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As an extension to our previous work for the development of new thalidomide analogs, the current work offers new insights into the immunomodulatory and anticancer activities of quinazolinone based molecules carrying a glutarimide moiety. The findings confirmed some previous findings and revealed some new information. Among the newly synthesized compounds, compounds 7d and 12 showed considerable immunomodulatory properties in comparison to thalidomide. 7d and 12 significantly reduced TNF-α levels in HepG-2 cells from 162.5 pg/mL to 57.4 pg/mL and 49.2 pg/mL, respectively compared to 53.1 pg/mL reported for thalidomide. Moreover, they caused 69.33% and 77.74% reduction in NF-κB P65, respectively, compared to 60.26% reduction for thalidomide. Similarly, they reduced VEGF from 432.5 pg/mL to 161.3 pg/mL and 132.8 pg/mL, respectively, in comparison to 153.2 pg/mL reported for thalidomide. The two new derivatives, 7d and 12 also showed about 8-fold increases in caspase-8 levels in cells treated with them. These results were slightly better than those of thalidomide. The obtained results revealed that Compound 12 had better immunomodulatory properties than thalidomide, with stronger effects on TNF-α, NF-B P65, VEGF, and caspase-8. Accordingly, this work indicates that compound 12 has interesting biological properties that should be further evaluated and modified in order to develop clinically useful thalidomide analogs.

An immunomodulator is a substance that stimulates or suppresses the immune system and may help the body fight cancer. The aim of this review is to highlight results of research done on immunomodulators of natural or synthetic origin showing different biological activities. The selection of papers was made using the most relevant scaffolds based on their immunomodulatory biological results. The review also discussed the different synthetic methods for various immunomodulatory drugs such as CC-122. The results showed that many drugs incorporating different scaffolds such as quinazolines revealed promising results for immunomodulatory therapeutic purposes. This work shall hopefully encourage researchers to undertake further work on design and synthesis of new potential immunomodulatory candidates.

Cancer is the second leading cause of death worldwide. This work is an effort to find new effective and safe anticancer agents. In accordance with thalidomide features as immunomodulator anticancer drug, we designed and synthesized ten new thalidomide analogs. The synthesized compounds were biologically evaluated for their anti-tumor activity against three human cancer cell lines namely; hepatocellular carcinoma (HepG2), prostate cancer (PC3) and breast cancer (MCF-7). Thalidomide was used as a reference drug. The obtained data showed that compound 10a is far better than thalidomide against the three cancer cell lines. It exhibited IC50 = 3.89, 4.01 and 2.91 µg/mL against the cell lines, respectively. While thalidomide exhibited IC50 values of 11.26, 14.58, and 16.87 µg/mL against the three cell lines, respectively. Moreover, compounds 7a, 6a and 8 were found to be better than thalidomide against MCF-7 cell line. As they showed IC50 values of 10.32, 12.15 and 15.32 µg/mL, respectively. Furthermore, compounds 6a, 7a, and 8 showed strong activity against the three cell lines. Results of docking studies showed that our compounds can accommodate the pocket of CRBN with binding energies too close to that of thalidomide.

Cancer is one of the major causes of human mortality worldwide. A number of approved antineoplastic medications and treatment regimens are already working in the field, and several new compounds are in different phases of clinical trials. An extensive series of anticancer drugs exist in the market, and studies explained that these molecules are associated with different types of adverse side effects. The reduction of the cytotoxicity of drugs to normal cells is a major problem in anticancer therapy. Therefore, researchers around the globe are involved in the development of more efficient and safer anticancer drugs. An interesting output of extensive research is that the quinazoline scaffold and its various derivatives can be explored further as a significant class of cancer chemotherapeutic agents that has already shown promising activities against different tumors. In general, quinazoline derivatives have already occupied a crucial place in modern medicinal chemistry. Quinazoline is one of the most studied moieties in medicinal chemistry due to the wide range of biological properties such as the anticancer, antibacterial, anti-inflammatory, antimalarial and antihypertensive activities. The anticancer activity of this scaffold has been well established.

