Synthesis of novel phthalazine-based derivatives with potent cytotoxicity against HCT-116 cells through apoptosis and VEGFR2 inhibition.

The parent ethyl 3-(4-benzyl-1-oxophthalazin-2(1H)-yl) propanoate (3) has 25 compounds. Their respective mono, dipeptides and hydrazones derivatives were produced by chemoselective N-alkylation via addition reaction of 4-benzylphthalazin-1(2H)-one (2) with ethyl acrylate and anhydrous potassium carbonate to give ethyl 3-(4-benzyl-1-oxophthalazin-2(1H)-yl) propanoate (3). The ester 3 was hydrazinolyzed to give the corresponding hydrazide 3-(4-benzyl-1-oxophthalazin-2(1H)-yl) propanehydrazide (5), then azide 6 coupled with amino acid ester hydrochloride and/or amines to afford several parent esters 8a-c, then a series of hydrazinolyzed reactions occurred to give corresponding hydrazides 9a-c. The hydrazide 9a was subjected to the azide coupling procedure, which resulted in the formation of various dipeptides. Subsequently, it was condensed with various aldehydes to yield hydrazone derivatives 13a-d. Interestingly, compounds 9c, 12b, and 13c exhibited potent cytotoxicity with IC50 values of 1.58, 0.32 and 0.64 µM compared to sorafenib (IC50 = 2.93 µM). Compound 12b exhibited potent VEGFR2 inhibition by 95.2% with an IC50 value of 17.8 µM compared to sorafenib (94.7% and IC50 of 32.1 µM). For apoptosis activity, 12b-treatment induced apoptosis in HCT-116 cells by 21.7-fold, arresting the cell proliferation at S-phase. Finally, it formed a good binding affinity towards VEGFR2 protein with a binding energy of -10.66 kcal mol-1, and it formed binding interactions with the key interactive amino acids.

Identification of potential antiviral compounds from Egyptian sea stars against MERS-CoV with the in vitro and in silico experiments.

Recently, the world faced many epidemics which were caused by viral respiratory pathogens. Marine creatures including Asteroidea class have been one of the recent research topics due to their diverse and complex secondary metabolites. Some of these constituents exhibit antiviral activities. The present study aimed to extract and identify the potential antiviral compounds from Pentaceraster cumingi, Astropecten polyacanthus and Pentaceraster mammillatus. The results showed that promising activity of the methanolic extract of P. cumingi with 50% inhibitory concentration (IC50) of 3.21 mg/ml against MERS-CoV with a selective index (SI) of 13.975. The biochemical components of the extracts were identified by GC/MS analysis. The Molecular docking study highlighted the virtual mechanism of binding the identified compounds towards three PDB codes of MERS-CoV non-structural protein 10/16. Interestingly, 2-mono Linolein showed promising binding energy of -14.75 Kcal/mol with the second PDB code (5YNI) and -15.22 Kcal/mol with the third PDB code (5YNQ).

Synthesis of novel bioactive pyrido[2,3-d]pyrimidine derivatives with potent cytotoxicity through apoptosis as PIM-1 kinase inhibitors.

Direct synthesis and cytotoxicity activity of new series of pyrido[2,3-d]pyrimidine was described. Nicotinamide 2 was synthesized via cyclization of N-cyclohexyl derivative with cyanoacetamide. The o-aminonicotinonitrile 2 was subjected to acylation or thio acylation process followed by intramolecular heterocyclization to afford the desired pyrido[2,3-d]pyrimidine (3-10) and pyrido triazine 11. Compounds 4 and 11 exhibited remarkable cytotoxicity against MCF-7 cells with IC50 values of 0.57 µM and 1.31 µM and IC50 values of 1.13 µM and 0.99 µM against HepG2 cells. Interestingly, compounds 4 and 10 had potent PIM-1 kinase inhibition with IC50 values of 11.4 and 17.2 nM, respectively, with inhibition of 97.8% and 94.6% compared to staurosporine (IC50 = 16.7 nM, with 95.6% inhibition). Moreover, compound 4 significantly activated apoptosis in MCF-7 cells, increasing the cell apoptosis by 58.29-fold by having 36.14% total apoptosis in treated cells compared to 0.62% for control. Moreover, it arrested the cell cycle at the G1 phase. PIM-1 kinase inhibition was virtually elucidated by the molecular docking study, highlighting binding interactions of the lead compound 4 towards the PIM-1 protein. Accordingly, compound 4 was validated as a promising PIM-1 targeted chemotherapeutic agent to treat breast cancer.

