Abdalla E. A. Hassan

A series of 2,4,6-trisubstituted nicotinonitriles, compounds 10 – 41 , was designed as pyridine bridged analogs of combretastatin A4 and evaluated as dual inhibitors of topoisomerase II and tubulin polymerization. Anticancer activity was tested in MCF7, HepG2, and HCT116 cells using the LDH assay. Several compounds including 19 – 24 , 26 – 27 , 33 – 35 , 37 – 38 , and 41 showed strong cytotoxicity in MCF7 cells, while compounds 20 , 26 , 38 , 39 , and 41 displayed moderate activity in HepG2 cells with good selectivity toward BJ1 normal cells. Tubulin polymerization assays identified compounds 20 , 26 , and 37 as the most active, showing inhibition values of 74.7%, 75.0%, and 74.3%, compared with 72.1% for combretastatin A4. Compound 37 showed strong topoisomerase II inhibition (82.4%), while compound 20 displayed moderate inhibition (70.3%), both compared with DOX (81.6%). Cell cycle analysis indicated that compounds 20 and 26 induced G2 and M phase arrest in MCF7 cells and promoted apoptosis. Molecular docking confirmed favorable binding interactions with both tubulin and topoisomerase II. These results highlight 2,4,6-trisubstituted nicotinonitriles as promising dual target anticancer candidates and support their further optimization.

Influenza viruses belong to the Orthomyxoviridae family and cause acute respiratory distress in humans. The developed drug resistance toward existing drugs and the emergence of viral mutants that can escape vaccines mandate the search for novel antiviral drugs. Herein, the synthesis of epimeric 4′‐methyl‐4′‐phosphonomethoxy [4′‐C‐Me‐4′‐C‐(O‐CH₂P═O)] pyrimidine ribonucleosides, their phosphonothioate [4′‐C‐Me‐4′‐C‐(O‐CH₂P═S)] derivatives, and their evaluation against an RNA viral panel are described. Selective formation of the α‐ l‐lyxo epimer, [4′‐C‐(α)‐Me‐4′‐C‐(β)‐(O‐CH₂‐P(═O)(OEt)₂)] over the β‐ d‐ribo epimer [4′‐C‐(β)‐Me‐4′‐C‐(α)‐(O‐CH₂‐P(═O)(OEt)₂)] was explained by DFT equilibrium geometry optimizations studies. Pyrimidine nucleosides having the [4′‐C‐(α)‐Me‐4′‐C‐(β)‐(O‐CH₂‐P(═O)(OEt)₂)] framework showed specific activity against influenza A virus. Significant anti‐influenza virus A (H1N1 California/07/2009 isolate) was observed with the 4′‐C‐(α)‐Me‐4′‐C‐(β)‐O‐CH₂‐P(═O)(OEt)₂‐uridine derivative 1 (EC₅₀ = 4.56 mM, SI₅₀ > 56), 4‐ethoxy‐2‐oxo‐1(2H)‐pyrimidin‐1‐yl derivative 3 (EC₅₀ = 5.44 mM, SI₅₀ > 43) and the cytidine derivative 2 (EC₅₀ = 0.81 mM, SI₅₀ > 13), respectively. The corresponding thiophosphonates 4′‐C‐(α)‐Me‐4′‐C‐(β)‐(O‐CH₂‐P( S)(OEt)₂) and thionopyrimidine nucleosides were devoid of any antiviral activity. This study shows that the 4′‐C‐(α)‐Me‐4′‐(β)‐O‐CH₂‐P(═O)(OEt)₂ ribonucleoside can be further optimized to provide potent antiviral agents.

A new series of nicotinonitrile derivatives 2–7 was designed and synthesized from the starting material (E)-3-(4-chlorophenyl)-1-(4-methoxyphenyl)prop-2-en-1-one (1) to assess their molluscicidal activity. The newly synthesized nicotinonitrile compounds 2–7 were characterized based on FTIR, ¹H-NMR, and ¹³C-APT NMR spectra as well as elemental microanalyses. The target compounds 2–7 were screened for their toxicity effect against M. cartusiana land snails and were compared to Acetamiprid as a reference compound. The results demonstrated that the nicotinonitrile-2-thiolate salts 4a and 4b had good mortality compared with that of Acetamiprid. The results of the in vivo effect of the prepared nicotinonitrile molecules 2, 4a, and 4b on biochemical parameters, including AChE, ALT, AST, and TSP, indicated a reduction in the level of AChE and TSP as well as an increase in the concentration of transaminases (ALT and AST). A histopathological study of the digestive gland sections of the M. cartusiana land snails was carried out. The nicotinonitrile-2-thiolate salts 4a,b showed vacuolization, causing the digestive gland to lose its function. It could be concluded that the water-soluble nicotinonitrile-2-thiolate salts 4a,b could be adequate molluscicidal molecules against M. cartusiana land snails.

