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Mostafa M Ghorab,1,2 Mansour S Alsaid,1 Maureen Higgins,3 Albena T Dinkova-Kostova,3–5 Abdelaaty A Shahat,1,6 Nehal H Elghazawy,7 Reem K Arafa7,8 1Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Kingdom of Saudi Arabia; 2Department of Drug Radiation Research, National Center for Radiation Research & Technology, Atomic Energy Authority, Cairo, Egypt; 3Jacqui Wood Cancer Centre, Division of Cancer Research, Medical Research Institute, University of Dundee, Dundee, UK; 4Department of Medicine, 5Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 6Phytochemistry Department, National Research Center, Dokki, Giza, 7Zewail City of Science and Technology, 8Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt Abstract: The Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response elements pathway enables cells to survive oxidative stress conditions through regulating the expression of cytoprotective enzymes such as NAD(P)H:quinone oxidoreductase 1 (NQO1). This work presents the design and synthesis of novel anilinoquinazoline derivatives (2–16a) and evaluation of their NQO1 inducer activity in murine cells. Molecular docking of the new compounds was performed to assess their ability to inhibit Keap1–Nrf2 protein–protein interaction through occupying the Keap1–Nrf2-binding domain, which leads to Nrf2 accumulation and enhanced gene expression of NQO1. Docking results showed that all compounds can potentially interact with Keap1; however, 1,5-dimethyl-2-phenyl-4-(2-phenylquinazolin-4-ylamino)-1,2-dihydropyrazol-3-one (9), the most potent inducer, showed the largest number of interactions with key amino acids in the binding pocket (Arg483, Tyr525, and Phe478) compared to the native ligand or any other compound in this series. Keywords: Kelch domain, molecular modeling, Keap1/Nrf2, cytoprotection, NQO1 induction

Magdy M Youssef,1,2 Reem K Arafa,3,4 Mohamed A Ismail1,21Department of Chemistry, College of Science, King Faisal University, Hofuf, Saudi Arabia; 2Department of Chemistry, Faculty of Science, Mansoura University, Mansoura, 3Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo, 4Biomedical Sciences Program, University of Science and Technology, Zewail City of Science and Technology, Cairo, EgyptAbstract: This research work deals with the design and synthesis of a series of substituted phenylfuranylnicotinamidines 4a–i. Facile preparation of the target compounds was achieved by Suzuki coupling-based synthesis of the nitrile precursors 3a–i, followed by their conversion to the corresponding nicotinamidines 4a–i utilizing LiN(TMS)2. The antimicrobial activities of the newly synthesized nicotinamidine derivatives were evaluated against the Gram-negative bacterial strains Escherichia coli and Pseudomonas aeruginosa as well as the Gram-positive bacterial strains Staphylococcus aureus and Bacillus megaterium. The minimum inhibitory concentration values of nicotinamidines against all tested microorganisms were in the range of 10–20 µM. In specific, compounds 4a and 4b showed excellent minimum inhibitory concentration values of 10 µM against Staphylococcus aureus bacterial strain and were similar to ampicillin as an antibacterial reference. On the other hand, selected nicotinamidine derivatives were biologically screened for their cytotoxic activities against a panel of 60 cell lines representing nine types of human cancer at a single high dose at National Cancer Institute, Bethesda, MD, USA. Nicotinamidines showing promising activities were further assessed in a five-dose screening assay to determine their compound concentration causing 50% growth inhibition of tested cell (GI50), compound concentration causing 100% growth inhibition of tested cell (TGI), and compound concentration causing 50% lethality of tested cell (LC50) values. Structure-activity relationship studies demonstrated that the activity of members of this series can be modulated from cytostatic to cytotoxic based on the substitution pattern/nature on the terminal phenyl ring. The most active compound was found to be 4e displaying a submicromolar GI50 value of 0.83 µM, with TGI and LC50 values of 2.51 and 100 µM, respectively. Finally, the possible underlying mechanism of action of this series of compounds was investigated by determining their nuclease-like DNA degradation ability in addition to their antioxidant power and all monocations proved to be effective in all assays.Keywords: substituted phenylfuranylnicotinamidines, Suzuki coupling, antiproliferative, antibacterial, antioxidant

Mohamed A Ismail,1,2 Reem K Arafa,3 Magdy M Youssef,1,2 Wael M El-Sayed1,4 1Departments of Chemistry and Biological Sciences, College of Science, King Faisal University, Hofuf, Saudi Arabia; 2Department of Chemistry, Faculty of Science, Mansoura University, Mansoura, Egypt; 3Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt; 4Department of Zoology, Faculty of Science, University of Ain Shams, Abbassia, Cairo, Egypt Abstract: A series of 15 monocationic bithiophenes and isosteres were prepared and subjected to in vitro antiproliferative screening using the full National Cancer Institute (NCI)-60 cell line panel, representing nine types of cancer. Among the nine types of cancer involved in a five-dose screen, non-small cell lung and breast cancer cell lines were the most responsive to the antiproliferative effect of the tested compounds, especially cell lines A549/ATCC, NCI-H322M, and NCI-H460, whereas compounds 1a, 1c, 1d, and 7 exhibited potent activity, with GI50 values (drug concentration that causes 50% inhibition of cell growth) from less than 10 nM to 102 nM. In addition, compounds 1c and 1d gave GI50 values of 73 nM and 79 nM, respectively, against the MDA-MB-468 breast cancer cell line. Structure–activity relationship findings indicated that the mononitriles were far less active than their corresponding monoamidines and, within the amidines series, the bioisosteric replacement of a thiophene ring by a furan led to a reduction in antiproliferative activity. Also, molecular manipulations, involving substitution on the phenyl ring, or its replacement by a pyridyl, or alteration of the position of the amidine group, led to significant alteration in antiproliferative activity. On the other hand, DNA studies demonstrated that these monoamidine bichalcophenes have promising ability to cleave the genomic DNA. These monoamidines show a wide range of DNA affinities, as judged from their DNA cleavage effect, which are remarkably sensitive to all kinds of structural modifications. Finally, the novel bichalcophenes were tested for their antioxidant property by the ABTS (2,2'-azino- bis(3-ethylbenzthiazoline-6-sulfonic acid) diammonium salt) assay, as well as lipid and nitric oxide scavenging techniques, and were found to exhibit good-to-potent antioxidant abilities. Keywords: bithiophenes, anticancer, DNA cleavage, antioxidant, Suzuki coupling, Stille coupling

Epidermal growth factor receptor (EGFR) is amongst the earliest targeted kinases by small-molecule inhibitors for the management of EGFR-positive cancer types. While a few inhibitors are granted FDA approval for clinical use, discovery of new inhibitors is still of merit to enhance ligand-binding stability and subsequent enzyme inhibition. Thus, a structure-based design approach was adopted to devise a new series of twenty-nine N3-substituted quinazolin-4-ones as type I ATP-competitive inhibitors targeting the deep hydrophobic pocket of EGFR. The most active compounds demonstrated potent IC 50 s against MDA-MB-231 and HepG2 cancer cells being comparable to or better than the reference drugs erlotinib and lapatinib. IC 50 s of 5f and 15a against MDA-MB-231 were 3.34 and 4.99, whilst those against HepG2 were 6.37 and 2.18 μM, respectively. Also, members of this series demonstrated selective cytotoxicity against cancer cell lines showing low toxicity on human skin fibroblast normal cells hFB-4. Both 5f and 15a also effectively inhibited EGFR with sub-micromolar respective IC 50 s of 0.07 and 0.12 μM. The two derivatives halted the cell cycle progression of treated cancer cells and induced apoptosis as affirmed by flow cytometry along with RT-PCR-determined overexpression of the pro-apoptotic genes p53, Caspase 3, and Bax. Notably, docking and molecular dynamics simulations of members of this series of quinazolin-4-one derivatives showed that analogs with a short linker at the N3 position of the quinazoline ring exemplified by 5f bind to the active form of EGFR with their terminal aryl ring dwelling in the BPI pocket similar to erlotinib, while those with a longer linker represented by 15a bind to the inactive form in a comparable manner to lapatinib lodging the terminal phenyl in the BPII pocket., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Ragaa Yasser reports financial support was provided by Academy of Scientific Research & Technology. Reem K. Arafa has patent pending to Zewail City of Science and Technology. Ragaa Yasser has patent pending to Zewail City of Science and Technology. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

An efficient synthesis of a series of uracil analogous was performed to obtain new potential anticancer agents. The cytotoxic effect of the synthesized derivatives was assessed in vitro against three cancer cell lines, namely hepatic cancer (HepG-2), colon cancer (HCT-116), and breast cancer (MCF-7). Among the tested compounds, 5, 11 and 15 stood as potent uracil derivatives with pan cytotoxicity against the 3 cell lines out-performing the reference compound 5-FU. Furthermore, selected compounds underwent thymidylate synthase (TS) enzyme inhibition assay and demonstrated effective inhibition of the enzyme's catalytic activity. Thereafter, flow cytometric apoptosis and protein expression of pro- and anti-apoptotic markers Bax, BCL-2, PI3K, and STAT1 proteins assays were performed employing the most active compound on the respective most responsive cell line and compounds demonstrated effectiveness in inducing apoptosis in the treated cell lines. Finally, in silico studies encompassing molecular docking and molecular dynamics studies were also conducted to predict the interaction mechanisms and stability of the active compounds within the active site of their biological target TS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. This work is protected under patent application (EG/P/2024/1425)., (Copyright © 2024. Published by Elsevier Inc.)