Thalidomide is a sedative drug discovered at the end of the 50s, it showed high anticancer activity so attempts were made to synthesize thalidomide analogs that had fewer side effects than the parent compound. DPDQA showed higher anticancer activities than thalidomide. Labeling of a DPDQA with 99mTc using Na2S2O4 as reducing agent was performed. The dependence of the radiolabeling yield on the concentrations of DPDQA and reducing agent, pH of the reaction mixture, reaction time, and reaction temperature was studied. Bio-distribution studies in mice with tumor induced in the right thigh were carried out. The tumor infected thigh/contralateral thigh uptake ratio (T/NT) was evaluated. The time for the maximum accumulation of the 99mTc–DPDQA in the tumor site was evaluated after administration of the compound.

A new series of pyrimidine-5-carbonitrile derivatives has been designed as ATP mimicking tyrosine kinase inhibitors of the epidermal growth factor receptor (EGFR). These compounds were synthesized and evaluated for their in vitro cytotoxic activities against a panel of four human tumor cell lines, namely colorectal carcinoma (HCT-116), hepatocellular carcinoma (HepG-2), breast cancer (MCF-7), and non-small cell lung cancer cells (A549). Five of the synthesized compounds, 11a, 11b, 12b, 15b and 16a, were found to exhibit moderate antiproliferative activity against the tested cell lines and were more active than the EGFR inhibitor erlotinib. In particular, compound 11b showed 4.5- to 8.4-fold erlotinib activity against HCT-116, HepG-2, MCF-7, and A549 cells with IC50 values of 3.37, 3.04, 4.14, and 2.4 μM respectively. Moreover, the most cytotoxic compounds that showed promising IC50 values against the four cancer cell lines were subjected to further investigation for their kinase inhibitory activities against EGFRWT and EGFRT790M using homogeneous time resolved fluorescence (HTRF) assay. Compound 11b was also found to be the most active compound against both EGFRWT and mutant EGFRT790M, exhibiting IC50 values of 0.09 and 4.03 μM, respectively. The cell cycle and apoptosis analyses revealed that compound 11b can arrest the cell cycle at the G2/M phase and induce significant apoptotic effects in HCT-116, HepG-2, and MCF-7 cells. Additionally, compound 11b upregulated the level of caspase-3 by 6.5 fold in HepG-2 when compared with the control. Finally, molecular docking studies were carried out to examine the binding mode of the synthesized compounds against the proposed targets; EGFRWT and EGFRT790M. Additional in silico ADMET studies were performed to explore drug-likeness properties.

Thalidomide and its analogs are immunomodulatory drugs that inhibit the production of certain inflammatory mediators associated with cancer. In the present work, a new series of thalidomide analogs was designed and synthesized to obtain new effective antitumor immunomodulatory agents. The synthesized compounds were evaluated for their cytotoxic activities against a panel of four cancer cell lines (HepG-2, HCT-116, PC3 and MCF-7). Compounds 33h, 33i, 42f and 42h showed strong potencies against all tested cell lines with IC50 values ranging from 14.63 to 49.90 µM comparable to that of thalidomide (IC50 values ranging from 32.12 to 76.91 µM). The most active compounds were further evaluated for their in vitro immunomodulatory activities via estimation of human tumor necrosis factor alpha (TNF-α), human caspase-8 (CASP8), human vascular endothelial growth factor (VEGF), and nuclear factor kappa-B P65 (NF-κB P65) in HCT-116 cells. Thalidomide was used as a positive control. Compounds 33h and 42f showed a significant reduction in TNF-α. Furthermore, compounds 33i and 42f exhibited significant elevation in CASP8 levels. Compounds 33i and 42f inhibited VEGF. In addition, compound 42f showed significant decrease in levels of NF-κB p65. Moreover, apoptosis and cell cycle tests of the most active compound 42f, were performed. The results indicated that compound 42f significantly induce apoptosis in HCT-116 cells and arrest cell cycle at the G2/M phase.