Exploring pyrrolidinyl-spirooxindole natural products as promising platforms for the synthesis of novel spirooxindoles as EGFR/CDK2 inhibitors for halting breast cancer cells.

Cancer represents a global challenge, and the pursuit of developing new cancer treatments that are potent, safe, less prone to drug resistance, and associated with fewer side effects poses a significant challenge in cancer research and drug discovery. Drawing inspiration from pyrrolidinyl-spirooxindole natural products, a novel series of spirooxindoles has been synthesized through a one-pot three-component reaction, involving a [3 + 2] cycloaddition reaction. The cytotoxicity against breast cancer cells (MCF-7 and MDA-MB-231) and safety profile against WISH cells of the newly developed library were assessed using the MTT assay. Compounds 5l and 5o exhibited notable cytotoxicity against MCF-7 cells (IC50 = 3.4 and 4.12 µM, respectively) and MDA-MB-231 cells (IC50 = 8.45 and 4.32 µM, respectively) compared to Erlotinib. Conversely, compounds 5a-f displayed promising cytotoxicity against MCF-7 cells with IC50 values range (IC50 = 5.87-18.5 µM) with selective activity against MDA-MB-231 cancer cells. Compound 5g demonstrated the highest cytotoxicity (IC50 = 2.8 µM) among the tested compounds. Additionally, compounds 5g, 5l, and 5n were found to be safe (non-cytotoxic) against WISH cells with higher IC50 values ranging from 39.33 to 47.2 µM. Compounds 5g, 5l, and 5n underwent testing for their inhibitory effects against EGFR and CDK-2. Remarkably, they demonstrated potent EGFR inhibition, with IC50 values of 0.026, 0.067, and 0.04 µM and inhibition percentages of 92.6%, 89.8%, and 91.2%, respectively, when compared to Erlotinib (IC50 = 0.03 µM, 95.4%). Furthermore, these compounds exhibited potent CDK-2 inhibition, with IC50 values of 0.301, 0.345, and 0.557 µM and inhibition percentages of 91.9%, 89.4%, and 88.7%, respectively, in contrast to Roscovitine (IC50 = 0.556 µM, 92.1%). RT-PCR analysis was performed on both untreated and 5g-treated MCF-7 cells to confirm apoptotic cell death. Treatment with 5g increased the gene expression of pro-apoptotic genes P53, Bax, caspases 3, 8, and 9 with notable fold changes while decreasing the expression of the anti-apoptotic gene Bcl-2. Molecular docking and dynamic simulations (100 ns simulation using AMBER22) were conducted to investigate the binding mode of the most potent candidates, namely, 5g, 5l, and 5n, within the active sites of EGFR and CDK-2.

N-allyl quinoxaline derivative exhibited potent and selective cytotoxicity through EGFR/VEGFR-mediated apoptosis: In vitro and in vivo studies.

