated the Bcl2 level. Compound 8i exhibited promising dual enzyme inhibition of PARP-1 (IC50 = 1.37 nM) compared to Olaparib (IC50 = 1.49 nM), and EGFR (IC50 = 64.65 nM) compared to Erlotinib (IC50 = 80 nM). These results agreed with the molecular docking studies that highlighted the binding disposition of compound 8i inside the PARP-1 and EGFR protein active sites. Hence, compound 8i may serve as a potential anti-breast cancer agent.

Antiviral activity of chitosan nanoparticles encapsulating silymarin (Sil-CNPs) against SARS-CoV-2 (in silico and in vitro study).

To develop a specific treatment against COVID-19, we investigated silymarin-chitosan nanoparticles (Sil-CNPs) as an antiviral agent against SARS-CoV-2 using in silico and in vitro approaches. Docking of Sil and CNPs was carried out against SARS-CoV-2 spike protein using AutoDock Vina. CNPs and Sil-CNPs were prepared by the ionic gelation method and characterized by TEM, FT-IR, zeta analysis, and the membrane diffusion method to determine the drug release profile. Cytotoxicity was tested on both Vero and Vero E6 cell lines using the MTT assay. Minimum binding energies with spike protein and ACE2 were -6.6, and -8.0 kcal mol-1 for CNPs, and -8.9, and -9.7 kcal mol-1 for Sil, respectively, compared to -6.6 and -8.4 kcal mol-1 respectively for remdesivir (RMV). CNPs and Sil-CNPs were prepared at sizes of 29 nm and 82 nm. The CC50 was 135, 35, and 110 µg mL-1 for CNPs, Sil, and Sil-CNPs, respectively, on Vero E6. The IC50 was determined at concentrations of 0.9, 12 and 0.8 µg mL-1 in virucidal/replication assays for CNPs, Sil, and Sil-CNPs respectively using crystal violet. These results indicate antiviral activity of Sil-CNPs against SARS-CoV-2.

Assessment of Thyroid Function and Oxidative Stress State in Foundry Workers Exposed to Lead.

BACKGROUND: Exposure to lead (Pb) has been associated with endocrine, hematological, gastrointestinal, renal and neurological problems in humans. However, effects on the thyroid gland are controversial. OBJECTIVES: The aim of the present study was to assess thyroid function in foundry workers occupationally exposed to Pb and the mechanism of oxidative-antioxidant imbalance. METHODS: Thyroid function parameters and markers of oxidative stress were examined in 59 adult males who had been occupationally exposed to Pb. The results were then compared to those of 28 male subjects who had no history of Pb exposure or thyroid abnormalities and served as a control group. RESULTS: Mean blood lead levels (16.5±1.74 µg/dl) were significantly higher among the exposed workers compared to those of the control group (12.8±1.16 µg/dl, (p <0.001)). The exposed group had significantly increased free triiodothyronine (FT3), free thyroxine (FT4) and significantly decreased thyroid stimulating hormone (TSH) (1.77±0.44 µIU/ml), whereas the control group had a TSH level of 2.61±0.94 µIU/ml (p< 0.0001). A state of oxidative stress was indicated by the significant increase in mean levels of malondialdehyde (MDA) and significant decrease in glutathione (GSH) (p < 0.0001). There was a significant positive correlation (r=0.358, p <0.05) between blood lead levels (BLL) and duration of employment, while BLL showed a significant negative correlation with TSH (r =-0.486, p <0.001), and GSH (r =-0.336, p <0.05). Of the occupationally exposed workers, 32.76% had elevated thyroid hormones. The results showed a significant positive relationship between GSH and TSH (ß coefficient=0.274, p < 0.05), MDA with FT3 (ß coefficient=0.355, p < 0.05) and FT4 (ß coefficient = 0.491, p < 0.0001) among exposed workers. CONCLUSIONS: Workers exposed to Pb dust proved to be at risk for hyperthyroidism, which was found to have a significant role in oxidative-antioxidant imbalance present among workers with increasing duration of exposure. PARTICIPANT CONSENT: Obtained. ETHICS APPROVAL: This study was approved by the Ethical Committee of the National Research Centre in Egypt (NRC) under the registration number 15225. COMPETING INTERESTS: The authors declare no competing financial interests.

