Discovery of novel quinolin-2-one derivatives as potential GSK-3ß inhibitors for treatment of Alzheimer's disease: Pharmacophore-based design, preliminary SAR, in vitro and in vivo biological evaluation.

Recently, glycogen synthase kinase-3ß (GSK-3ß) has been considered as a critical factor implicated in Alzheimer's disease (AD). In a previous work, a 3D pharmacophore model for GSK-3ß inhibitors was created and the results suggested that derivative ZINC67773573, VIII, may provide a promising lead for developing novel GSK-3ß inhibitors for the AD's treatment. Consequently, in this work, novel series of quinolin-2-one derivatives were synthesized and assessed for their GSK-3ß inhibitory properties. In vitro screening identified three compounds: 7c, 7e and 7f as promising GSK-3ß inhibitors. Compounds 7c, 7e and 7f were found to exhibit superior inhibitory effect on GSK-3ß with IC50 value ranges between 4.68 ± 0.59 to 8.27 ± 0.60 nM compared to that of staurosporine (IC50 = 6.12 ± 0.74 nM). Considerably, compounds 7c, 7e and 7f effectively lowered tau hyperphosphorylated aggregates and proving their safety towards the SH-SY5Y and THLE2 normal cell lines. The most promising compound 7c alleviated cognitive impairments in the scopolamine-induced model in mice. Compound 7c's activity profile, while not highly selective, may provide a starting point and valuable insights into the design of multi-target inhibitors. According to the ADME prediction results, compounds 7c, 7e and 7f followed Lipinski's rule of five and could almost permeate through the BBB. Molecular docking simulations showed that these compounds are well accommodated in the ATP binding site interacting by its quinoline-2-one ring through hydrogen bonding with the key amino acids Asp133 and Val135 at the hinge region. The findings of this study suggested that these new compounds may have potential as anti-AD drugs targeting GSK-3ß.

Novel VEGFR-2 inhibitors as antiangiogenic and apoptotic agents via paracrine and autocrine cascades: Design, synthesis, and biological evaluation.

Appertaining to its paracrine and autocrine signaling loops, VEGFR-2 succeeded in grabbing attention as one of the leading targets in cancer treatment. Based on the foregoing and our comprehensive studies regarding pharmacophoric features and activity of sorafenib, novel phenylpyridazinone based VEGFR-2 inhibitors 4, 6a-e, 7a,b, 9a,b, 12a-c, 13a,b, 14a,b, 15a,b, and 17a-d were optimized. An assortment of biological assays was conducted to assess the antiangiogenic and apoptotic activities of the synthesized derivatives. In vitro VEGFR-2 kinase assay verified the inhibitory activity of the synthesized derivatives with IC50 values from 49.1 to 418.0 nM relative to the reference drug sorafenib (IC50 = 81.8 nM). Antiproliferative activity against HUVECs revealed that compounds 2-{2-[2-(6-oxo-3-phenylpyridazin-1(6H)-yl)acetyl]hydrazineyl}-N-(p-tolyl)acetamide (12c) and 2-[(5-mercapto-4-methyl-4H-1,2,4-triazol-3-yl)methyl]-6-phenylpyridazin-3(2H)-one (13a) possessed superior activity (IC50 values = 11.5 and 12.3 nM, respectively) in comparison to sorafenib (IC50 = 23.2 nM). For the purpose of appraising their antiproliferative effect, derivatives 12c and 13a were exposed to cell cycle analysis, apoptotic, cell invasion and migration assays in addition to determination of VEGFR-2 in protein level. Moreover, cytotoxicity as well as selectivity index against WI-38 cell line was measured to examine safety of derivatives 12c and 13a. After that, molecular docking study was executed on the top five compounds in the in vitro VEGFR-2 kinase assay 6d, 12c, 13a, 14a and 17c to get a deep perception on binding mode of the synthesized compounds and correlate the design strategy with biological results. Finally, physicochemical, pharmacokinetic properties, and drug-likeness studies were performed on the top five derivative in in vitro VEGFR-2 kinase assay.

Arylidine extensions of 3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-benzenesulfonamide derivatives: Synthesis, computational simulations and biological evaluation as tumor-associated carbonic anhydrase inhibitors.

Several pyrazole-benzene sulfonamides were reported as human carbonic anhydrase inhibitors. In this research work, a design of Arylidine-extented 5-oxo-pyrazole benzenesulfonamides (4a-i), (8a-d) and (10a-e) were reported based on tail-approach design. Beside the reported synthetic procedures and confirmation by different analytical procedures, a DFT study was employed to confirm the Z- conformer of the synthesized compounds. In vitro biological assay against four different human carbonic anhydrases took place and based on the results, SAR study was illustrated and selectivity indexes were discussed. Compounds 4g and 8a exhibited the best inhibitory activity among the target compounds with values (hCAIX: KI = 71.2 nM, hCAXII: KI = 22.5 nM), (hCAIX: KI = 34.3 nM, hCAXII: KI = 74.3 nM); respectively. Both of them were subjected to cellular assay against two different cancer cell lines with expressing nature to hCA isoforms under both normoxic and hypoxic conditions. Compound 4g showed the highest cytotoxic activity against MCF-7 cancer cell line (IC50 = 4.15 µM under hypoxic conditions and IC50 = 8.59 µM under normoxic conditions) compared to the reference drug doxorubicin under normoxic, (IC50 = 4.34 µM), and hypoxic, (IC50 = 2.23 µM), conditions. Further cellular investigations were employed to study the effect of this compound on the cell cycle of the affected cell line. Finally, molecular docking supported by molecular dynamic simulation was utilized to understand the mechanism of the inhibitory activity of two of these compounds - as representative examples- based on the designed rational.