Dual-targeting drug design has become a popular approach in investigating and developing potent anticancer agents. In this regard, carbonic anhydrase (CAIX) and vascular endothelial growth factor receptor (VEGFR-2) are emerging as highly effective targets in the battle against cancer. In the present study, two series of 4-thiazolidinones/2,4-thiazolidinediones carrying 2-methylbenzenesulfonamide derivatives were designed and synthesized as potential dual CAIX/VEGFR-2 inhibitors. All the target compounds were evaluated against CAIX enzyme compared to dorzolamide and acetazolamide, subsequently the most potent CAIX inhibitors (3a, 3b, 3o, 6d, 6g, and 6i) were selected to evaluate their inhibitory activity against VEGFR-2 using sorafenib as a reference drug. These compounds were also evaluated against MCF-7 breast cancer cells and the murine fibroblast 3T3 cell line. According to the results, 3b (CAIX IC 50  = 0.035 µM, VEGFR-2 IC 50  = 0.093 µM) and 6i (CAIX IC 50  = 0.041 µM, VEGFR-2 IC 50  = 0.048 µM) emerged the most potent compounds against CAIX and VEGFR-2. Furthermore, docking studies of selected compounds were performed with the CAIX and the tyrosine kinase domain of VEGFR-2 to comprehend the ligand-binding interactions. Physicochemical predictions were examined using in silico techniques. In conclusion, these scaffolds present promising leads and furnish promising chemical backbones for the design of potent dual CAIX and VEGFR-2 inhibitors.b., (© 2024 Wiley Periodicals LLC.)

The cardioprotective drug cyclocreatine phosphate has been awarded Food and Drug Administration-orphan drug designation for the prevention of ischemic injury to enhance cardiac graft recovery and survival in heart transplantation. Cyclocreatine phosphate is the water-soluble derivative of cyclocreatine. Estimating the levels of Cyclocreatine phosphate, Adenosine triphosphate, Creatine Phosphate, Creatine and Cyclocreatine helps us in understanding the energy state as well as evaluating the heart cells' function. The quantification of endogenous compounds imposes a challenging task for analysts because of the absence of a true blank matrix, whose use is required according to international guidelines. Recently, the International Council for Harmonization issued a new guideline that contains guidance on the validation of methods used to quantify endogenous components, such as the background subtraction approach that was employed in our current study. Specifically, we developed and validated a sensitive, reliable and accurate liquid chromatography-tandem mass spectrometry assay to determine simultaneously the levels of mentioned endogenous compounds in rat heart tissue. Tissue samples were prepared by protein precipitation extraction using water: methanol (1:1). Using Ultra Performance Liquid Chromatography, Chromatographic separation was achieved with ZORBAX Eclipse Plus C18 4.6 × 100 mm,3.5 μm column and conditions as following: ammonium acetate (pH 8.5): acetonitrile, 70:30 mobile phase, 0.7 mL/min flow rate and 25 °C temperature. Electrospray ionization mass detector with Multiple reaction monitoring mode was then employed, using both positive and negative modes, Analysis was carried out using 5.00-2000.00 ng/mL linear concentration range within 2 min for each analyte. According to Food and Drug Administration guidelines for bioanalytical methods, validation was carried out. We investigated the matrix effect, recovery efficiency and process efficiency for the analyte in neat solvent, postextraction matrix and tissue. The results stated mean percentage recoveries higher than 99%, accuracy 93.32-111.99%, and Relative Standard Deviation (RSD) below 15% within the concentration range of our study which indicated that target analytes' stability in their real matrix is sufficient under the employed experimental conditions., (© 2024. The Author(s).)

Alzheimer's disease (AD) is challenging due to its irreversible declining cognitive symptoms and multifactorial nature. This work tackles targeting both acetylcholinesterase (AChE) and BuChE with a multitarget-directed ligand (MTDL) through design, synthesis, and biological and in silico evaluation of a series of twenty eight new 5-substituted-2-anilino-1,3,4-oxadiazole derivatives 4a-g, 5a-g, 9a-g and 13a-g dual inhibitors of the target biomolecules. In vitro cholinesterases inhibition and selectivity assay of the synthesized derivatives showed excellent nanomolar level inhibitory activities. Compound 5a, the most potent inhibitor, elicited IC 50 s of 46.9 and 3.5 nM against AChE and BuChE, respectively (SI = 0.07), 5 folds better than the known dual inhibitor Rivastagmine. In vivo and ex vivo investigation showed that 5a significantly inhibited MDA levels and increased GSH contents, thus, attenuating the brain tissue oxidative stress. Additionally, 5a significantly decreased AChE and BuChE levels and inhibited self-mediated β-amyloid aggregation in brains of treated rats. Histopathological and immunohistochemical evaluation demonstrated lessened damage and decreased caspase-3 and VEGF expression levels. In silico prediction of 5a's pharmacokinetics and toxicity profiles reflected promising results. Finally, 5a demonstrated tight binding interactions with the two target biomolecules upon docking along with stable complex formation with its bio-targets throughout the 100 ns MD trajectories., Competing Interests: Declaration of competing interest Reem K. Arafa reports financial support was provided by Science and Technology Development Fund. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Discovering effective anti-cancer agents poses a formidable challenge given the limited efficacy of current therapeutic modalities against various cancer types due to intrinsic resistance mechanisms. Cancer immunochemotherapy is an alternative strategy for breast cancer treatment and overcoming cancer resistance. Human Indoleamine 2,3-dioxygenase (hIDO1) and human Tryptophan 2,3-dioxygenase 2 (hTDO2) play pivotal roles in tryptophan metabolism, leading to the generation of kynurenine and other bioactive metabolites. This process facilitates the de novo synthesis of Nicotinamide Dinucleotide (NAD), promoting cancer resistance. This study identified a new dual hIDO1/hTDO2 inhibitor using a drug repurposing strategy of FDA-approved drugs. Herein, we delineate the development of a ligand-based pharmacophore model based on a training set of 12 compounds with reported hIDO1/hTDO2 inhibitory activity. We conducted a pharmacophore search followed by high-throughput virtual screening of 2568 FDA-approved drugs against both enzymes, resulting in ten hits, four of them with high potential of dual inhibitory activity. For further in silico and in vitro biological investigation, the anti-hypercholesterolemic drug Pitavastatin deemed the drug of choice in this study. Molecular dynamics (MD) simulations demonstrated that Pitavastatin forms stable complexes with both hIDO1 and hTDO2 receptors, providing a structural basis for its potential therapeutic efficacy. At nanomolar (nM) concentration, it exhibited remarkable in vitro enzyme inhibitory activity against both examined enzymes. Additionally, Pitavastatin demonstrated potent cytotoxic activity against BT-549, MCF-7, and HepG2 cell lines (IC 50  = 16.82, 9.52, and 1.84 µM, respectively). Its anticancer activity was primarily due to the induction of G1/S phase arrest as discovered through cell cycle analysis of HepG2 cancer cells. Ultimately, treating HepG2 cancer cells with Pitavastatin affected significant activation of caspase-3 accompanied by down-regulation of cellular apoptotic biomarkers such as IDO, TDO, STAT3, P21, P27, IL-6, and AhR., (© 2024. The Author(s).)

In this study, flower and leaf extracts of Colvillea racemosa were considered a source of bioactive compounds. In this context, the objective of the study focused on investigating the anticancer potential as well as the phytochemical composition of both extracts. The extracts were analyzed by UPLC-ESI-QTOF-MS, and the bioactivity was tested using in vitro antioxidant assays (FRAP, DPPH, and ABTS) in addition to cytotoxic assays on non-small cell lung cancer cell line (A549). Our results clearly indicated the potent radical scavenging capacity of both extracts. Importantly, the flower extract exhibited a greater antioxidant capacity than the leaf extract. In terms of cytotoxic activity, leaf and flower extracts significantly inhibited cell viability with IC 50 values of 17.0 and 17.2 µg/mL, respectively. The phytochemical characterization enabled the putative annotation of 42 metabolites, such as saccharides, phenolic acids, flavonoids, amino acids, and fatty acids. Among them, the flavonoid C -glycosides stand out due to their high relative abundance and previous reports on their anticancer bioactivity. For a better understanding of the bioactive mechanisms, four flavonoids (vitexin, kaempferol-3- O -rutinoside, luteolin, and isoorientin) were selected for molecular docking on hallmark protein targets in lung cancer as represented by γ-PI3K, EGFR, and CDK2 through in-silico studies. In these models, kaempferol-3- O -rutinoside and vitexin had the highest binding scores on γ-PI3K and CDK2, followed by isoorientin, so they could be highly responsible for the bioactive properties of C. racemosa extracts.

A new series of thieno[2,3- d ][1,2,4]triazolo[1,5- a ]pyrimidines was designed and synthesized using readily available starting materials, specifically, β -enaminoester. Their cytotoxicity was screened against three cancer cell lines, namely, MCF-7, HCT-116, and PC-3. 2-(4-bromophenyl)triazole 10b and 2-(anthracen-9-yl)triazole 10e afforded excellent potency against MCF-7 cell lines (IC 50 = 19.4 ± 0.22 and 14.5 ± 0.30 μM, respectively) compared with doxorubicin (IC 50 = 40.0 ± 3.9 μM). The latter derivatives 10b and 10e were further subjected to in silico ADME and docking simulation studies against EGFR and PI3K and could serve as ideal leads for additional modification in the field of anticancer research.