Zinc is an essential metal for humans and plays key roles in several biological events such as immunity, allergy, growth, and inflammation. The deficiency in zinc causes an increased infection rate with pathogens. Organo-zincates such as zinc gluconate are known for better absorption compared with their inorganic zinc salts. Its role in enhancing the immune system has driven a huge demand for organo-zinc supplements and in the treatment protocol of coronavirus disease, the causative agent of the COVID-19 pandemic. Herein, we report on a quantitative analysis of zinc gluconate in the authentic form in presence of vitamin C, and the method was applied to their dosage form (Utozinc^® tablets). The method is simple, accurate, and validated according to ICH guidelines. Quantification of zinc gluconate formulated with vitamin C (Utozinc tablets) using Q-¹HNMR. Maleic acid and deuterium oxide were used as internal standards and solvents, respectively. The linearity range, the limit of detection and quantification, stability, precision, and accuracy, were validated. The validation of the method within five concentration levels (from 10 to 50 mg/0.5 mL D₂O) afforded a limit of detection of 4.58 mg/mL, a quantification limit of 15.27 mg/mL, and excellent linearity. The method proposed in the present study is simple, fast, nondestructive, and accurate. Zinc gluconate quantification values obtained by the Q-¹HNMR method were found to show an acceptable correlation with those obtained by the thin-layer chromatographic technique. The method was successfully applied to Utozinc tablets, and the results were compared with the reported reference pharmacopeial method. The salt exchange between maleic acid (IS) and zinc gluconate was tested by noticing the change in the chemical shift of IS and zinc gluconate.

Pathogenic CUG and CCUG RNA repeats have been associated with myotonic dystrophy type 1 and 2 (DM1 and DM2), respectively. Identifying small molecules that can bind these RNA repeats is of great significance to develop potential therapeutics to treat these neurodegenerative diseases. Some studies have shown that aminoglycosides and their derivatives could work as potential lead compounds targeting these RNA repeats. In this work, sisomicin, previously known to bind HIV-1 TAR, is investigated as a possible ligand for CUG RNA repeats. We designed a novel fluorescence-labeled RNA sequence of r(CUG)₁₀ to mimic cellular RNA repeats and improve the detecting sensitivity. The interaction of sisomicin with CUG RNA repeats is characterized by the change of fluorescent signal, which is initially minimized by covalently incorporating the fluorescein into the RNA bases and later increased upon ligand binding. The results show that sisomicin can bind and stabilize the folded RNA structure. We demonstrate that this new fluorescence-based binding characterization assay is consistent with the classic UV T_m technique, indicating its feasibility for high-throughput screening of ligand-RNA binding interactions and wide applications to measure the thermodynamic parameters in addition to binding constants and kinetics when probing such interactions.

Exosomes (EXOs) were given attention as an extracellular vesicle (EV) with a pivotal pathophysiological role in the development of certain neurodegenerative disorders (NDD), such as Parkinson’s and Alzheimer’s disease (AD). EXOs have shown the potential to carry pathological and therapeutic cargo; thus, researchers have harnessed EXOs in drug delivery applications. EXOs have shown low immunogenicity as natural drug delivery vehicles, thus ensuring efficient drug delivery without causing significant adverse reactions. Recently, EXOs provided potential drug delivery opportunities in AD and promising future clinical applications with the diagnosis of NDD and were studied for their usefulness in disease detection and prediction prior to the emergence of symptoms. In the future, the microfluidics technique will play an essential role in isolating and detecting EXOs to diagnose AD before the development of advanced symptoms. This review is not reiterative literature but will discuss why EXOs have strong potential in treating AD and how they can be used as a tool to predict and diagnose this disorder.