Design and synthesis of some new 6-bromo-2-(pyridin-3-yl)-4-substituted quinazolines as multi tyrosine kinase inhibitors.

The present study involves design and synthesis of five series of 6-bromo-2-(pyridin-3-yl)-4-substituted quinazolines 9a-l, 11a-e, 13a-c, 14a-f and 15a-e. Candidates 9a-l and 11a-e were evaluated for their EGFR and HER2 inhibitory activity compared to Lapatinib. Compounds 9b, 9d, 9f, 11b and 11c were further screened for their in vitro cytotoxicity against two human breast cancer cell lines: AU-565 and MDA-MB-231 in addition to normal breast cell line MCF10A. Compound 9d revealed a remarkable cytotoxic efficacy against AU-565 cell line (IC50 = 1.54 µM) relative to Lapatinib (IC50 = 0.48 µM), whereas compounds 9d and 11c showed a superior cytotoxicity towards MDA-MB-231 (IC50 = 2.67 and 1.75 µM, respectively) in comparison to Lapatinib (IC50 = 9.29 µM). Moreover, compounds 13a-c, 13a-c, 14a-f and 15a-e were tested for their VEGFR-2 inhibitory activity compared to Sorafenib. Compounds 13a, 14c and 14e exhibited remarkable inhibition (IC50 = 79.80, 50.22 and 78.02 nM, respectively) relative to Sorafenib (IC50 = 51.87 nM). In vitro cytotoxicity of these compounds against HepG2, HCT-116 and normal cell (WISH) revealed a superior cytotoxicity against HepG2, HCT-116 especially 13a (IC50 = 17.51 and 5.56 µM, respectively) and 14c (IC50 = 10.40 and 3.37 µM, respectively) compared to Sorafenib (IC50 = 19.33 and 6.82 µM, respectively). Compounds 9d, 11c and 14c were subjected to cell cycle analysis and apoptotic assay. Molecular docking and ADME prediction studies were fulfilled to illustrate the interaction of the potent derivatives with the hot spots of the active site of EGFR, HER2 and VEGFR-2 along with prediction of their pharmacokinetic and physicochemical properties.

Design and synthesis of novel pyridopyrimidine derivatives with anchoring non-coplanar aromatic extensions of EGFR inhibitory activity.

The present study describes the synthesis of three series of 4-substituted pyridopyrimidin derivatives 4a-h, 5a-d. 6a-d, starting from 2-amino-6-(4-methoxyphenyl)-4-(4-(substituted) phenyl)nicotinonitrile 2a-d via the reaction with N,N-dimethyl-N-' substituted phenyl formimidamide to obtain 4a-h or with either phenyl isothiocyanate 1:1 and 1:2 to obtain 5a-d, 6a-d respectively. The synthesized compounds were evaluated for their effectiveness as EGFR inhibitors against Gefitinib. Six compounds; 4b,g,h, 5c and 6a,d prompted significantly higher EGFR inhibitory activity relative to that of Gefitinib. While two compounds 4d and 4f showed IC50 values non-significantly different from that of the reference drug. Furthermore, compounds 4a, 4 h, 6a and 6d were chosen to be assessed in vitro for their cytotoxicity against two EGFR-overexpressing cell lines; two human cancer cell lines namely: MCF7 and MDA-MB-361. Moreover, cell cycle analysis and apoptotic assay was applied for compound 4b that showed most potent inhibitory activity on EGFR, and the highest cytotoxicity against MCF7 and MDA-MB-361, where cell cycle arrest was achieved at pre G and S phases with increased apoptosis. Additionally, a molecular docking study was achieved to inspect the interaction of this compound with the active site of EGFR-TK.

Design and synthesis of novel coumarin derivatives as potential acetylcholinesterase inhibitors for Alzheimer's disease.

Twenty novel 7-benzyloxycoumarin based compounds were synthesized with a variety of bioactive chemical fragments. The synthesized compounds showed remarkable acetylcholinesterase (AChE) inhibitory activity. In vitro assay revealed that compounds 7-benzyloxy-4-{[(4-phenylthiazol-2(3H)-ylidene)hydrazono]methyl}-2H-chromen-2-one (5b, IC50= 0.451µM), 7-benzyloxy-4-({[4-(4-methoxyphenyl)thiazol-2(3H)-ylidene]hydrazono}methyl)-2H-chromen-2-one (5d, IC50= 0.625µM), 5-amino-1-[2-(7-benzyloxy-2-oxo-2H-chromen-4-yl)acetyl]-1H-pyrazole-4-carbonitrile (13c, IC50= 0.466µM), 2-(7-benzyloxy-2-oxo-2H-chromen-4-yl)-N-(2-methylimino-4-phenylthiazol-3(2H)-yl)acetamide (16a, IC50= 0.500µM) and 2-(7-benzyloxy-2-oxo-2H-chromen-4-yl)-N-[4-(4-methoxyphenyl)-2-methyliminothiazol-3(2H)-yl]acetamide (16b, IC50= 0.590µM) exhibited promising AChE inhibitory activity even better than donepezil (IC50= 0.711µM). Kinetic study for compound 5b implied mixed type inhibitor which could bind peripheral anionic site (PAS) and catalytic active site (CAS) of AChE enzyme. In addition, in vivo evaluation of compounds 5b, 13c and 16a confirmed significant memory improvement in scopolamine-induced impairment model in tested mice. Furthermore, in silico studies were performed on the synthesized compounds which included molecular docking study at the active site of recombinant human acetylcholinesterase enzyme (rhAChE) as well as prediction of ADMET and other physicochemical parameters. A correlation between the docking results and IC50 of tested compounds was routinely observed and shared similar binding pattern to the co-crystallized ligand donepezil.