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 Aβ 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 Aβ 42 oligomers at 10 μM. In addition, dose-dependent screening of AM5 and AM10 was performed, giving half-maximal AChE inhibitory concentration (IC 50 ) 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 Aβ 42 oligomers with estimated IC 50 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 Aβ 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 β-amyloid (Aβ) aggregation.

Alzheimer's disease (AD) is a neurological disease that affects the memory. AD has been attributed to the aggregations of amyloid-β (Aβ) peptides which result in the formation of plaques that block the neuron-transferring process done by the brain memory cells. These plaques are formed upon cleavage of Amyloid Precursor Protein (APP) by Gamma-Secretase (GS). GS protein has around 141 substrates, the important two are APP and Notch. Considering one of the hot spots in AD research, we focused on GS and its relation to AD. Moreover, a lot of research was done on beta-secretase and drugs were developed to target it however, few drugs are established for GS. GS contains four subunits: Presenilin (PS), PEN-2, Nicastrin, and APH-1. The catalytic subunit is PS, which contains the active site for substrate binding, as well as the allosteric and docking sites. Both PEN-2 and APH-1 are regulators for the stability and activity of GS. Nicastrin, helps the substrates bind to the PS. Additionally, the role of the immuno-protein named "IFITM3" and how it affects the immune system and its relation to AD is presented. GS is one of the most studied proteins with many developed candidates as inhibitors (GSI) and modulators (GSM). Examples of GSI are Semagacestat and Avagacestat while GSM includes E2012; which inhibits the cleavage activity of GS. In this report, each of the four subunits of GS is described in detail, along with the interactions between GS and its inhibitors or modulators. In addition, the FDA-approved drugs are enlisted., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: The COVID-19 pandemic has led to significant loss of life and economic disruption worldwide. Currently, there are limited effective treatments available for this disease. SARS-CoV-2 RNA-dependent RNA polymerase (SARS-CoV-2 RdRp) has been identified as a potential target for drug development against COVID-19. Natural products have been shown to possess antiviral properties, making them a promising source for developing drugs against SARS-CoV-2., Objectives: The objective of this study is to identify the most effective natural inhibitors of SARS-CoV-2 RdRp among a set of 4924 African natural products using a multi-phase in silico approach., Methods: The study utilized remdesivir (RTP), the co-crystallized ligand of RdRp, as a starting point to select compounds that have the most similar chemical structures among the examined set of compounds. Molecular fingerprints and structure similarity studies were carried out in the first part of the study. The second part of the study included molecular docking against SARS-CoV-2 RdRp (PDB ID: 7BV2) and Molecular Dynamics (MD) simulations including the calculation of RMSD, RMSF, Rg, SASA, hydrogen bonding, and PLIP. Moreover, the calculations of Molecular mechanics with generalised Born and surface area solvation (MM-GBSA) Lennard-Jones and Columbic electrostatic interaction energies have been conducted. Additionally, in silico ADMET and toxicity studies were performed to examine the drug likeness degrees of the selected compounds., Results: Eight compounds were identified as the most effective natural inhibitors of SARS-CoV-2 RdRp. These compounds are kaempferol 3-galactoside, kaempferol 3- O - β -D-glucopyranoside, mangiferin methyl ether, luteolin 7- O - β -D-glucopyranoside, quercetin- O - β -D-3-glucopyranoside, 1-methoxy-3-indolylmethyl glucosinolate, naringenin, and asphodelin A 4'- O - β -D-glucopyranoside., Conclusion: The results of this study provide valuable information for the development of natural product-based drugs against COVID-19. However, the elected compounds should be further studied in vitro and in vivo to confirm their efficacy in treating COVID-19.

In the current study, we designed and synthesized a series of new quinoline derivatives 10a-p as antiproliferative agents targeting cancer through inhibition of VEGFR-2. Preliminary molecular docking to assess the interactions of the designed derivatives with the binding site of VEGFR-2 (PDB code: 4ASD) displayed binding poses and interactions comparable to sorafenib. The synthesized compounds exhibited VEGFR-2 inhibitory activity with IC 50 ranging from 36 nM to 2.23 μM compared to sorafenib (IC 50  = 45 nM), where derivative 10i was the most potent. Additionally, the synthesized derivatives were evaluated in vitro for their cytotoxic activity against HepG2 cancer cell line. Seven compounds 10a, 10c, 10d, 10e, 10i, 10n and 10o (IC 50  = 4.60, 4.14, 1.07, 0.88, 1.60, 2.88 and 2.76 μM respectively) displayed better antiproliferative activity than sorafenib (IC 50  = 8.38 μM). Compound 10i was tested against Transformed Human Liver Epithelial-2 normal cell line (THLE-2) to evaluate its selective cytotoxicity. Furthermore, 10i, as a potent representative of the series, was assayed for its apoptotic activity and cell cycle kinetics' influence on HepG2, its effects on the gene expression of VEGFR-2, and protein expression of the apoptotic markers Caspase-7 and Bax. Compound 10i proved to have a potential role in apoptosis by causing significant increase in the early and late apoptotic quartiles, a remarkable activity in elevating the relative protein expression of Bax and Caspase-7 and a significant reduction of VEGFR-2 gene expression. Collectively, the obtained results indicate that compound 10i has a promising potential as a lead compound for the development of new anticancer agents., (© 2023. The Author(s).)

Irreversible myocardial injury causes the exhaustion of cellular adenosine triphosphate (ATP) contributing to heart failure (HF). Cyclocreatine phosphate (CCrP) was shown to preserve myocardial ATP during ischemia and maintain cardiac function in various animal models of ischemia/reperfusion. We tested whether CCrP administered prophylactically/therapeutically prevents HF secondary to ischemic injury in an isoproterenol (ISO) rat model. Thirty-nine rats were allocated into five groups: control/saline, control/CCrP, ISO/saline (85 and 170 mg/kg/day s.c. for 2 consecutive days), and ISO/CCrP (0.8 g/kg/day i.p.) either administrated 24 h or 1 h before ISO administration (prophylactic regimen) or 1 h after the last ISO injection (therapeutic regimen) and then daily for 2 weeks. CCrP protected against ISO-induced CK-MB elevation and ECG/ST changes when administered prophylactically or therapeutically. CCrP administered prophylactically decreased heart weight, hs-TnI, TNF-α, TGF-β, and caspase-3, as well as increased EF%, eNOS, and connexin-43, and maintained physical activity. Histology indicated a marked decrease in cardiac remodeling (fibrin and collagen deposition) in the ISO/CCrP rats. Similarly, therapeutically administered CCrP showed normal EF% and physical activity, as well as normal serum levels of hs-TnI and BNP. In conclusion, the bioenergetic/anti-inflammatory CCrP is a promising safe drug against myocardial ischemic sequelae, including HF, promoting its clinical application to salvage poorly functioning hearts.

PIM-1 kinases play an established role in prostate cancer development and progression. This research work tackles the design and synthesis of new PIM-1 kinase targeting 2,5-disubstituted-1,3,4-oxadiazoles 10a-g&11a-f, and investigation thereof as potential anti-cancer agents through in vitro cytotoxicity assay followed by in vivo studies along with exploration of this chemotype's plausible mechanism of action. In vitro cytotoxicity experiments have disclosed 10f as the most potent derivative against PC-3 cells (IC 50  = 16 nM) compared to the reference drug Staurosporine (IC 50  = 0.36 μM), also eliciting good cytotoxicity against HepG2 and MCF-7 cells (IC 50  = 0.13 and 5.37 μM, respectively). Investigating PIM-1 kinase inhibitory activity of compound 10f revealed an IC 50 of 17 nM paralleled to that of Staurosporine (IC 50  = 16.7 nM). Furthermore, compound 10f displayed an antioxidant activity eliciting a DPPH inhibition ratio of 94% as compared to Trolox (96%). Further investigation demonstrated that 10f induced apoptosis in treated PC-3 cells by 43.2-fold (19.44%) compared to 0.45% in control. 10f also disrupted the PC-3 cell cycle by increasing the cell population at the PreG1-phase by 19.29-fold while decreasing the G2/M-phase by 0.56-fold compared to control. Moreover, 10f affected a downregulation of JAK2, STAT3 and Bcl-2 and upregulation of caspases 3, 8 and 9 levels that activated the caspase-dependent apoptosis. Finally, in vivo 10f-treatment caused a significant increase in tumor inhibition by 64.2% compared to 44.5% in Staurosporine treatment of the PC-3 xenograft mouse model. Additionally, it improved the hematological, biochemical parameters, and histopathological examinations compared to control untreated animals. Finally, docking of 10f with the ATP-binding site of PIM-1 kinase demonstrated good recognition of and effective binding to the active site. In conclusion, compound 10f represents a promising lead compound that merits further future optimization for controlling prostate cancer., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Reem K. Arafa reports financial support was provided by ASRT. Anne-Sophie Castanet reports financial support was provided by Hubert Curien Partnership., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Fascin is an actin-bundling protein overexpressed in various invasive metastatic carcinomas through promoting cell migration and invasion. Therefore, blocking Fascin binding sites is considered a vital target for antimetastatic drugs. This inspired us to find new Fascin binding site blockers. First, we built an active compound set by collecting reported small molecules binding to Fascin's binding site 2. Consequently, a high-quality decoys set was generated employing DEKOIS 2.0 protocol to be applied in conducting the benchmarking analysis against the selected Fascin structures. Four docking programs, MOE, AutoDock Vina, VinaXB, and PLANTS were evaluated in the benchmarking study. All tools indicated better-than-random performance reflected by their pROC-AUC values against the Fascin crystal structure (PDB: ID 6I18). Interestingly, PLANTS exhibited the best screening performance and recognized potent actives at early enrichment. Accordingly, PLANTS was utilized in the prospective virtual screening effort for repurposing FDA-approved drugs (DrugBank database) and natural products (NANPDB). Further assessment via molecular dynamics simulations for 100 ns endorsed Remdesivir (DrugBank) and NANPDB3 (NANPDB) as potential binders to Fascin binding site 2. In conclusion, this study delivers a model for implementing a customized DEKOIS 2.0 benchmark set to enhance the VS success rate against new potential targets for cancer therapies.