The cytotoxic activity, EGFR/VEGFR2 target inhibition, apoptotic activity, RT-PCR gene expression, in vivo employing a solid-Ehrlich carcinoma model, and in silico investigations for highlighting the binding affinity of eight quinoxaline derivatives were tested for anticancer activities. The results showed that compound 8 (N-allyl quinoxaline) had potent cytotoxicity against A594 and MCF-7 cancer cells with IC50 values of 0.86 and 1.06 µM, respectively, with noncytotoxic activity against WISH and MCF-10A cells having IC50 values more than 100 µM. Furthermore, it strongly induced apoptotic cell death in A549 and MCF-7 cells by 43.13% and 34.07%, respectively, stopping the cell cycle at S and G1-phases. For the molecular target, the results showed that compound 8 had a promising EGFR inhibition activity with an IC50 value of 0.088 µM compared to Sorafenib (IC50 = 0.056 µM), and it had a promising VEGFR2 inhibition activity with an IC50 value of 0.108 µM compared to Sorafenib (IC50 = 0.049 µM). Treatment with compound 8 ameliorated biochemical and histochemical parameters near normal in the in vivo investigation, with a tumor inhibition ratio of 68.19% compared to 64.8% for 5-FU treatment. Finally, the molecular docking study demonstrated the binding affinity through binding energy and interactive binding mode inside the EGFR/VEGFR2 proteins. Potent EGFR and VEGFR2 inhibition of compound 8 suggests its potential for development as a selective anticancer drug.

A quinoxaline-based derivative exhibited potent and selective anticancer activity with apoptosis induction in PC-3 cells through Topo II inhibition.

Quinoxaline constitutes a variety of derivatives that exhibit a range of biological characteristics, including anti-inflammatory and antitumor effects, and their importance in therapeutic chemistry is rising. The cytotoxicity effects of four quinoxaline compounds (I, II, III, and IV) against liver cancer cells (HepG2), prostate cancer cells (PC-3), and normal cells (Vero) were evaluated using the MTT assay. Compounds III and IV had the most anti-proliferative effects and highly selective indices against PC-3 cells with IC50 values of 4.11 and 2.11 µM, respectively. The apoptotic cell death for compounds III and IV in PC-3 cells was investigated using cell cycle, Annexin V-FITC/PI double staining-based flow cytometry, and DNA fragmentation assay. Compounds III or IV arrested the cell cycle at the S phase and caused apoptosis in PC-3 cells. Compounds III and IV showed inhibitory effects against topoisomerase II enzyme with IC50 values 21.98 and 7.529 µM, respectively, when compared to doxorubicin as a reference drug. Western Blot analysis displayed that compound IV treatment has significantly upregulated the pro-apoptotic proteins (p53, caspase-3, caspase-8) and downregulated the anti-apoptotic protein Bcl-2 in PC-3 cells in a dose-dependent manner, leading to cell apoptosis. The molecular docking study exhibited that compound IV had a good binding affinity for inhibiting topoisomerase II, consistent with the apoptotic mechanism. In vivo study using Ehrlich solid tumor model demonstrated that compound IV significantly reduced tumor volume and weight in vivo with minimal toxicity. This study reveals significant evidence for the antitumor efficacy of compound IV against prostate cancer cells as a topoisomerase II inhibitor.Communicated by Ramaswamy H. Sarma.

Metabolite profiling and in-silico studies show multiple effects of insecticidal actinobacterium on Spodoptera littoralis.

The polyphagous pest, Spodoptera littoralis (Boisduval), poses a significant global economic threat by gregariously feeding on over a hundred plant species, causing substantial agricultural losses. Addressing this challenge requires ongoing research to identify environmentally safe control agents. This study aimed to elucidate the insecticidal activity of the metabolite (ES2) from a promising endophytic actinobacterium strain, Streptomyces sp. ES2 EMCC2291. We assessed the activity of ES2 against the eggs and fourth-instar larvae of S. littoralis through spectrophotometric measurements of total soluble protein, α- and ß-esterases, polyphenol oxidase (PPO), and catalase enzyme (CAT). The assessments were compared to commercial Biosad® 22.8% SC. Untargeted metabolomics using LC-QTOF-MS/MS identified 83 metabolic compounds as chemical constituents of ES2. The median lethal concentration (LC50) of ES2 (165 mg/mL) for treated Spodoptera littoralis eggs showed significant differences in polyphenol oxidase and catalase enzymatic activities, while the LC50 of ES2 (695 mg/mL) for treated S. littoralis fourth instar larvae showed lower significance in α- and ß-esterase activities. Molecular docking of ES2 identified seven potent biocidal compounds, showing strong affinity to PPO and catalase CAT proteins in S. littoralis eggs while displaying limited binding to alpha and beta esterase proteins in the larvae. The results contribute to the understanding of ES2 as a promising alternative biopesticide, providing insights for future research and innovative applications in sustainable pest management strategies.

