Mohammad H. Semreen

Design, Synthesis, and Qualitative Structure–Activity Evaluations of Novel β-Secretase Inhibitors as Potential Alzheimer’s Drug Leads

We have identified highly selective imidazopyridines armed with benzimidazol and/or arylimidazole as potent β-secretase inhibitors. The most effective and selective analogues demonstrated low nanomolar potency for the BACE1 enzyme as measured by FRET and cell-based (ELISA) assays and exhibited comparable affinity (KI) and high ligand efficiency (LE). In addition, these motifs were highly selective (>200) against the structurally related aspartyl protease BACE2. Our design strategy followed a traditional SAR approach and was supported by molecular modeling studies based on the previously reported hydroxyethylene transition state inhibitor derived from isophthalic acid I. Of the most potent compounds, 34 displayed an IC50 for BACE1 of 18 nM and exhibited cellular activity with an EC50 of 37 nM in the cell-based ELISA assay, as well as high affinity (KI=17 nM) and ligand efficiency (LE=1.7 kJ/mol). Compound 34 was found to be 204-fold more selective for BACE1 compared to the closely related aspartyl protease BACE2.

Modulation of DNA damage response and induction of apoptosis mediates synergism between doxorubicin and a new imidazopyridine derivative in breast and lung cancer cells

DNA damage response machinery (DDR) is an attractive target of cancer therapy. Modulation of DDR network may alter the response of cancer cells to DNA damaging anticancer drugs such as doxorubicin. The aim of the present study is to investigate the effects of a newly developed imidazopyridine (IAZP) derivative on the DDR after induction of DNA damage in cancer cells by doxorubicin. Cytotoxicity sulphrhodamine-B assay showed a weak anti-proliferative effect of IAZP alone on six cancer cell lines (MCF7, A549, A549DOX11, HepG2, HeLa and M8) and a normal fibroblast strain. Combination of IAZP with doxorubicin resulted in synergism in lung (A549) and breast (MCF7) cancer cells but neither in the other cancer cell lines nor in normal fibroblasts. Molecular studies revealed that synergism is mediated by modulation of DNA damage response and induction of apoptosis. Using constant-field gel electrophoresis and immunofluorescence detection of γ-H2AX foci, IAZP was shown to inhibit the repair of doxorubicin-induced DNA damage in A549 and MCF7 cells. Immunoblot analysis showed that IAZP suppresses the phosphorylation of the ataxia lelangiectasia and Rad3 related (ATR) protein, which is an important player in the response of cancer cells to chemotherapy-induced DNA damage. Moreover, IAZP augmented the doxorubicin-induced degradation of p21, activation of p53, CDK2, caspase 3/7 and phosphorylation of Rb protein. These effects enhanced doxorubicin-induced apoptosis in both cell lines. Our results indicate that IAZP is a promising agent that may enhance the cytotoxic effects of doxorubicin on some cancer cells through targeting the DDR. It is a preliminary step toward the clinical application of IAZP in combination with anticancer drugs and opens the avenue for the development of compounds targeting the DDR pathway that might improve the therapeutic index of anticancer drugs and enhance their cure rate.

Tandem Multicomponent Reactions Toward the Design and Synthesis of Novel Antibacterial and Cytotoxic Motifs

The synthesis of polysubstituted imidazopyridines and imidazopyrazines through the orthogonal union of Groebke-Blackburn and Ugi reactions is described. These motifs were produced efficiently in a tandem operation without intermediate isolation. The synthesized scaffolds were biologically evaluated and found to possess potent anticancer and anti bacterial activities. Importantly, some of these motifs (e.g. compound 5) were found to possess specific anti-breast cancer activity against MCF7 cell line and others (e.g. compound 15) possess specific effects against melanoma cancer cell line (M8). Interestingly, the introduction of imidazobenzothiazole framework produced compounds with potent anti cancer activities (e.g. compounds 29 and 33) in vitro. Interestingly, many of synthesized compounds displayed potent and broad spectrum antibacterial activity against hospital-resistant clinical isolates namely, Escherichia coli, Klebsiellapneuomoniae, Staph. epidermidis, Ps. aeruginosa and Proteus vulgaris. Furthermore, many of the synthesized motifs were found to effective against Gram positive methicillin-sensitive Staphylococcus aureus (MMSA; ATCC 25923), andmethicillin-resistant Staphylococcus aureus (MRSA; ATCC 35591). These findings, however, form the foundation for further investigation in our continuing efforts to develop selective anticancer and antibacterial agents.

Determination of Heavy Metal Content in Wild-Edible Mushroom from Jordan

The heavy metal content was investigated for six mushroom species native to Jordan. Metal (Cu, Pb, Cd, Fe, Zn, Mn, Ni, and Co) content in soil substrate and their relation to metal concentrations in mushroom and underlying soil were determined by flame and graphite furnace atomic absorption spectrometry. Mushroom species and soil were collected from different places in Jordan. The highest Cu level was 51.84 µg g−1 for the species Lepista nuda; whereas, the lowest Cu level was found to be 18.51 µg g−1 in Calvatia utriformis. Among the wild mushrooms, the highest Pb level was found as 4.81 µg g−1 in Bovista plumbea, whereas the lowest Pb concentration was 2.01 µg g−1 in Calvatia utriformis. The highest Cd level was determined as 1.9 µg g−1 for Lepista nuda, whereas the lowest Cd level was 0.58 µg g−1 for the species of Polyporus frondosus. The highest Zn level was 58.77 µg g−1 for the species of Lepista nuda and the lowest Zn concentration was found 35.98 µg g−1 in Calvatia utriformis. The highest Fe level was found as 317 µg g−1 in Lepista nuda, whereas the lowest Fe concentration was 211.7 µg g−1 in Calvatia utriformis. The highest Mn content was 36.55 µg g−1 for Russula delica, whereas the lowest Mn level was 24.5 µg g−1 for the species Bovista plumbea. The highest Ni content was found as 12.65 µg g−1 for Russula delica, whereas the lowest Ni level was 0.17 µg g−1 for Bovista plumbea. The highest Co content in the tested mushrooms was found as 3.5 µg g−1 for the species of Agaricus bisporus, whereas the lowest Co level was 0.85 µg g−1 for Polyporus frondosus. The results indicated that, in general, heavy metal contents in all mushroom species were lower than the underlying soil substrates except for some mushroom species.