A naturally inspired chemical library of 25 molecules was synthesised guided by 3-D dimensionality and natural product likeness factors to explore a new chemical space. The synthesised chemical library, consisting of fused-bridged dodecahydro-2 a ,6-epoxyazepino[3,4,5- c , d ]indole skeletons, followed lead likeness factors in terms of molecular weight, C-sp 3 fraction and Clog  P . Screening of the 25 compounds against lung cells infected with SARS-CoV-2 led to the identification of 2 hits. Although the chemical library showed cytotoxicity, the two hits (3b, 9e) showed the highest antiviral activity (EC 50 values of 3.7 and 1.4 μM, respectively) with an acceptable cytotoxicity difference. Computational analysis based on docking and molecular dynamics simulations against main protein targets in SARS-CoV-2 (main protease M pro , nucleocapsid phosphoprotein, non-structural protein nsp10-nsp16 complex and RBD/ACE2 complex) were performed. The computational analysis proposed the possible binding targets to be either M pro or the nsp10-nsp16 complex. Biological assays were performed to confirm this proposition. A cell-based assay for M pro protease activity using a reverse-nanoluciferase (Rev-Nluc) reporter confirmed that 3b targets M pro . These results open the way towards further hit-to-lead optimisations., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

COVID-19 also known as SARS-CoV-2 outbreak in late 2019 and its worldwide pandemic spread has taken the world by surprise. The minute-to-minute increasing coronavirus cases (>85 M) and progressive deaths (≈1.8 M) calls for finding a cure to this devastating pandemic. While there have been many attempts to find biologically active molecules targeting SARS-CoV-2 for treatment of this viral infection, none has found a way to the clinic yet. In this study, a 3-feature structure-based pharmacophore model was designed for SARS-CoV-2 main protease (M Pro ) that plays a vital role in the viral cellular penetration. High throughput virtual screening of the lead-like ZINC library was then performed to find a potent inhibitor employing the predesigned pharmacophore. In-silico pharmacokinetics/toxicity prediction study was subsequently applied towards the best hits. Finally, a 50 ns molecular dynamics simulation was carried out for the best hit and compared to the co-crystallized ligand where the hit compound displayed high binding and comparable interactions. The results identified new hits for SARS-CoV-2 M Pro inhibition showing good docking score, pharmacokinetics and toxicity profile, drug-likeness, high binding energy in addition to a promising synthetic accessibility. Identifying new small compounds as potential leads for inhibiting SARS-CoV-2 is a very important step towards designing a synthesizing of promising drug candidates.Communicated by Ramaswamy H. Sarma.

Over a span of two years ago, since the emergence of the first case of the novel coronavirus (SARS-CoV-2) in China, the pandemic has crossed borders causing serious health emergencies, immense economic crisis and impacting the daily life worldwide. Despite the discovery of numerous forms of precautionary vaccines along with other recently approved orally available drugs, yet effective antiviral therapeutics are necessarily needed to hunt this virus and its variants. Historically, naturally occurring chemicals have always been considered the primary source of beneficial medications. Considering the SARS-CoV-2 main protease (M pro ) as the duplicate key element of the viral cycle and its main target, in this paper, an extensive virtual screening for a focused chemical library of 15 batzelladine marine alkaloids, was virtually examined against SARS-CoV-2 main protease (M pro ) using an integrated set of modern computational tools including molecular docking (MDock), molecule dynamic (MD) simulations and structure-activity relationships (SARs) as well. The molecular docking predictions had disclosed four promising compounds including batzelladines H-I (8-9) and batzelladines F-G (6-7), respectively according to their prominent ligand-protein energy scores and relevant binding affinities with the (M pro ) pocket residues. The best two chemical hits, batzelladines H-I (8-9) were further investigated thermodynamically though studying their MD simulations at 100 ns, where they showed excellent stability within the accommodated (M pro ) pocket. Moreover, SARs studies imply the crucial roles of the fused tricyclic guanidinic moieties, its degree of unsaturation, position of the N-OH functionality and the length of the side chain as a spacer linking between two active sites, which disclosed fundamental structural and pharmacophoric features for efficient protein-ligand interaction. Such interesting findings are greatly highlighting further in vitro/vivo examinations regarding those marine natural products (MNPs) and their synthetic equivalents as promising antivirals., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Finding an effective anti-Alzheimer agent is quite challenging due to its multifactorial nature. As such, multitarget directed ligands (MTDLs) could be a promising paradigm for finding potential therapeutically effective new small-molecule bioactive agents against Alzheimer's disease (AD). We herein present the design, synthesis, and biological evaluation of a new series of compounds based on a 5-pyrid-3-yl-1,3,4-oxadiazole scaffold. Our synthesized compounds displayed excellent in vitro enzyme inhibitory activity at nanomolar (nM) concentrations against two major AD disease-modifying targets, i.e., acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Among our compounds, 5e was considered the best dual inhibitor of both AChE (IC 50 = 50.87 nM) and BuChE (IC 50 = 4.77 nM), where these values surpassed those of rivastagmine (the only FDA-approved dual AChE and BuChE inhibitor) in our study. Furthermore, in vivo and ex vivo testing of the hit compound 5e highlighted its significant AD-biotargeting effects including reducing the elevated levels of lipid peroxidation and glutathione (GSH), normalizing levels of 8-OHdG, and, most importantly, decreasing the levels of the well-known AD hallmark β-amyloid protein. Finally, the binding ability of 5e to each of our targets, AChE and BuChE, was confirmed through additional molecular docking and molecular dynamics (MD) simulations that reflected good interactions of 5e to the active site of both targets. Hence, we herein present a series of new 1,3,4-oxadiazoles that are promising leads for the development of dual-acting AChE and BuChE inhibitors for the management of AD.

VEGFR-2 is a tyrosine kinase receptor for VEGFs that play a central role in tumor angiogenesis. The inhibition of the tyrosine kinase domain of VEGFR-2 has become an attractive therapeutic strategy in recent years for inhibiting tumor growth. In this study, a series of novel 2-oxoquinoxalinyl-1,2,4-triazoles were designed and synthesized as potential antitumor agents and VEGFR-2 inhibitors. Eight compounds in this series showed high growth inhibition against MCF-7 with GI 50 ranging from 1.6 to 8.06 µM compared to staurosporine (GI 50  = 8.39 µM) and sorafenib (GI 50  = 11.20 µM). In addition, the results of the in vitro tyrosine kinase inhibition of VEGFR-2 revealed that most of the compounds possessed IC 50 values in the sub-micromolar range. Compound 6g (IC 50  = 0.037 µM) showed more potent VEGFR-2 inhibitory activity than sorafenib (IC 50  = 0.045 µM). Furthermore, docking studies of the compounds with tyrosine kinase domain of VEGFR-2 (PDB ID: 4ASD) were performed. According to the results, 6g exhibited hydrogen bonding interactions with Glu885, Asp1046 and Cys919 amino acids in a similar way to sorafenib. Finally, physicochemical predictions of target compounds were examined in silico. The results revealed that all the compounds possessed promising drug-likeness profile., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The need for new chemotherapeutics to overcome development of resistance merits research to discover new agents. Benzocaine derivatives are essential compounds in medicinal chemistry due to their various biological activities including antibacterial and anticancer activities. Therefore, this study focuses on the synthesis of new benzocaine derivatives 3a-e, 6, 7a and 7b, 8, 10-14, and 16a-d and their in vitro evaluation as antibacterial agents against gram +ve and -ve strains and as anticancer agents against HepG-2, HCT-116, and MCF-7 human cancer cell lines. The obtained results demonstrated that thiazolidines 6 and 7b showed higher antibacterial and anticancer activity in comparison with the reference drugs. In addition, 6 and 7b showed high potency as inhibitors toward their biological targets, that is DNA gyrase and human topoisomerase IIα, as compared to the reference standard drugs novobiocin and etoposide, respectively. Molecular docking demonstrated that both compounds could identify the active site of their target enzymes and develop effective binding interactions. Absorption, distribution, metabolism and elimination (ADME) and drug-likeness predictions of both compounds showed that they both have good ADME profiles and no structural alerts that might cause toxicity. Based on this, 6 and 7b could serve as lead compounds for the design of more potent antibacterial and anticancer agents., (© 2022 Deutsche Pharmazeutische Gesellschaft.)

