In silico screening of anticholinesterase alkaloids for cyclooxygenase-2 (COX-2) and matrix metalloproteinase 8 (MMP-8) inhibitory potentials as multi-target inhibitors of Alzheimer’s disease Abstract Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with yet no effective drug treatment; although several anticholinesterases are being used to offer relief from the symptoms of the disease. Recent studies have indicated that over-activation of cyclooxygenase-2 (COX-2) and matrix metalloproteinase-8 (MMP-8) may cause neuronal death in the brain of AD subjects, suggesting that inhibition of COX-2 and MMP-8 may be of therapeutic value in the management of AD. Therefore, it is important and rational to investigate new agents with anticholinesterase, COX-2 and MMP-8 inhibitory activities. In this study, molecular docking study was performed with earlier identified anticholinesterase alkaloids to search for compounds with high affinity for COX-2 and MMP-8. Molecular docking was done using Blind Docking Server while ligand-protein molecular interaction of compounds with remarkable inhibitory characteristics against COX-2 and MMP-8 were viewed with PyMOL. Alkaloids with high binding affinity and remarkable binding interaction with the target proteins were subjected to drug likeness investigation based on absorption-distribution-metabolism-excretion (ADME) properties using the Swiss online ADME web tool. Nine alkaloids (haloxysterol A, haloxysterol B, haloxysterol C, haloxysterol D, sarcodine, isosarcodine, axillaridine A, sarsalignenone and voacangine hydroxyindolenine) showed high affinities for both COX-2 and MMP-8. Thus, this in silico study identified 9 orally drugable, anticholinesterase alkaloids with COX-2 and MMP-8 multi-target activities that could be studied further as agents against AD.

New histone deacetylase inhibitors and anticancer agents from Curcuma longa Abstract The aims of this study were to explore histone deacetylase inhibitory and antioxidant activities of curcuminoids as well as derivatives of curcumin. Curcumin (6), demethoxycurcumin (7), dihydrocurcumin (8), bisdemethoxycurcumin (9), and hydroxycurcumin (10) were isolated and tested against histone deacetylases in HeLa nuclear extract. Hydroxycurcumin (10) showed the best inhibition among the isolated compounds. Some curcumin derivatives were also prepared and tested. The potential derivatives were tested on five cancer cell lines. All compounds exhibited slightly weaker antiproliferative activities against cancer cells and less toxic to non-cancer cells than curcumin (6). The least toxic derivative (17) exhibited the best antiproliferative activity against human cervical cancer cell lines (HeLa) with the IC50 value of 4.69 ± 0.14 μM. The most active histone deacetylase inhibitor (19) showed the highest potency against human colon cancer cell lines (HCT116) and the selective binding to HDAC4 based on molecular docking experiments. Most derivatives possessed antioxidant activities superior to curcumin. The results suggested potential candidates for anticancer agents.

Design, synthesis, and biological evaluation of matrine derivatives possessing piperazine moiety as antitumor agents Abstract Using matrine (1) as the lead compound, a series of new piperazinyl matrine derivatives were designed, synthesized and evaluated for their antitumor activities in vitro and in vivo. Structure activity relationship (SAR) analysis indicated that introduction of substituted piperazine on matrine might significantly enhance the antiproliferative activity. Moreover, types of substituents of piperazine exhibited great different effects on the antiproliferative activity of target compounds against Bel-7402 and RKO cell lines. The in vivo antitumor assay results revealed that some of the target derivatives possessed better therapeutic efficacy than matrine and low toxicity. More importantly, among the newly synthesized compounds, M16 and M26 possessed strong antitumor activity against the two cell lines. Moreover, six of the synthesized compounds M1, M3, M7, M10, M11 and M17 proved to be of much better therapeutic efficacy than matrine via in vivo antitumor assay. The study provides a theoretical basis for further structural optimizations and discovery of the antitumor pathways of this kind of compounds.