Design and synthesis of quinazolin-4-one derivatives as potential anticancer agents and investigation of their interaction with RecQ helicases.

The upregulation of RecQ helicases has been associated with cancer cell survival and resistance to chemotherapy, making them appealing targets for therapeutic intervention. In this study, twenty-nine novel quinazolinone derivatives were designed and synthesized. The anti-proliferative activity of all compounds was evaluated against 60 cancer cell lines at the National Cancer Institute Developmental Therapeutic Program, with six compounds (11f, 11g, 11k, 11n, 11p, and 11q) being promoted to a five-dose screen. Compound 11g demonstrated high cytotoxic activity against all examined cell lines. The compounds were further assayed for Bloom syndrome (BLM) helicase inhibition, where 11g, 11q, and 11u showed moderate activity. These compounds were counter-screened against WRN and RECQ1 helicases, where 11g moderately inhibited both enzymes. An ATP competition assay confirmed that the compounds bound to the ATP site of RecQ helicases, and molecular docking simulations were used to study the binding mode within the active site of BLM, WRN, and RECQ1 helicases. Compound 11g induced apoptosis in both HCT-116 and MDA-MB-231 cell lines, but also caused an G2/M phase cell cycle arrest in HCT-116 cells. This data revealed the potential of 11g as a modulator of cell cycle dynamics and supports its interaction with RecQ helicases. In addition, compound 11g displayed non-significant toxicity against FCH normal colon cells at doses up to 100 µM, which confirming its high safety margin and selectivity on cancer cells. Overall, these findings suggest compound 11g as a potential pan RecQ helicase inhibitor with high anticancer potency and a favorable safety margin and selectivity.

Selenium alleviates modafinil-induced neurobehavioral toxicity in rat via PI3K/Akt/mTOR/GSK3B signaling pathway and suppression of oxidative stress and apoptosis: in vivo and in silico study.

Nonmedical use of modafinil (MOD) led to increased rates of overdose toxicity, road accidents, addiction, withdrawal, suicide, and mental illnesses. The current study aims to determine the probable MOD brain toxicity and elucidate the possible role of selenium (Se) in ameliorating the neurotoxicity in rat models. Fifty-four male Albino rats were randomly assigned into nine groups. The groups were G1 (control negative), G2 (Se0.1), G3 (Se0.2), G4 (MOD300), G5 (MOD600), G6 (Se0.1 + MOD300), G7 (Se0.2 + MOD300), G8 (Se0.1 + MOD600), and G9 (Se0.2 + MOD600). After finishing the experiment, blood and brain tissue were harvested for biochemical and histological investigation. Neurobehavior parameters were assessed. Tissue neurotransmitter levels and oxidative stress markers were assessed. Gene expression of PI3K/Akt/mTOR-GSK3B, orexin, and orexin receptor2 was measured by qRT-PCR. Histological and immunohistochemistry assessments, as well as molecular docking, were carried out. MOD-induced neurobehavioral toxicity exhibited by behavioral and cognitive function impairments, which are associated with decreased antioxidant activities, increased MDA levels, and decreases in neurotransmitter levels. Brain levels of mRNA expression of PI3K, Akt, and mTOR were decreased, while GS3K, orexin, and orexin receptors were significantly elevated. These disturbances were confirmed by histopathological brain changes with increased silver and Bax immunostaining and decreased crystal violet levels. MOD induced neurotoxic effects in a dose-dependent manner. Compared with the MOD groups, SE coadministration significantly attenuates MOD-induced toxic changes. Docking study shows the protective role of Se as an apoptosis inhibitor and inflammation inhibitor. In conclusion, Se could be used as a biologically effective antioxidant compound to protect from MOD neurobehavioral toxicity in Wistar rats by reversing behavioral alterations, inflammation, apoptosis, and oxidative injury.