Nowadays, novel Biochemistry lab techniques are being introduced at a very fast pace in scientific research. This requires development of new labs for undergraduate Biochemistry courses to equip the students with up-to-date techniques. However, the time limit of Biochemistry labs for undergraduate students represents a major obstacle. This article presents a clear set of laboratory exercises designed to introduce students to the use of polymerase chain reaction-restriction-fragment length polymorphism (PCR-RFLP) as a means of detection of genetic variants. Three consecutive lab experiments have been designed for the undergraduate students to serve this purpose. The first session was performed in a computer lab (dry lab) where students were taught how to obtain a specific gene sequence, identify an exact single nucleotide polymorphism location, choose the target sequence for amplification, design specific primers for this particular sequence and choose the most suitable restriction enzyme from web tools. The second and third lab sessions were performed as wet labs where in the second lab session, students optimized PCR conditions and performed a successful PCR. The PCR products were kept for use in the third lab session where they utilized the selected restriction enzyme and carried out gel electrophoresis to determine the exact genotype., (© 2022 International Union of Biochemistry and Molecular Biology.)

In the past few years, researchers have shed light on the immense importance of ubiquitin in numerous regulatory pathways. The post-translational addition of mono or poly-ubiquitin molecules namely "ubiquitinoylation" is therefore pivotal to maintain the cell's vitality, maturation, differentiation, and division. Part of conserving homeostasis stems from maintaining the ubiquitin pool in the vicinity of the cell's intracellular environment; this crucial role is played by deubiquitylating enzymes (DUBs) that cleave ubiquitin molecules from target molecules. To date, they are categorized into 7 families with ubiquitin carboxyl c-terminal de-hydrolase family (UCH) as the most common and well-studied. Ubiquitin C-terminal hydrolase L (UCH-L3) is a significant protein in this family as it has been implicated in many molecular and cellular processes with its mRNA identified in a range of body tissues including the brain. It goes without saying that it manifests in maintaining health and when abnormally regulated in disease. As it is an attractive small molecule drug target, scientists have used high throughput screening (HTS) and other drug discovery methods to discover inhibitors for this enzyme for the treatment of cancer and neurodegenerative diseases. In this review we present an overview of UCH-L3 catalytic mechanism, structure, its role in DNA repair and cancer along with the inhibitors discovered so far to halt its activity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

New semi-synthetic effective and safe anticancer agents isoeugenol derivatives were synthesized, characterized, and screened for their cytotoxic activity against MCF-7. Moreover, their selective cytotoxicity was assessed against MCF-10A. Three derivatives, 2, 8 and 10 were significantly more active than the reference drug 5-FU with IC 50 values of 6.59, 8.07 and 9.63 and 30.93 μM, respectively. Also interestingly, these derivatives demonstrated some degree of selectivity to cancer cells over normal cells. Furthermore, derivative 2 was subjected to other in vitro experiments against MCF-7 where it inhibited colony formation by 87.5% and lowered ERα concentration to 395.7 pg/mL compared to 1129 pg/mL in untreated control cells. In continuation of the investigation, the apoptotic activity of compound 2, was assessed where it significantly enhanced total apoptotic cell death by 9.16-fold (18.70% compared to 1.64% for the untreated MCF-7 control cells) and arrested the cell cycle at the G2/M phase. Furthermore, the molecular mechanism of apoptotic activity was investigated at both the gene (RT-PCR) and protein (western plotting) levels where upregulation of pro-apoptotic and down regulation of anti-apoptotic genes was detected. Additionally, compound 2 treatment enhanced the antioxidant (GSH, CAT, SOD) activities. Finally, in vivo experiments verified the effective anticancer activity of compound 2 through inhibition of tumor proliferation by 47.6% compared to 22.9% for 5-FU and amelioration of the hematological, biochemical, and histopathological examinations near normal. In effect, compound 2 can be viewed as a promising semi-synthetic derivative of isoeugenol with some degree of selectivity for management of breast cancer through apoptotic induction and ERα downregulation., (Copyright © 2021 Elsevier B.V. All rights reserved.)

UCHL3 (ubiquitin C-terminal hydrolase-L3) is a de-ubiquitinating enzyme involved in the homologous recombination repair mechanism of double-strand breaks (DBS) of the DNA. Multiple studies indicated that UCHL3 inhibitors could be used in combination therapy with high therapeutic efficacy against cancer thus highlighting the validity of directing research against UCHL3 as a druggable target in oncology. In this study, a combination of virtual screening methods was utilized to identify new potential UCHL3 inhibitors. A series of UCHL3 ligands were identified by applying a combination of cheminformatics and molecular modeling filtration techniques to a ChemBl database of over two million small molecules viz. Lipinski's Rule of Five, Veber's rule, pharmacophore model, Hierarchical molecular docking, Pan-assay Interference Compounds (PAINS) alerts, toxicity filter, and single-point Molecular mechanics Poisson/Boltzmann surface area (MM/PBSA) docking pose rescoring. This multi-layer filtration strategy led to the identification of twenty-one compounds as potential UCHL3 inhibitors that were subsequently subjected to a 50 ns molecular dynamics (MD) simulations predict the stability of their ligand-protein complexes. Furthermore, MM/PBSA calculations based on MD trajectories were performed, and the energy contribution per residue to the binding energy was calculated. Three compounds, 1 , 2 and 3 , were finally recognized as having the highest potential of being UCHL3 inhibitors. Therefore, those were used for binding mode analysis to the UCHL3 active site, leading to identification of four residues as key for binding viz. Pro8, Leu55, Val166, and Leu168.Communicated by Ramaswamy H. Sarma.

This work presents the design and synthesis of a series of new quinazolin-4-one derivatives, based on the established effectiveness of quinazoline-based small molecules as anticancer agents. Synthesized compounds were more potent against MCF-7 than A-549 with low to submicromolar IC 50 s. Compound 17 exhibited the best IC 50 being equipotent with the positive control doxorubicin (IC 50 = 0.06 μM) and better than 5-fluorouracil (IC 50 = 2.13 μM). Compound 17 was further tested against MDA-MB-231 and MCF-10A and was found to be > 2 folds more cytotoxic on MCF-7. Significant apoptotic activity was elicited by 17 on MCF-7 where it increased apoptotic cell death along with induction of pre-G1 and G1-phase cell cycle arrest. Similarly, 17 was able to induce apoptosis in MD-MB-231 treated cells associated with a disruption of the cell cycle causing arrest at the pre-G1 and S phases. Investigation of gene expression in MCF-7 demonstrated an increased expression of the proapoptotic genes P53, PUMA, Bax, caspases 3, 8 and 9 and a decrease of the anti-apoptotic gene Bcl2. Also, 17 reduced autophagy giving way for apoptosis to induce cancer cells death. This latter observation was associated with downregulation of EGFR and its downstream effectors PI3K, AKT and mTor. As its biomolecular target, 17 also inhibited EGFR similar to erlotinib (IC 50  = 0.072 and 0.087 μM, respectively). Additionally, in vivo testing in a mouse model of breast cancer affirmed the anti-tumor efficacy of 17. Finally, docking of 17 against EGFR ATP binding site demonstrated its ability to bind with EGFR resembling erlotinib., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Dicationic diamidines have been well established as potent antiparasitic agents with proven activity against tropical diseases like trypanosomiasis and malaria. This work presents the synthesis of new mono and diflexible triaryl amidines (6a-c, 13a,b and 17), their aza analogues (23 and 27) and respective methoxyamidine prodrugs (5, 7, 12a,b, 22 and 26). All diamidines were assessed in vitro against Trypanosoma brucei rhodesiense (T. b. r.) and Plasmodium falciparum (P. f.) where they displayed potent to moderate activities at the nanomolar level with IC 50 s = 11-378 nM for T. b. r. and 4-323 nM against P. f.. In vivo efficacy testing against T. b. r. STIB900 has shown the monoflexible diamidine 6c as the most potent derivative in this study eliciting 4/4 cures of infected mice for a treatment period of >60 days upon a 4 × 5 mg/kg dose i. p. treatment. Moreover, thermal melting analysis measurement ΔT m for this series of diamidines/poly (dA-dT) complexes fell between 0.5 and 19 °C with 6c showing the highest binding to the DNA minor groove. Finally, a 50 ns molecular dynamics study of an AT-rich DNA dodecamer with compound 6c revealed a strong binding complex supported by vdW and electrostatic interactions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

There have been more than 150 million confirmed cases of SARS-CoV-2 since the beginning of the pandemic in 2019. By June 2021, the mortality from such infections approached 3.9 million people. Despite the availability of a number of vaccines which provide protection against this virus, the evolution of new viral variants, inconsistent availability of the vaccine around the world, and vaccine hesitancy, in some countries, makes it unreasonable to rely on mass vaccination alone to combat this pandemic. Consequently, much effort is directed to identifying potential antiviral treatments. Marine brominated tyrosine alkaloids are recognized to have antiviral potential. We test here the antiviral capacity of fourteen marine brominated tyrosine alkaloids against five different target proteins from SARS-CoV-2, including main protease (M pro ) (PDB ID: 6lu7), spike glycoprotein (PDB ID: 6VYB), nucleocapsid phosphoprotein (PDB ID: 6VYO), membrane glycoprotein (PDB ID: 6M17), and non-structural protein 10 (nsp10) (PDB ID: 6W4H). These marine alkaloids, particularly the hexabrominated compound, fistularin-3, shows promising docking interactions with predicted binding affinities (S-score = -7.78, -7.65, -6.39, -6.28, -8.84 Kcal/mol) for the main protease (M pro ) (PDB ID: 6lu7), spike glycoprotein (PDB ID: 6VYB), nucleocapsid phosphoprotein (PDB ID: 6VYO), membrane glycoprotein (PDB ID: 6M17), and non-structural protein 10 (nsp10) (PDB ID: 6W4H), respectively, where it forms better interactions with the protein pockets than the native interaction. It also shows promising molecular dynamics, pharmacokinetics, and toxicity profiles. As such, further exploration of the antiviral properties of fistularin-3 against SARS-CoV-2 is merited.