Globally cancer is the second leading cause of death. So that this work is an attempt to develop new effective anti-cancer agents. In line with pharmacophoric features of VEGFR-2 kinase inhibitors, new nineteen quinazolin-4-one derivatives were designed, synthesized and biologically evaluated for their potential anticancer activity. All target compounds were evaluated in vitro for VEGFR-2 tyrosine kinase inhibition. Then, nine compounds of best results were further investigated by in vitro assay against three human cancer cell lines, namely HepG2, PC3 and MCF. N’-{2-](3-Ethyl-6-nitro-4-oxo-3,4-dihydroquinazoline-2-yl)thio[acetyl}benzohydrazide (36) was found to be the most potent candidate as it showed IC50 = 4.6 ± 0.06 µM against VEGFR-2 kinase. It also exhibited IC50 = 17.23 ± 1.5, 26.10 ± 2.2 and 30.85 ± 2.3 µg/mL against HepG2, PC3 and MCF, respectively. At the same time it showed IC50 = 145.93 ± 1.1 µg/mL against the normal human lung fibroblasts cell line (WI-38), indicating good selectivity index. Further investigation into HepG2 cell cycle showed the ability of compound 36 to induce apoptosis and arrest cell growth at G2/M phase. Moreover, docking studies demonstrated the ability of compound 36 to bind VEGFR-2 in a correct manner making three essential hydrogen bonds with the key residues Glu885, Asp1046 and Cys919. In sum, this work suggests that compound 36 can serve as a lead for development of effective anticancer agents targeting VEGFR-2.

New series of phthalimide-sulfonylurea hybrids were prepared and examined for their in vivo anti-hyperglycemic activities in STZ-induced hyperglycemic rats using glibenclamide as a reference drug. Compounds 6c, 6d, 6g, 6h, 6j and 6k induced significant reduction in the blood glucose levels of diabetic rats ranging from 24.43 to 21.43%. Moreover, molecular docking and pharmacophore approaches were carried out to examine binding modes and fit values of the prepared compounds against PPARγ and SUR, respectively. Compounds 6c, 6d, 6j and 6m exhibited the highest binding free energies against PPARγ. Compounds 6c, 6j, 6k, 6l, and 6n showed the highest fit values against the generated pharmacophore model. Also, QSAR technique was carried out to estimate the proposed PPARγ binding affinities and insulin-secreting abilities. The synthesized compounds showed promising estimated activities. In-silico ADMET studies were performed to investigate pharmacokinetics of the synthesized compounds. They showed considerable human intestinal absorption with low BBB penetration.

Certain new nitrogen-substituted derivatives of cyclic imides phthalimide (a), 1,8-naphthalimide (b), and diphenimide (c), were synthesized aiming to obtain potent hypolipidemic agents. Thus, 2-(N-imido) propanoic acids, 2-(N-phthalimido)-2-methylpropionic acid, and their ethyl esters were synthesized (Target derivative A). Also their corresponding N-substituted-2-(N-imido) propionamides and 2-(N-phthalimido)-2-methylpropionamides were prepared (Target derivative B). In addition, N-phthalimidomethyleneoxy acetate was prepared. Some of the newly prepared compounds were subjected to 3D studies and were found to be superimposed on Clofibrate, which is the first generation of fibrate drugs. The preliminary evaluation of hypolipidemic activity of the newly prepared compounds against triton WR-1339-induced hyperlipidemia in rat showed that several derivatives have demonstrated significant lowering of serum total cholesterol and triglyceride levels at dose of 150 mg/kg/i.p. comparing with Fenofibrate which is one of the second generations of fibrate drugs.

The structural requirements for decreasing cholesterol and triglyceride levels remain largely uninvestigated. Thus a systematic investigation of certain N-substituted dibenz(c,e)azepines is necessary. Twenty-four compounds of certain new N-substituted derivatives of dibenz(c,e)azepines-5,7-diones were synthesized and tested for their anticholestesrolemic and antitriglyceridimic activities. The evaluation of antihyperlipidemic activity of dibenz(c,e)azepine-5,7-diones (VII, X-XII) against Triton-WR1339-induced hyperlipidemia in rats showed a significant lowering of serum total cholesterol and triglyceride levels at a dose of 150 mg/kg compared with the control value. The phenyl substituted derivatives of diphenimide have shown a pronounced decrease in both triglyceride and cholesterol levels.