Designing of novel ERRγ inverse agonists by molecular modeling studies of docking and 3D-QSAR on hydroxytamoxifen derivatives Abstract ERRγinverse agonist is a powerful therapeutic target for the treatment of cancers and certain metabolic disorders. Until now, only GSK5814 was reported as selective ERRγinverse agonist. So 60 newly hydroxytamoxifen analogues were selected to perform molecular docking and 3D-QSAR study to design more selective inverse agonist of ERRγ. Both established CoMFA and CoMSIA models obtained high predictive and satisfactory value, demonstrated that bulky, hydrophobic and negative electrostatic substitutions are preferred at R2 position, and introducing hydrophilic and H-bond donor and acceptor groups at R1 and R4 positions is greatly important for improving binding activities. The obtained information will be useful to provide clues for rationally designing novel and high potency ERRγinverse agonists.

Discovery of 3-(thiophen/thiazole-2-ylthio)pyridine derivatives as multitarget anticancer agents Abstract A series of novel 3-(thiophen/thiazole-2-ylthio)pyridine derivatives were designed and synthesized as IGF-1R tyrosine kinase inhibitors. All the target compounds were tested for their IGF-1R kinase inhibitory activities and cytotoxicities against five cancer cell lines (K562, Hep-G2, HCT-116, WSU-DLCL2, and A549). Although all these compounds exhibited moderate to potent cancer cell proliferation inhibitory activities (the most potent compound 43 showed IC50 value of 1.3 ± 0.9 μM against WSU-DLCL2 cell line), IGF-1R inhibition were not observed. In order to identify the exact target of these analogues, selected compounds were further screened for various kinases. The results indicated that this series of compounds may exert their anticancer activities through inhibiting various kinases including FGFR 3, EGFR, JAK, and RON. In addition, cell cycle analysis of compound 43 on Hep-G2 cells showed cell cycle arrest at G1/G0 phase. All the experiments validated the potential of 3-(thiophen/thiazole-2-ylthio)pyridine analogues as multi-target anticancer agents.

Synthesis, in vitro assays, molecular docking, theoretical ADMET prediction, and evaluation of 4-methoxy-phenylthiazole-2-amine derivatives as acetylcholinesterase inhibitors Abstract Based on the cholinergic hypothesis of the reported compound, N-(4-(4-methoxy-phenyl)thiazol-2-yl)-3-(pyrrolidin-1-yl)propionamide, which had a good inhibitory activity to acetylcholinesterase (AChE), the new 4-methoxy-phenylthiazole-2-amine derivatives as AChE inhibitors (AChEIs) have been designed and synthesized in this study. Their chemical structures were confirmed by proton nuclear magnetic resonance, carbon-13 nuclear magnetic resonance, mass spectrometry, and infrared. Furthermore, their inhibitory activities against AChE in vitro were also tested by Ellman spectrophotometry, and the inhibitory activity test results showed that most of the compounds of 4-methoxy-phenylthiazole-2-amine derivatives had a certain AChE inhibitory activity in vitro, and the IC50 (half-maximal inhibitory concentration) value of compound 5g was 5.84 μmol/L, which was higher than that of the reference compound, rivastigmine. Moreover, it had almost no inhibitory effect on butyrylcholinesterase. In addition, compound 5g was subjected to enzyme inhibition kinetics experiments, and the result of Lineweaver–Burk’s V−1–[S]−1 double-reciprocal plot showed that the acting type of compound 5g was mixed inhibition type. Furthermore, the AChE inhibitory activity mechanism of compound 5g was explored by the conformational analysis and molecular docking, which was based on the principle of the four-point pharmacophore model necessary for AChE inhibition. Finally, in silico molecular property and ADMET (absorption, distribution, metabolism, excretion, and toxicity) of the synthesized compounds were predicted by using Molinspiration and PreADMET online servers, respectively. It can be concluded that the lead AChEI compound 5g presented satisfactory drug-like characteristics and ADME properties.