Tailored horseshoe-shaped nicotinonitrile scaffold as dual promising c-Met and Pim-1 inhibitors: Design, synthesis, SAR and in silico study.

For the horseshoe tactic to succeed in inhibiting c-Met and Pim-1, the nicotinonitrile derivatives (2a-n) were produced in high quantities by coupling acetyl phenylpyrazole (1) with the proper aldehydes and ethyl cyanoacetate under basic conditions. Consistent basic and spectroscopic data (NMR, IR, Mass, and HPLC) supported the new products' structural findings. With IC50 potency in nanomolar ranges, these compounds had effectively repressed them, particularly compounds 2d and 2 h, with IC50 values below 200 nM. The most potent compounds (2d and 2 h) were tested for their antitumor effects against prostate (PC-3), colon (HCT-116), and breast (MDA-MB-231) and were evaluated in comparison to the anticancer drug tivantinib using the MTT assay. Similar to tivantinib, these compounds showed good antiproliferative properties against the HCT-116 tumor cells while having low cytotoxicity towards healthy fetal colon (FHC) cells. In the HCT-116 cell line, their ability to trigger the apoptotic cascade was also investigated by looking at the level of Bax and Bcl-2 as well as the activation of the proteolytic caspase cascade. When HCT-116 cells were exposed to compounds 2d and 2 h in comparison to the control, active caspase-3 levels increased. The HCT-116 cell line also upregulated Bcl-2 protein levels and downregulated Bax levels. Additionally, when treated with compound 2d, the HCT-116 cell cycle was primarily stopped at the S phase. Compared to the control, compound 2d treatment significantly inhibited the protein expression levels of c-Met and Pim-1 kinases in the treated HCT-116 cells. Thorough molecular modeling analyses, such as molecular docking and dynamic simulation, were performed to ascertain the binding mechanism and stability of the target compounds.

Discovery of Quinolinone Hybrids as Dual Inhibitors of Acetylcholinesterase and Aß Aggregation for Alzheimer's Disease Therapy.

The development of multitargeted therapeutics has evolved as a promising strategy to identify efficient therapeutics for neurological disorders. We report herein new quinolinone hybrids as dual inhibitors of acetylcholinesterase (AChE) and Aß aggregation that function as multitargeted ligands for Alzheimer's disease. The quinoline hybrids (AM1-AM16) were screened for their ability to inhibit AChE, BACE1, amyloid fibrillation, α-syn aggregation, and tau aggregation. Among the tested compounds, AM5 and AM10 inhibited AChE activity by more than 80% at single-dose screening and possessed a remarkable ability to inhibit the fibrillation of Aß42 oligomers at 10 µM. In addition, dose-dependent screening of AM5 and AM10 was performed, giving half-maximal AChE inhibitory concentration (IC50) values of 1.29 ± 0.13 and 1.72 ± 0.18 µM, respectively. In addition, AM5 and AM10 demonstrated concentration-dependent inhibitory profiles for the aggregation of Aß42 oligomers with estimated IC50 values of 4.93 ± 0.8 and 1.42 ± 0.3 µM, respectively. Moreover, the neuroprotective properties of the lead compounds AM5 and AM10 were determined in SH-SY5Y cells incubated with Aß oligomers. This work would enable future research efforts aiming at the structural optimization of AM5 and AM10 to develop potent dual inhibitors of AChE and amyloid aggregation. Furthermore, the in vivo assay confirmed the antioxidant activity of compounds AM5 and AM10 through increasing GSH, CAT, and SOD activities that are responsible for scavenging the ROS and restoring its normal level. Blood investigation illustrated the protective activity of the two compounds against lead-induced neurotoxicity through retaining hematological and liver enzymes near normal levels. Finally, immunohistochemistry investigation revealed the inhibitory activity of ß-amyloid (Aß) aggregation.

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.