Cancer is a multifaceted disease. With the development of multi drug resistance, the need for the arousal of novel targets in order to avoid these drawbacks increased. A new series of acrylamide derivatives was synthesized from starting material 4-(furan-2-ylmethylene)-2-(3,4,5-trimethoxyphenyl)oxazol-5(4H)–one (1), and they are evaluated for their inhibitory activity against β-tubulin polymerization. The target molecules 2–5 d were screened for their cytotoxic activity against breast cancer MCF-7 cell line. The results of cytotoxicity screening revealed that compounds 4e and 5d showed good cytotoxic profile against MCF-7 cells. Compounds 4e produced significant reduction in cellular tubulin with excellent β-tubulin polymerization inhibition activity. In addition, compound 4e exhibited cytotoxic activity against MCF-7 cells by cell cycle arrest at pre-G1 and G2/M phases, as shown by DNA flow cytometry assay. Aiming to enhance the limited aqueous solubility and, hence, poor oral bioavailability of the prepared lead acrylamide molecule, 4e-charged PEGylated bilosomes were successfully fabricated via thin film hydration techniques as an attempt to improve these pitfalls. 2³ full factorial designs were manipulated to examine the influence of formulation variables: types of bile salt including either sodium deoxy cholate (SDC) or sodium tauro cholate (STC), amount of bile salt (15 mg or 30 mg) and amount of DSPE–mPEG-2000 amount (25 mg or 50 mg) on the characteristics of the nanosystem. The F7 formula of entrapment efficiency (E.E% = 100 ± 5.6%), particle size (PS = 280.3 ± 15.4 nm) and zeta potential (ZP = −22.5 ± 3.4 mv) was picked as an optimum formula with a desirability value of 0.868. Moreover, prominent enhancement was observed at the compound’s cytotoxic activity (IC₅₀ = 0.75 ± 0.03 µM) instead of (IC₅₀ = 2.11 ± 0.19 µM) for the unformulated 4e after being included in the nano-PEGylated bilosomal system.

6‐Methylpurine (MeP) is a cytotoxic adenine analog that does not exhibit selectivity when administered systemically and could be very useful in a gene therapy approach to cancer treatment involving Escherichia coli purine nucleoside phosphorylase (PNP). 9‐(6‐Deoxy‐β‐D‐allofuranosyl)‐6‐methylpurine [methyl(allo)‐MePR, 18] and 9‐(6‐deoxy‐α‐L‐talofuranosyl)‐6‐methylpurine [methyl(talo)‐MePR, 21] were synthesized as potential prodrugs for MeP in the E. coli PNP/prodrug cancer gene therapy approach. The detailed syntheses of [methyl(allo)‐MePR] and [methyl(talo)‐MePR] are described. The glycosyl donors, 1,2‐di‐O‐acetyl‐3,5‐di‐O‐benzyl‐α‐D‐allofuranose (12) and 1‐O‐acetyl‐3‐O‐benzyl‐2,5‐di‐O‐benzoyl‐α‐L‐talofuranose (16) were prepared from 1,2:5,6‐di‐O‐isopropylidene‐α‐D‐glucofuranose (4) in nine and eleven steps, respectively. Vorbrüggen coupling of the latter glycosyl donors with 6‐methylpurine (3), followed by deprotection of the sugar hydroxyl groups, gave the title compounds in good overall yields. © 2020 by John Wiley & Sons, Inc.Basic Protocol 1: Preparation of 6‐methylpurineBasic Protocol 2: Preparation of the D‐allofuranose derivative (12)Basic Protocol 3: Preparation of 6‐deoxy‐α‐L‐talofuranosideBasic Protocol 4: Preparation of methyl(allo)‐MePR (18)Basic Protocol 5: Preparation of methyl(talo)‐MePR (21)

Synthesis and biological evaluations of a series of 2‐oxonicotinonitriles (2‐ONNs) derivatives are described. Incorporation of branching and solubilizing groups to the 2‐ONN derivative 7 was attained by coupling with several organo‐halides/alkylating agents including three glycosyl bromides under basic conditions. Coupling of 2‐ONNs occurred mainly at the ring nitrogen position and to a lesser extent at the 2‐oxo position giving the O‐alkylated products. Alkylated ONNs and free nucleosides/glycosides derived from the 2‐ONN derivative 7 were tested for their antibacterial, antifungal, and antiviral activities. N‐propargyl and N‐allyl derivatives 23 and 25 showed significant anti‐SARS‐CoV. The N‐butylacetate and O‐allyl derivatives 18 and 26 showed potent antibacterial activities against both Gram‐positive (Staphylococcus aureus, Micrococci luteus) and Gram‐negative (Pseudomonas aeruginosa, Escherichia coli) bacterial strains. The N‐glucoside derivative 8 showed significant antifungal activity.