Quercetin analogs with high fetal hemoglobin-inducing activity Abstract β-Thalassemia is the major health problems in developing countries, when affected patients and healthy carriers are numerous, resulting a total absence or severe decrease in the production of β-globin chains. The use of chemical agents for increasing the production of fetal hemoglobin (HbF) by reactivating γ-globin gene to balance excess α-globin chains is an alternative therapeutic approach. Therefore, the search for molecules exhibiting the property of inducing γ-globin gene expression is of great interest. In this report, we discovered that quercetin (1), the major flavonoid isolated from the heartwoods of the medicinal plant Anaxagorea luzonensis promoted the expression of γ-globin gene. Chemical modification of 1 to fourteen methyl ether analogs (2−15) was conducted. The structures of these compounds were established on the basis of their spectroscopic data and by comparison with those of the reported values. The parent flavonoid and its chemically modified analogs were investigated for their γ-globin gene induction for the first time. The parent compound 1 exhibited less induced γ-globin gene expression than cisplatin and hemin, the positive controls. 3,4′-Di-O-methylquercetin (7), the modified analog, significantly enhanced γ-globin gene expression with 2.6-fold change at 8 μM, which was slightly higher than cisplatin and hemin. Moreover, compounds 1 and 7 displayed less cytotoxic activity against K562::ΔGγAγEGFP cells than cisplatin. Structure-activity relationship (SAR) study revealed that the methoxyl groups at the 3- and 4ʹ-positions and the free hydroxyl group at the 7-position are required for strong HbF-inducing activity.

Synthesis, sciatic nerve block activity evaluation and molecular docking of fluoro-substituted lidocaine analogs as local anesthetic agents Abstract Thirty fluoro-substituted lidocaine analogs (10a–e, 11a–e, 14a–e, 15a–e, 18a–e and 19a–e) were synthesized, and their sciatic nerve block activity were evaluated as local anesthesia. Most of the compounds displayed significant potency, and compound 10a in particular was much more potent than the parent lidocaine. Fifteen analogs including 10a demonstrated pKa values of 7.5–7.8 suitable for local anesthesia. Compound 10a, 14e, and lidocaine were docked into three target receptors of local anesthetics by molecular docking studies to delineate structure-activity relationships and explain the differences in activities. Hydrophobic interactions and hydrogen bonds were identified key to molecular binding, suggesting that optimization of these interactions and/or trifluoro-substitution at the benzene ring of lidocaine could enhance the properties of lidocine analogs for local anesthesia.

FOXO signal activating alkaloids isolated from Ochrosia elliptica leaf cultivated in Egypt Abstract A new yohimbine type alkaloid N-methylarcinine (1), and the known alkaloid, holeinine (2), have been isolated from the methanolic leaf extract of Ochrosia elliptica grown in Egypt. The structures of the isolated metabolites were elucidated via 1D and 2D NMR data, as well as HRESIMS spectra and the spectral data were compared with the existing data available from literature. These two alkaloids are very different in activity from previously reported class type alkaloids, where they showed weak cytotoxic activity against K-562 leukemia cells while other compounds from this class were highly toxic in nature. Interestingly, holeinine (2) showed unique induction of FOXO expression, a cancer signaling pathway. FOXO is involved in the expression of death receptor ligands, such as TNF apoptosis ligand, where its activation plays a critical role in tumor suppression. As several anticancer leads targeting FOXO signaling gain more attention, this compound could be a candidate for drug development after the determination of its therapeutic efficacy and more mechanistic studies need to be evaluated.

Nitrogenous phytoconstituents of genus Moringa : spectrophotometrical and pharmacological characteristics Abstract Moringa Adans. (Moringaceae) is a multipurpose plant showing uncountable uses due to nutritional, folklore, and pharmacological worldwide applications. Moringa is rich in nitrogenous compounds, viz., glucosinolates, thiocarbamates, cyanogens, isothiocyanates, and alkaloids. Plants of this genus are a good source of vitamins, β-carotene, proteins, and various phenolics. This review focuses on spectrophotometrical characteristics of nitrogenous compounds along with their pharmacological properties. Aligning traditional usage with scientific assessment, Moringa have compounds with a great commercial potential especially nitrogenous compounds. We hope to support a new research on Moringa, especially on those species whose biological properties have not been studied to date moreover explore the mechanisms at the molecular level.