Background: Cyclocreatine phosphate (CCrP) is a potent bioenergetic cardioprotective compound known to preserve high levels of cellular adenosine triphosphate during ischemia. Using the standard Isoproterenol (ISO) rat model of heart failure (HF), we recently demonstrated that the administration of CCrP prevented the development of HF by markedly reducing cardiac remodeling (fibrosis and collagen deposition) and maintaining normal ejection fraction and heart weight, as well as physical activity. The novel inflammatory mediator, Nourin is a 3-KDa formyl peptide rapidly released by ischemic myocardium and is associated with post-ischemic cardiac inflammation. We reported that the Nourin-associated miR-137 (marker of cell damage) and miR-106b-5p (marker of inflammation) are significantly upregulated in unstable angina patients and patients with acute myocardial infarction, but not in healthy subjects., Objectives: To test the hypothesis that Nourin-associated miR-137 and miR-106b-5p are upregulated in ISO-induced "HF rats" and that the administration of CCrP prevents myocardial injury (MI) and reduces Nourin gene expression in "non-HF rats"., Methods: 25 male Wistar rats (180-220 g) were used: ISO/saline ( n = 6), ISO/CCrP (0.8 g/kg/day) ( n = 5), control/saline ( n = 5), and control/CCrP (0.8 g/kg/day) ( n = 4). In a limited study, CCrP at a lower dose of 0.4 g/kg/day ( n = 3) and a higher dose of 1.2 g/kg/day ( n = 2) were also tested. The Rats were injected SC with ISO for two consecutive days at doses of 85 and 170 mg/kg/day, respectively, then allowed to survive for an additional two weeks. CCrP and saline were injected IP (1 mL) 24 h and 1 h before first ISO administration, then daily for two weeks. Serum CK-MB (U/L) was measured 24 h after the second ISO injection to confirm myocardial injury. After 14 days, gene expression levels of miR-137 and miR-106b-5p were measured in serum samples using quantitative real-time PCR (qPCR)., Results: While high levels of CK-MB were detected after 24 h in the ISO/saline rats indicative of MI, the ISO/CCrP rats showed normal CK-MB levels, supporting prevention of MI by CCrP. After 14 days, gene expression profiles showed significant upregulation of miR-137 and miR-106b-5p by 8.6-fold and 8.7-fold increase, respectively, in the ISO/saline rats, "HF rats," compared to the control/saline group. On the contrary, CCrP treatment at 0.8 g/kg/day markedly reduced gene expression of miR-137 by 75% and of miR-106b-5p by 44% in the ISO/CCrP rats, "non-HF rats," compared to the ISO/Saline rats, "HF rats." Additionally, healthy rats treated with CCrP for 14 days showed no toxicity in heart, liver, and renal function., Conclusions: Results suggest a role of Nourin-associated miR-137 and miR-106b-5p in the pathogenesis of HF and that CCrP treatment prevented ischemic injury in "non-HF rats" and significantly reduced Nourin gene expression levels in a dose-response manner. The Nourin gene-based mRNAs may, therefore, potentially be used as monitoring markers of drug therapy response in HF, and CCrP-as a novel preventive therapy of HF due to ischemia.

The huge global expansion of the COVID-19 pandemic caused by the novel SARS-corona virus-2 is an extraordinary public health emergency. The unavailability of specific treatment against SARS-CoV-2 infection necessitates the focus of all scientists in this direction. The reported antiviral activities of guanidine alkaloids encouraged us to run a comprehensive in silico binding affinity of fifteen guanidine alkaloids against five different proteins of SARS-CoV-2, which we investigated. The investigated proteins are COVID-19 main protease (M pro ) (PDB ID: 6lu7), spike glycoprotein (PDB ID: 6VYB), nucleocapsid phosphoprotein (PDB ID: 6VYO), membrane glycoprotein (PDB ID: 6M17), and a non-structural protein (nsp10) (PDB ID: 6W4H). The binding energies for all tested compounds indicated promising binding affinities. A noticeable superiority for the pentacyclic alkaloids particularly, crambescidin 786 ( 5 ) and crambescidin 826 ( 13 ) has been observed. Compound 5 exhibited very good binding affinities against Mpro (ΔG = -8.05 kcal/mol), nucleocapsid phosphoprotein (ΔG = -6.49 kcal/mol), and nsp10 (ΔG = -9.06 kcal/mol). Compound 13 showed promising binding affinities against M pro (ΔG = -7.99 kcal/mol), spike glycoproteins (ΔG = -6.95 kcal/mol), and nucleocapsid phosphoprotein (ΔG = -8.01 kcal/mol). Such promising activities might be attributed to the long ω-fatty acid chain, which may play a vital role in binding within the active sites. The correlation of c Log P with free binding energies has been calculated. Furthermore, the SAR of the active compounds has been clarified. The Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) studies were carried out in silico for the 15 compounds; most examined compounds showed optimal to good range levels of ADMET aqueous solubility, intestinal absorption and being unable to pass blood brain barrier (BBB), non-inhibitors of CYP2D6, non-hepatotoxic, and bind plasma protein with a percentage less than 90%. The toxicity of the tested compounds was screened in silico against five models (FDA rodent carcinogenicity, carcinogenic potency TD 50 , rat maximum tolerated dose, rat oral LD 50 , and rat chronic lowest observed adverse effect level (LOAEL)). All compounds showed expected low toxicity against the tested models. Molecular dynamic (MD) simulations were also carried out to confirm the stable binding interactions of the most promising compounds, 5 and 13, with their targets. In conclusion, the examined 15 alkaloids specially 5 and 13 showed promising docking, ADMET, toxicity and MD results which open the door for further investigations for them against SARS-CoV-2.

As cancer continues to be one of the leading causes of death, various cancer treatments are being developed from traditional surgery to the more recent emergence of target therapy. However, therapy resistance is a restricting problem that needs to be overcome. Henceforth, the field of research shifts to new plausible drug targets, among which is the ubiquitin-proteasome system. This review is focused on the ubiquitin carboxyl-terminal hydrolase (UCH) protease family, which are members of Deubiquitinating enzymes (DUBs), specifically Ubiquitin carboxyl-terminal hydrolase L3 (UCHL3). DUBs regulate a broad array of regulatory processes, including cell-cycle progression, tissue development, and differentiation. DUBs are classified into seven subfamilies, including ubiquitin-specific proteases (USPs), JAB1/MPN/Mov34 metalloenzyme, ovarian tumor proteases (OTUs), Josephin and JAB1/MPN+(MJP), MIU-containing novel DUB (MINDY), zinc finger-containing ubiquitin peptidase 1 (ZUP1), and ubiquitin C-terminal hydrolases (UCHs). Having a significant role in tumorigenesis, UCHL3 is thus emerging as a therapeutic target. Knowing its involvement in cancer, it is important to understand the structure of UCHL3, its substrate specificity, and interaction to pave the way for the development of potential inhibitors. This review covers several directions of proteasome inhibitors drug discovery and small molecule inhibitors development., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

VEGFR-2 is a key regulator in cancer angiogenesis. This research displays the design and synthesis of novel 3-cyano-6-naphthylpyridine scaffold-based derivatives as selective VEGFR-2 inhibitors and cytotoxic agents. In vitro percent kinase activity inhibition screening against a panel of 23 kinases at a single high dose (30 nM) affirmed that VEGFR-2 was selectively the most responsive to inhibition by the investigated chemotypes. IC 50 values determination demonstrated kinase inhibitory activities of the test compounds at the sub-nanomolar level. In vitro testing of the new compounds against two prostate cancer cell lines namely PC3 and DU145 and two breast cancer cell lines namely MCF-7 and MDA-MB435 confirmed their potent cytotoxic activity with IC 50 s at the nanomolar level. The most active compound against MCF-7 viz.11d was subjected to an in vivo examination against a xenograft mouse model and was found effective. Studying the tissue mRNA expression levels of various cell cycle controlling biomolecules in 11d-treated MCF-7 cells demonstrated (i) upregulation of p53, p21 and p27, (ii) cleavage of PARP protein, (iii) activation of caspase-3, -8 and -9, (iv) downregulation of the anti-apoptotic protein Bcl, (v) upregulation of the pro-apoptotic protein Bax, and (vi) decreased expression of Cdks 2, 4, 6 and cyclin D1. Additionally, 11d affected a cell cycle arrest at the G1 phase in treated MCF-7 cells and an S phase arrest in MCF-7 p53 knockdown cells. Additionally, molecular docking was performed to predict how 11d might bind to its biological target VEGFR-2. Finally, in-silico ADME and drug-likeness profiling of these derivatives demonstrated favorable properties thereof., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Despite advances in cancer treatment modalities, DNA still stands as one of the targets for anticancer agents. DNA minor groove binders (MGBs) represent an important investigational chemotherapeutic class with promising cytotoxic capacity. Herein this study reports the potent cytotoxic effect of a series of repurposed flexible bis-imidamides 1-4, triaryl bis-guanidine 5 and bis-N-substituted guanidines 6,7 having a 1,4-diphenoxybenzene scaffold backbone on MCF-7 and MDA-MB-231 breast cancer cell lines. Of these compounds, imidamide 4 was chosen for further in-vitro, in-vivo and molecular dynamics (MD) studies owing to its promising anti-tumor activity, with IC 50 values on MCF-7 and MDA-MB-231 breast cancer cell lines of 1.9 and 2.08 μM, respectively. Annexin V/propidium iodide apoptosis assay revealed apoptosis induction on imidamide 4 treated MCF-7 cells. RT-PCR assay results demonstrated the proapoptotic effect of compound 4 through increase of mRNA levels of the pro-apoptotic genes; p53, PUMA, and Bax, and inhibiting the anti-apoptotic Bcl-2 gene expression in MCF-7 cells. Moreover, compound 4 induced a G 0 /G 1 cell-cycle arrest in MCF-7 in a dose-dependent manner. Corroborating in-vivo experiments on Ehrlich ascites carcinoma (EAC)-bearing mice, reflected the anticancer strength of derivative 4. For further target validation, molecular dynamics (MD) studies demonstrated an energetically favorable binding of imidamide 4 with the DNA minor groove AT rich site. In effect, imidamide 4 can be viewed as a promising hit dicationic compound with good cytotoxic and apoptotic inducing activity against breast cancer that can be adopted for future optimization., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