Evaluation of antioxidant, anti-inflammatory, anticancer activities and molecular docking of Moringa oleifera seed oil extract against experimental model of Ehrlich ascites carcinoma in Swiss female albino mice.

The current research intended to evaluate the antitumor properties of Moringa oleifera oil extract (MOE). Fifty-six female Swiss albino mice were employed in this study. Animals were assigned into four groups: control (C) group, moringa oil extract (MOE) group administered (500 mg/kg b. wt) MOE daily via gavage, Ehrlich ascites carcinoma (EAC) group and EAC group administered daily with (500 mg/kg b.wt) MOE for two weeks (EAC/MOE). The results showed that MOE significantly ameliorated the EAC increase in body weight and reduced the EAC cell viability. In addition, they upgraded the levels of hepatic and renal functions, inflammatory cytokines, oxidative stress markers and EAC-induced hepatic and renal histopathological changes. Treatment of EAC with MOE induced antitumor, anti-inflammatory and antioxidant effects and normalized most of the tested parameters besides the histopathological alterations in both renal and hepatic tissues. HPLC for the MOE identified Cinnamic acid, Ellagic acid, Quercetin, Gallic acid, Vanillin and Hesperidin as major compounds. The molecular docking study highlighted the virtual binding of the identified compounds inside the GSH and SOD proteins, especially for Quercetin which exhibited promising binding affinity with good interactive binding mode with the key amino acids. These results demonstrate that the antitumor constituents of MOE against EAC induced oxidative stress and inflammation by preventing oxidative damage and controlling EAC increase.

Design and Synthesis of Novel Pyridine-Based Compounds as Potential PIM-1 Kinase Inhibitors, Apoptosis, and Autophagy Inducers Targeting MCF-7 Cell Lines: In Vitro and In Vivo Studies.

2-((3-Cyano-4,6-dimethylpyridin-2-yl)oxy)acetohydrazide 1 was used as the precursor for the synthesis of 5-thioxo-1,3,4-oxadiazol-2-yl)methoxy)nicotinonitrile 2. The latter was alkylated with different alkylating agents to produce the S-alkylated products 3-6. Galactosylation of 5-thioxo-1,3,4-oxadiazol-2-yl)methoxy)nicotinonitrile 2 produces a mixture of S- and N-galactosides 8 and 9. The hydrazide 1 is converted to azide 10, coupled with glycine methyl ester hydrochloride and a set of amines to produce the target coupled amides 11-15. New compounds were assigned using NMR and elemental analysis. Compound 12 had potent cytotoxicity with IC50 values of 0.5 and 5.27 µM against MCF-7 and HepG2 cell lines compared with doxorubicin, which displayed the following IC50: 2.14 and 2.48 µM for the mentioned cell lines, respectively. Regarding the molecular target, compound 12 exhibited potent PIM-1 inhibition activity with 97.5% with an IC50 value of 14.3 nM compared to Staurosporine (96.8%, IC50 = 16.7 nM). Moreover, compound 12 significantly activated apoptotic cell death in MCF-7 cells, increasing the cell population by total apoptosis by 33.43% (23.18% for early apoptosis and 10.25% for late apoptosis) compared to the untreated control group (0.64%), and arresting the cell cycle at S-phase by 36.02% compared to control 29.12%. Besides, compound 12 caused tumor inhibition by 42.1% in solid tumors in the SEC-bearing mice. Results disclosed that compound 12 significantly impeded cell migration and cell proliferation by interfering with PIM-1 enzymatic activity via considerable apoptosis-induction, which made it an attractive lead compound for the development of chemotherapeutics to treat breast cancer.

Identification of potential antiviral compounds from Egyptian marine algae against influenza A virus.