Design, Synthesis and Qualitative Structure Activity Relationship Evaluations of Quinoline-Based Bisarylimidazoles as Antibacterial Motifs

BACKGROUND The emergence of drug-resistant bacteria in clinical practice has propelled a concerted effort to find new classes of antibiotics that will circumvent current modes of resistance. We previously described a set of imidazopyridine antibacterial leads that contain a core composed of benzimidazole and a central phthalic acid linker. These compounds showed potent antibacterial properties against a wide range of Gram-positive and Gram-negative bacteria. In this respect, we conducted a systematic exploration of new disubstituted imidazole functionalities on quinoline 4-position as the central linker, to determine the factors that direct the potent antibacterial activity. We found that some of the newly synthesized compounds possessed more potent activity compared to currently available medications. The newly synthesized compounds were screened against several clinical isolates and Staphylococcus aureus, including the methicillinresistant (MRSA) and the methicillin-sensitive (MSAA). METHODS The goal of this work is to undertake rigorous testing of new hybrid scaffolds of quinoline flanked by diaryl imidazoles and their structure-activity against a range of bacterial strains. Described herein is the account of the modification of the central linker region, the imidazole functionality, and substituents at the 4-position of the quinoline, and their effect on the antibacterial potency of the resulting derivatives. Our efforts here have been driven by previous reports on the applications of Pfitzinger cyclization protocol. This complexity-generating reaction transforms a relatively simple substrate, into a more complex products with the potential for diversification via functionalization of the resultant acid. RESULTS We identified compounds that possess potent and broad-spectrum antibacterial activities against clinical isolates and drug resistant strains. Structure-Activity relationships of these compounds were further explored to determine the crucial structural features needed to enhance their antibacterial activity. In this respect, it was found that, hydrophobic and electron-withdrawing moieties, such as halogens, were required on each end of the isoquinoline-based bisaryl imidazole hybrid motifs to produce broad-spectrum activity against the tested strains. Thus, molecules containing halophenyl or pyridyl arms were found more potent than molecules containing thiophene and/or electron-releasing groups on the phenyl arms, which showed much less antibacterial activity against the tested strains. CONCLUSION In summary, 4-(4,5-diphenyl-1H-imidazol-2-yl)-2-phenylquinoline systems can be assembled efficiently through the Pfitzinger ring expansion- condensation strategy. This approach appears to hold considerable synthetic utility. The particular value of such a synthetic route resides on the conciseness and efficiency through which imidazo-quinoline construction can be synthesized from structurally simple and accessible acetophenone precursors.

Design, synthesis, and biological evaluation of new arylamide derivatives possessing sulfonate or sulfamate moieties as steroid sulfatase enzyme inhibitors

Graphical abstract

Targeting γ-Aminobutyric Acid (GABA) Carriers to the Brain: Potential Relevance as Antiepileptic Pro-Drugs

The search for antiepileptic compounds with more selective activity continues to be an area of intensive investigation in medicinal chemistry. 3,5-Disubstituted tetrahydro-2H-1,3,5-thiadiazine-2-thione (THTT) derivatives, 3a-g, potential prodrugs incorporating the neurotransmitter GABA were synthesized and studied for crossing the blood-brain barrier (BBB). Compounds were prepared from primary amines and carbon disulfide to give dithiocarbamates 2a-g which upon reaction in situ with formaldehyde provided the intermediates Ia-g. Addition of Ia-g onto GABA furnished the title compounds 3a-g. The structures were verified by spectral data and the amounts of the compounds in the brain were investigated by using HPLC. The concentration profiles of the tested compounds in mice brain were determined and the in vivo anticonvulsant activity was measured.

LC-UV METHOD DEVELOPMENT AND VALIDATION FOR THE NON STEROIDAL ANTI-INFLAMMATORY AGENT TENOXICAM

A rapid and sensitive reversed phase high performance liquid chromatographic (HPLC) method was developed and validated for the analysis of tenoxicam in raw material and its pharmaceutical formulation. The analysis was carried out on a reversed phase C18 column, using mixtures of buffer/acetonitrile (40:60, v/v) with flow rate was of 1 mL min−1. The method was validated statistically for its linearity (correlation coefficient = 0.9983), accuracy, robustness, and intermediate precision. An experimental design was used during validation to evaluate method robustness and for the determination of intermediate precision. To test robustness, four factors were considered, mainly, percentage of organic modifier in the mobile phase, pH, flow rate, and different wavelengths. An increase of the flow rate results in a decrease of the drug concentration found, while the percentage of organic modifier, pH, and wavelength have no significant effect on the response. For intermediate precision the factors examined were multiple analysts, multiple instruments, and multiple days. The RSD value (0.49%, n = 24) indicated a good precision of the analytical method. Due to its simplicity, accuracy, sensitivity, and precision the method may be used for routine quality control analysis.

Recent updates of marine antimicrobial peptides

Graphical abstract

Quantitative determination of doxorubicin in the exosomes of A549/MCF-7 cancer cells and human plasma using ultra performance liquid chromatography-tandem mass spectrometry

Graphical abstract