A series of novel derivatives of hydrazinylpyrimidines, pyrazolylpyrimidines and 3-amino[3,4-d]pyrazolopyrimidines have been synthesized and tested for their in vitro cytotoxic activity against 60 tumor cell lines by NCI. The in vitro cytotoxic IC 50 values for the most active compounds were determined against the colon-KM12 cell line (5d, 7c and 7d), breast-MCF-7 (6a) and melanoma-MDA-MB-435 (6h) using 5-fluorouracil (5-FU) as a positive control. Derivatives 5d and 7c were found to be the most potent derivatives against KM12 cell line (IC 50  = 1.73 and 1.21 µM, respectively) with a high selectivity index (SI) (18.82 and 35.49, respectively) compared to 5-FU (IC 50  = 12.26 µM, SI = 1.93). Compounds 5d and 7c were further investigated for their apoptotic behavior in KM12 cell line. The investigations showed the up-regulation of caspase 3/9 and the pro-apoptotic factor Bax. On the other hand, the expression of the anti-apoptotic factor Bcl-2, was down-regulated, as well as its inhibition at a nanomolar concentration. Furthermore, the apoptotic effect for derivatives 5d and 7c in KM12 cells was detected using annexin V-FITC staining method., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

A new series of thiazolidinone (5a-g), thiazinone (9a-g) and dithiazepinone (9a-g) heterocycles bearing a benzenesulfonamide scaffold was synthesized. Cytotoxicity of these derivatives was assessed against MCF-7, HepG2, HCT-116 and A549 cancer cell lines and activity was compared to the known cytotoxic agents doxorubicin and 5-FU where the most active compounds displayed better to nearly similar IC 50 values to the reference compounds. For assessing selectivity, the most active derivatives against MCF-7, 5b, 5c and 5e, were also assessed against the normal breast cell line MCF-10 A where they demonstrated high selective cytotoxicity to cancerous cells over that to normal cells. Further, the effect of the most active compounds 5b-e on MCF-7 and HepG2 cell cycle phase distribution was assessed and the tested sulfonamide derivatives were found to induce accumulation of cells in the <2n phase. To further confirm apoptosis induction, caspase 8 and 9 levels in MCF-7 and HepG2 were evaluated before and after treatment with compounds 5b-e and were found to be significantly higher after exposure to the test agents. Since 5c was the most active, its effect on the cell cycle regulation was confirmed where it showed inhibition of the CDK2/cyclin E1. Finally, in vivo biodistribution study using radioiodinated-5c revealed a significant uptake and targeting ability into solid tumor in a xenograft mouse model., Competing Interests: Declaration of Competing Interest RKA wishes to acknowledge STDF for supporting part of this research project through the grant fund provided to her “STDF 25839”., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Novel heterocyclic oxadiazoles viz. 2-subsituted-5-(4-pyridyl)-1,3,4-oxadiazoles, 2-subsituted-5-(3-pyridyl)-1,3,4-oxadiazoles and 2-subsituted-5-(phenyl or 4-chlorophenyl-1,3,4-oxadiazoles) were designed and synthesized as potential anticancer agents. In this investigation, all compounds were evaluated for their COX-1 and COX-2 inhibitory activity in vitro as new therapeutic approaches assumed cytotoxic effect associated with selective COX-2 inhibition. Results showed that most of the derivatives demonstrated inhibition towards both isoforms of COX comparable to the standard reference drugs indomethacin, diclofenac sodium and celecoxib. Then, nine selected compounds (IIId, VIb, VIIc, IX, XI, XIIa, XIVa, XVIb and XVIIIb) were subjected to cytotoxic screening against UO-31 renal cancer cell line using MTT assay. Compounds IIId, IX and XIIa displayed promising behavior by showing good anticancer activity. Moreover, kinase inhibitory assay against the tyrosine kinase EGFR was performed for the three compounds showing the highest cytotoxic activity. The tested compounds were potent against EGFR with the highest activity being observed for compound IX showing nearly double the potency of the reference drug Erlotinib. Moreover, molecular docking and molecular dynamics were performed for IIId, IX and XIIa against EGFR, in an attempt to elucidate a model for their binding at the molecular level, simulate and understand the possible binding interactions underlying the association between these small molecules and the kinase enzyme ATP binding pocket essential amino acids. Finally, in silico pharmacokinetic profile predication was investigated for IIId, IX and XIIIa using SWISS/ADME to identify the most promising small-molecule cytotoxic agent on the basis of displaying the best drug-like properties. Results indicated that compound IX has a potential to serve as a lead compound for developing novel anticancer therapeutic agents., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

A series of thirteen new aryl/hetarylbichalcophene-5-carboxamidines was prepared and screened for an in vitro anti-proliferative activity against sixty cancer cell lines. The tested monocationic bichalcophenes displayed promising potent anticancer activity against most cancer cell lines with GI 50 values of 1.34-3.09 μM. The most potent compound was derivative 8 (median GI 50 and TGI values of 1.34 and 3.23 μM, respectively), being also the least cytotoxic in this bichalcophene series with an LC 50 of 77.6 μM. The most responsive cancer cell lines were leukemia (SR and K-562) and colon (HCT-15 and HT29) with GI 50 in the sub-micromolar range. The effect of the tested bichalcophenes on normal human lung fibroblast (WI-38) cell line showed that they exerted their antiproliferative activity outside the realms of causing any toxicity in normal cells. To study apoptotic profiles of representatives of this class, compounds 4h, 4i, and 8 were found to cause significant reductions in cdk1 expression in HCT-116 colon cells by 46, 79, and 84%, respectively versus 52% reduction by 5- Flourouracil (5-FU). These three compounds were also unique being the only derivatives that significantly elevated the expression of p53 by ∼2, 4, and 5 folds, respectively. The tested bichalcophenes exhibited moderate to potent antioxidant activity in DPPH and ABTS as well as hydroxyl radical scavenging assays. Moreover, compounds IIIb, IIIc, 4c, and 4i, showed the highest pro-oxidant activity. Finally, to aid future endeavors for optimization of this series, a 5 descriptor 2D-QSAR model was derived from the common physicochemical parameters of these bichalcophenes and the external validation proved the model's good predictive efficiency., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

A series of new visnagin and benzofuran scaffold-based molecules was designed and synthesized as anti-inflammatory and analgesic agents. Biological screening of these compounds showed that they exhibit potent anti-inflammatory/analgesic activity with a safer side effect profile in in vivo mouse models. In vitro cyclooxygenase (COX) inhibition assay showed that the compounds elicit their function through selective COX-2 inhibition. Molecular docking study also revealed the ability of the compounds to correctly recognize the active site and achieve noncovalent binding interactions with key residues therein. The best combined profile of anti-inflammatory, analgesic and COX-2 selective inhibition properties in association with low gastrotoxicity was displayed by the analogs 8, 11b and 19d, which can be considered as promising leads for further future optimization.

Two new series of furochromone and benzofuran derivatives were designed, synthesized and evaluated for their in vitro anticancer activity against MCF-7 and MDA231 breast cancer cell lines. Compounds 5, 6, 7, 9, 15a, 16, 17a and 18 exhibited the best antiproliferative activities with IC 50 values ranging from 1.19 to 2.78 µM against MCF-7 superior to lapatinib as reference standard (IC 50 ; 4.69 µM). Compounds 15a and 18 revealed significant cytotoxic activity against MCF-7 and MDA231, therefore their inhibitory potencies against p38α MAP kinase were evaluated. Remarkably they exhibited significant IC 50 of 0.04 µM comparable to SB203580 (IC 50 ; 0.50 µM) as a reference standard. These promising results of cytotoxic activity and significant inhibition of p38α MAP kinase, were confirmed by exploring the effect of benzofuran derivative (18) on the apoptotic induction and cell cycle progression of MCF-7 cell line. Compound 18 induced preG1 apoptosis and cell growth arrest at G2/M phase preventing the mitotic cycle. Moreover it activated the caspase-7 which executes apoptosis. Molecular docking study was carried out using GOLD program to predict the mode of binding interaction of the synthesized compounds into the target p38α MAPK. Additionally, the physicochemical properties and ADME parameters of compound 18 were examined in silico to investigate its drug-likeness., (Copyright © 2019. Published by Elsevier Ltd.)