Influenza is a contagious viral infection of the respiratory tract, affecting nearly 10% of the world's population, each year. The aim of this study was to extract and identify antiviral compounds against the influenza-A virus (H1N1) from different species of Egyptian marine algae. Three samples of marine macroalgae species were extracted and the antiviral activity of the extracts were tested on Madin Darby Canine Kidney cells. The bioactive compounds present in the most active fractions were identified using gas chromatography-mass spectrometry (GC-MS), then the binding potentials of the identified compounds were examined towards neuraminidase (NA) of the influenza-A virus using molecular docking. The methanolic extract of Sargassum aquifolium showed promising in-vitro antiviral activity with a selectivity index (SI) value of 101. The GC-MS analysis showed twelve compounds and the molecular docking analysis found that tetradecanoic acid showed the strongest binding affinities towards the NA enzyme.

In Vitro and In Vivo Effects of Synthesis Novel Phenoxyacetamide Derivatives as Potent Apoptotic Inducer against HepG2 Cells through PARP-1 Inhibition.

To discover potential cytotoxic agents, new semi-synthetic phenoxy acetamide derivatives, compound I and compound II, were synthesized, characterized, and screened for their cytotoxic activity against breast cancer (MCF-7) and liver cancer (HepG2) cell lines. The two compounds were more promising against HepG2 than the MCF-7 cell line according to IC50 values. When tested against the HepG2 cell line, compound I, and compound II both had significantly increased cytotoxic activity when compared to the reference medication 5-Fluorouracil (5-FU), with IC50 values of 1.43 M, 5.32 M, and 6.52 M for compound 1, 5-FU and compound II, respectively. Also, compound I displayed a degree of selectivity towards cancer cells compared to normal cells. Compound I significantly enhanced HepG2 total apoptotic cell death by about a 24.51-fold increase. According to cell cycle analysis, compound I induced the arrest of the cell cycle phases G1/S and blocked the progression of the HepG2 cells. Applying the RT-PCR technique achieved a highly significant upregulation in pro-apoptotic genes. The anti-apoptotic gene was significantly downregulated. There was an intrinsic and extrinsic pathway, but the intrinsic pathway was the dominant one. Tumor growth suppression as measured by tumor weight and volume and other hematological, biochemical, and histopathological analyses confirmed the efficacy of compound I as an anticancer agent in vivo examination. Finally, the molecular docking study revealed that compound I was properly docked inside the binding site of PARP-1 protein with stable binding energies and interactive binding modes. Therefore, compound I shows promise as a selective anti-cancer derivative for the treatment of liver cancer after more investigations and clinical studies. This selectivity is a favorable characteristic in the developing cytotoxic agents for cancer treatment, as it indicates a potential for reduced harm to health tissues.

New spiro-indeno[1,2-b]quinoxalines clubbed with benzimidazole scaffold as CDK2 inhibitors for halting non-small cell lung cancer; stereoselective synthesis, molecular dynamics and structural insights.

Despite the crucial role of CDK2 in tumorigenesis, few inhibitors reached clinical trials for managing lung cancer, the leading cause of cancer death. Herein, we report combinatorial stereoselective synthesis of rationally designed spiroindeno[1,2-b]quinoxaline-based CDK2 inhibitors for NSCLC therapy. The design relied on merging pharmacophoric motifs and biomimetic scaffold hopping into this privileged skeleton via cost-effective one-pot multicomponent [3 + 2] cycloaddition reaction. Absolute configuration was assigned by single crystal x-ray diffraction analysis and reaction mechanism was studied by Molecular Electron Density Theory. Initial MTT screening of the series against A549 cells and normal lung fibroblasts Wi-38 elected 6b as the study hit regarding potency (IC50 = 54 nM) and safety (SI = 6.64). In vitro CDK2 inhibition assay revealed that 6b (IC50 = 177 nM) was comparable to roscovitine (IC50 = 141 nM). Docking and molecular dynamic simulations suggested that 6b was stabilised into CDK2 cavity by hydrophobic interactions with key aminoacids.

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).

Silver nanoparticles formulation of Marrubium alysson L. phenolic extract potentiates cytotoxicity through apoptosis with molecular docking study as Bcl-2 inhibitors.