Synthesis and antimicrobial evaluation of some new cyclooctanones and cyclooctane-based heterocycles.

The versatile synthon (E)-2-((dimethyl amino)methylene)cyclooctanone (2) was used as a key intermediate for the synthesis of cyclooctanones and cyclooctane-based heterocycles with pyrazole, isoxazole, pyrimidine, pyrazolopyrimidine, triazolopyrimidine and imidazopyrimidine derivatives via its reactions with several nitrogen nucleophiles. The newly synthesized compounds were screened in vitro for their antimicrobial activity against pathogenic microorganisms (Listeria monocytogenes, methicillin-resistant Staphylococcus aureus (MRSA), Staphylococcus aureus, Pseudomonas aeruginosa and Candida albicans). Most of the tested compounds showed moderate to high antibacterial and antifungal effects against the tested pathogenic microorganisms. Among the synthesized compounds, 2-((p-sulfonamidophenyl)methylene)cyclooctanone (5) showed excellent activity against Listeria monocytogenes.

Synthesis of new functionalized 3-substituted [1,2,4]triazolo [4,3-a]pyrimidine derivatives: potential antihypertensive agents.

A convenient synthesis of a series of thiosemicarbazide, 1,3,4-oxadiazole, 1,3,4-thiadiazole, thiazole, 1,2,4-triazole, pyrazole and dioxoisoindoline derivatives incorporating 1,2,4-triazolo[4,3-a]pyrimidine via the reaction of the readily accessible 1,5-dihydro-5-oxo-1.7-diphenyl-1,2.4-triazolo[4,3-a]pyrimidine-3-carbohydrazide (2) with the appropriate reagents is described. The newly synthesized compounds were found to possess antihypertensive and diuretic activities compared to captopril and furosemide as reference controls, respectively.

Synthesis, anti-HCV, antioxidant, and peroxynitrite inhibitory activity of fused benzosuberone derivatives.

Reaction of benzosuberone 1 with dimethylformamide-dimethylacetal (DMF-DMA) gives 2-dimethylamino-methylenebenozosuberone 2 which in turn reacts with heterocyclic amines to furnish new heterocyclic ring systems 6-9. Moreover, enaminone 2 reacts with hydrazine hydrate and hydroxylamine hydrochloride to afford the corresponding benzo[6,7]cyclohepta[1,2-c]pyrazole (10) and benzo[6,7]cyclohepta[2,1-d]isoxazole (12), respectively. In addition, the reactions of enaminone 2 with active methylene compounds afforded benzo[6,7]cyclohepta[1,2-b]pyridines (13-18). The X-ray crystallographic analysis of compounds 6 and 16, were recorded. We demonstrated the ability of nine new synthesized compounds to inhibit Hepatitis C Virus (HCV) and Subacute Sclerosing Panencephalitis (SSPE) due to structural similarity between ribavirin and some of the newly synthesized compounds were they contain triazoles and its bioisosters. In addition, the ability of ten synthesized compounds to react with the biologically relevant reactive nitrogen species, peroxynitrite was investigated indirectly by measurement of their ability to inhibit ONOO(-)-induced tyrosine nitration. The antioxidant activity of these ten compounds was also studied using 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay.

Synthesis and biological evaluation of new 3-substituted indole derivatives as potential anti-inflammatory and analgesic agents.

Treatment of 3-cyanoacetyl indole 1 with the diazonium salts of 3-phenyl-5-aminopyrazole and 2-aminobenzimidazole afforded the corresponding hydrazones 4 and 5. 3-Cyanoacetyl indole reacted with phenylisothiocyanate to give the corresponding thioacetanilide derivative 7. Treatment of 7 with hydrazonoyl chlorides afforded the corresponding 1,3,4-thiadiazole derivatives 8a-f and 9. Also, the thioacetanilide reacted with alpha-haloketones to afford thiophene derivatives 10a,b (tenidap analogues), or thiazolidin-4-one derivative 11. The newly synthesized compounds were found to possess potential anti-inflammatory and analgesic activities.