A series of twenty five new thiobarbituric acid derivatives, viz. 3a-h, 4-7, 8a-c, 9, 10a-c, 11 and 12a-d, were designed and synthesized as potential cytotoxic agents. In-vitro screening of the new compounds against the three human cancer cell lines Caco-2, HepG-2 and MCF-7 was performed to assess their intrinsic activity. Compound 12d exhibited potent sub-micromolar activity against HepG-2 and MCF-7 (IC 50  = 0.07 and 0.08 μM, respectively). In-silico pharmacophore modelling of this chemotype compounds disclosed a five features' pharmacophore model representing essential steric and electronic fingerprints essential for activity. Finally, a 2D-QSAR model was devised to quantitatively correlate the 2D molecular feature descriptors of this series of thiobarbiturates with their cytotoxic activity against MCF-7. Finally, in silico evaluation of the physicochemical and ADME properties of these derivatives was performed., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Despite advances in therapy of breast and ovarian cancers, they still remain among the most imperative causes of cancer death in women. The first can be considered one of the most widespread diseases among females, while the latter is more lethal and needs prompt treatment. Thus, the research field can still benefit from discovery of new compounds that can be of potential use in management of these grave illnesses. We hereby aimed to assess the antitumor activity of the phytosterol α-spinasterol isolated from Ganoderma resinaceum mushroom on human breast cancer cell lines (MCF-7, MDA-MB-231), as well as, on human ovarian cancer cell line (SKOV-3). The anti-tumor activity of α-spinasterol, isolated from the mycelial extract of the Egyptian G. resinaceum, on human breast and ovarian cancer cell lines was evaluated by MTT cell viability assay and AnnexinV/propidium iodide apoptosis assay. The molecular mechanism underlying this effect was assessed by the relative expression of the following markers; tumor suppressor (p53, BRCA1, BRCA2), apoptotic marker (Bax) and cell cycle progression markers (cyclin dependent kinases cdk4/6) using real-time PCR. Cell cycle analysis was performed for the three investigated cancer cell lines to explore the effect on cell cycle progression. Our findings showed that α-spinasterol exhibited a higher antitumor activity on MCF-7 cells relative to SKOV-3 cells, while its lowest antitumor activity was against MDA-MB-231 cells. A significant increase in the expression of p53 and Bax was observed in cells treated with α-spinasterol, while cdk4/6 were significantly down-regulated upon exposure to α-spinasterol. Cell cycle analysis of α-spinasterol treated cells showed a G 0 -G 1 arrest. In conclusion, α-spinasterol isolated from G. resinaceum mushroom exerts a potent inhibitory activity on breast and ovarian cancer cell lines in a time- and dose-dependent manner. This can be reasonified in lights of the compound's ability to increase p53 and Bax expressions, and to lower the expression of cdk4/6., (© 2017 Wiley Periodicals, Inc.)

Globally, invasive fungal infections pose a significant challenge to modern human medicine due to the limited number of antifungal drugs and the rise in resistance to current antifungal agents. A vast majority of invasive fungal infections are caused by species of Candida, Cryptococcus, and Aspergillus. Novel antifungal molecules consisting of unexploited chemical scaffolds with a unique mechanism are a pressing need. The present study identifies a dibromoquinoline compound (4b) with broad-spectrum antifungal activity that inhibits the growth of pertinent species of Candida (chiefly C. albicans), Cryptococcus, and Aspergillus at a concentration of as low as 0.5 μg/mL. Furthermore, 4b, at a subinhibitory concentration, interfered with the expression of two key virulence factors (hyphae and biofilm formation) involved in C. albicans pathogenesis. Three yeast deletion strains ( cox17Δ, ssa1Δ, and aft2Δ) related to metal ion homeostasis were found to be highly sensitive to 4b in growth assays, indicating that the compound exerts its antifungal effect through a unique, previously unexploited mechanism. Supplementing the media with either copper or iron ions reversed the strain sensitivity to 4b, further corroborating that the compound targets metal ion homeostasis. 4b's potent antifungal activity was validated in vivo, as the compound enhanced the survival of Caenorhabditis elegans infected with fluconazole-resistant C. albicans. The present study indicates that 4b warrants further investigation as a novel antifungal agent.

Background & Method: A series of thirty-one new 1-phthalazinones was designed and synthesized based on the well-known VEGFR inhibitor vatalanib. The obtained phthalazinones were screened for their cytotoxic activity against DLD-1 and LoVo (colon), and Panc-1 and Paca-2 (pancreas) cancer cell lines using MTT assay. The tested compounds revealed exceptionally promising cytotoxic activity against LoVo cell lines with IC50 ranges 0.18-780 nM., Conclusion: Finally, these compounds were also found to be dual inhibitors of VEGFR-2 and EGFR in the in vitro enzyme assay with higher potency against the former (IC50 = 0.023-0.41 nM)., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

A new series of 5,7-dibromoquinoline scaffold-based derivatives with varied flexibility substituents at position 8 of the ring system has been synthesized as potential anticancer agents. The new compounds were evaluated for their in vitro antiproliferative activity versus the human breast cancer cell lines MCF-7 and MDA-MB231. Generally, both cell lines were responsive to the cytotoxic effect of the synthesized analogues. Compounds 4a, 5c and 7b were chosen for nanoformulation studies to assess the effect of enhancing their solubility profile on their cytotoxic ability. Indeed, the pluronic nanomicelles of the three formulated derivatives showed an observable significant increase in their cytotoxic efficacy demonstrating a positive impact of the used nanoformulations on the delivery of the active compounds to their cellular biological targets., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Eleven compounds of substituted 4-(5-arylthiophen-2-yl)benzamidines 4a-k were synthesized from their corresponding mononitriles via treatment with lithium trimethylsilylamide and subsequent de-protection with ethanol/hydrogen chloride. In vitro antiproliferative activities of the new monocationic arylthiophenes were evaluated against 60 human cell lines at NCI, USA. This class of compounds displayed promising submicromolar antiproliferative activities with the most potent compound being 4i (GI 50 and TGI of 0.20 and 0.37 μM, respectively). On the other hand, most of the tested compounds exhibited LC 50 at concentrations much higher than those they had GI 50 at; ∼10× (for 4b) up to 228× (for 4e) which indicates lower lethality and efficient growth inhibition. Cancer cell lines, HCC-2998 colon, SNB-75 CNS, MDA-MB-435 melanoma, and MCF-7 breast cancer were the most responsive, with GI 50s of 0.156, 0.165, 0.163, and 0.168 μM, respectively. The p-chlorophenyl derivatives 4e and 4i discerned themselves with GI 50 values at 0.36 and 0.20 μM, respectively, and LC 50 values at ∼83 and 36 μM, respectively, but safe to RBCs at 1000 μM. The cytotoxic activity data of these compounds in two normal cell lines; WI38 and WISH proved that they are very safe on normal cells. The plausible mechanism of action of the tested monocations was examined by evaluating their antioxidant power, nuclease-like DNA degradation aptitude and tyrosine kinase (TK) inhibition activities. The tested monocations showed potent activity in all assays. Compounds 4e and 4i caused 88 and 98%, respectively, inhibition in TK activity at 1 μM and the IC 50 for 4i was 13 nM. The tested monocations have selective anticancer activity without insulting normal cells most probably due to inhibition of the key enzyme TK at nanomolar concentrations., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Alzheimer's disease (AD) is one of the most common neurological disorders with vast reaching worldwide prevalence. Research attempts to decipher what's happening to the human mind have shown that pathogenesis of AD is associated with misfolded protein intermediates displaying tertiary structure conformational changes eventually leading to forming large polymers of unwanted aggregates. The two hallmarks of AD pathological protein aggregates are extraneuronal β-amyloid (Aβ) based senile plaques and intraneuronal neurofibrillary tangles (NFTs). As such, AD is categorized as a protein misfolding neurodegenerative disease (PMND) . Therapeutic interventions interfering with the formation of these protein aggregates have been widely explored as potential pathways for thwarting AD progression. One such tactic is modulating the function of enzymes involved in the metabolic pathways leading to formation of these misfolded protein aggregates. Much evidence has shown that glycogen synthase kinase-3β (GSK-3β) plays a key role in hyperphosphorylation of tau protein leading eventually to its aggregation to form NFTs. Data presented hereby will display a plethora of information as to how to interfere with progression of AD through the route of GSK-3β activity control.

Reactive oxygen species (ROS) play an integral role in the pathogenesis of most diseases. This work presents the design and synthesis of novel 2-phenylquinazolin-4-amine derivatives (2-12) and evaluation of their, Nad(p)h: quinone oxidoreductase 1 (NQO1) inducer activity in murine cells. Also, molecular docking of all the new compounds was performed to assess their ability to inhibit Keap1-Nrf2 protein-protein interaction through occupying the Keap1-Nrf2-binding domain which biologically leads to a consequent Nrf2 accumulation and enhanced gene expression of NQO1. Docking results showed that all compounds have the ability to interact with Keap1; however compound 7, the most active compound in this study, showed more interactions with key amino acids.