Crude or semi-purified extracts of plants can play a significant role as antitumor agents. They were used as stabilizing and reducing agents in the preparation of silver nanoparticles (AgNPs) that allows these particles to have more efficient cytotoxic activity. In the current study, the extract of Marrubium alysson L., a plant of common occurrence in Egypt was used to synthesize AgNPs for the first time, where comparison of anticancer activity of crude and phenolic extracts with the AgNPs were extensively studied against cancer cell lines PC-3 and HCT-116. Interestingly, AgNPs of the crude extract exhibited promising cytotoxicity with IC50 values of 10.4 and 16.3 µg/ml, while AgNPs of the phenolic extract exhibited very potent cytotoxicity with IC50 values of 2.66 and 1.34 µg/ml compared to Doxorubicin (as a standard reference drug) that exhibited IC50 values of 5.13 and 4.36 µg/ml, respectively against the tested cells. Additionally, AgNPs of the phenolic extract induced apoptosis in HCT-116 with a higher ratio than in PC-3 cells. It induced apoptosis in PC-3 cells by 79.3-fold change, while it induced total colon apoptotic cell death by 228.3-fold change compared to untreated control. Finally, the apoptotic activity of AgNPs of the phenolic extract in the treated PC-3 and HCT-116 cells was confirmed using RT-PCR. As a result, AgNPs of the phenolic extract could be considered a promising anticancer candidate through apoptosis-induction.Communicated by Ramaswamy H. Sarma.

Structure Activity Relationship and Molecular Docking of Some Quinazolines Bearing Sulfamerazine Moiety as New 3CLpro, cPLA2, sPLA2 Inhibitors.

The current work was conducted to synthesize several novel anti-inflammatory quinazolines having sulfamerazine moieties as new 3CLpro, cPLA2, and sPLA2 inhibitors. The thioureido derivative 3 was formed when compound 2 was treated with sulfamerazine. Also, compound 3 was reacted with NH2-NH2 in ethanol to produce the N-aminoquinazoline derivative. Additionally, derivative 4 was reacted with 4-hydroxy-3-methoxybenzaldehyde, ethyl chloroacetate, and/or diethyl oxalate to produce quinazoline derivatives 5, 6, and 12, respectively. The results of the pharmacological study indicated that the synthesized 4-6 and 12 derivatives showed good 3CLpro, cPLA2, and sPLA2 inhibitory activity. The IC50 values of the target compounds 4-6, and 12 against the SARS-CoV-2 main protease were 2.012, 3.68, 1.18, and 5.47 µM, respectively, whereas those of baicalein and ivermectin were 1.72 and 42.39 µM, respectively. The IC50 values of the target compounds 4-6, and 12 against sPLA2 were 2.84, 2.73, 1.016, and 4.45 µM, respectively, whereas those of baicalein and ivermectin were 0.89 and 109.6 µM, respectively. The IC50 values of the target compounds 4-6, and 12 against cPLA2 were 1.44, 2.08, 0.5, and 2.39 µM, respectively, whereas those of baicalein and ivermectin were 3.88 and 138.0 µM, respectively. Also, incubation of lung cells with LPS plus derivatives 4-6, and 12 caused a significant decrease in levels of sPLA2, cPLA2, IL-8, TNF-α, and NO. The inhibitory activity of the synthesized compounds was more pronounced compared to baicalein and ivermectin. In contrast to ivermectin and baicalein, bioinformatics investigations were carried out to establish the possible binding interactions between the newly synthesized compounds 2-6 and 12 and the active site of 3CLpro. Docking simulations were utilized to identify the binding affinity and binding mode of compounds 2-6 and 12 with the active sites of 3CLpro, sPLA2, and cPLA2 enzymes. Our findings demonstrated that all compounds had outstanding binding affinities, especially with the key amino acids of the target enzymes. These findings imply that compound 6 is a potential lead for the development of more effective SARS-CoV-2 Mpro inhibitors and anti-COVID-19 quinazoline derivative-based drugs. Compound 6 was shown to have more antiviral activity than baicalein and against 3CLpro. Furthermore, the IC50 value of ivermectin against the SARS-CoV-2 main protease was revealed to be 42.39 µM, indicating that it has low effectiveness.