Objective: Asthma is an inflammatory disease of the airways appropriate to pulmonary eosinophilia, airway hyperresponsiveness (AHR) and mucus overproduction. We now investigate the level of Periostin serum concentration in Egyptian asthmatic patients and define any correlation between periostin and Pulmonary Function Tests (PFT) Methods: 80 subjects were enrolled in the study: 20 control (11 male and 9 female), 28 atopic asthmatic patients (19 male and 9 female) and 32 non- atopic asthmatic patients (14 male and 18 female).Blood samples were obtained from the subjects for laboratory investigations which divided into two aliquots, First aliquot for whole blood used for complete blood count to determine blood eosinophil count by using Sysmex XP-300 and Second aliquot for serum used for estimation of Periostin, Transforming Growth Factor (TGF-β1) and Total Immunoglobulin (IgE) using enzyme-linked immunosorbent assays(ELISA).Results: Periostin concentrations were significantly higher in atopic and non- atopic groups (mean±SE; 6889±393.8 and 6212±348.8 pg/ml respectively) compared to control group (3053±446.5 pg/ml) at P < 0.05.TGF-β1 were significantly higher in atopic and non- atopic groups (mean±SE;75.83 ±1.53and 73.47±1.09 pg/ml respectively) compared to control group (51.26±2.65 pg/ml) at P < 0.05and IgE were significantly higher in atopic group (mean±SE;151.3±15.10IU /ml) compared to control group and non- atopic groups (52.47±3.045 and 48.51±1.827 IU /ml respectively) at P < 0.05.Periostin correlated negatively with PFT which Forced Vital Capacity (FVC), Forced Expiratory Volume1(FEV1) and Forced Expiratory Volume 1% (FEV1%).Conclusions: Serum Periostin is increased in Egyptian asthmatic (atopic and non- atopic) patients compared to control and Periostin correlated negatively with pulmonary function tests in asthmatic patients. Asthma is the most significant variable relates to high Periostin serum concentration.

The emerging resistance to antimicrobial drugs demands the synthesis of new remedies for microbial infections. Attempts have been made to prepare new compounds by modifications in the quinolone structure. An important method for the synthesis of new quinolone is using Vilsmeier approach but has its own limitations. The present work aimed to synthesize novel norfloxacin analogues using modified Vilsmeier approach and conduct preliminary investigations for the evaluation of their physicochemical properties, photochemical probe, and antimicrobial effects. In an effort to synthesize norfloxacin analogues, only 7-bromo-6-N-benzyl piperazinyl-4-oxoquinoline-3-carboxylic acid was isolated using Vilsmeier approach at high temperature, where N,N′-bis-(4-fluoro-3-nitrophenyl)-oxalamide and N,N′-bis-(3-chloro-4-fluorophenyl)-malonamide were obtained at low temperature. Correlation results showed that lipophilicity, molecular mass, and electronic factors might influence the activity. The synthesized compounds were evaluated for their antimicrobial effects against important pathogens, for their potential use in the inhibition of vitiligo.

N-Methyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane (methylenedioxy- methamphetamine, MDMA, Ecstasy) and its structurally abbreviated congener N-methyl-1-(4-methoxyphenyl)-2-aminopropane (para-methoxymethamphetamine, PMMA) are chemically related designer drugs, and PMMA is sometimes sold on the clandestine market as a substitute for MDMA. Prior drug discrimination studies have found that MDMA and PMMA substitute for one another suggesting that they produce similar discriminative stimulus effects in rats. However, there also are some indications that the two agents produce distinct stimulus effects. In this study, further comparisons were made between the stimulus effects of these two agents. Sprague-Dawley rats were trained to discriminate either 1.25 mg/kg of PMMA or 1.5 mg/kg of MDMA from saline vehicle in a two-lever operant paradigm. A structure-activity comparison revealed that MDMA and PMMA behave similarly upon homologation of their terminal amine substituents. In contrast, the PMMA stimulus, unlike an MDMA stimulus, failed to generalize completely to the psychostimulant cocaine, 8-hydroxy-2-(N, N-di-n-propylamino)tetralin (8-OH DPAT), and R(−)-1-(3-methoxyphenyl)-2-aminopropane [R(−)MMA]. In an additional group of animals, a (+)amphetamine stimulus partially generalized to R(−)MMA. Taken together, the results argue and re-emphasize the conclusion that the stimulus effects produced by MDMA and PMMA are similar, but non-identical, and that PMMA is the less “stimulant-like” of the two.

6-(2-Phenylethyl)nicotine (1b; K(i)=15 nM) was unexpectedly found to bind at alpha4beta2 nicotinic cholinergic (nACh) receptors. Although this compound failed to produce nicotine-like agonist action in several functional assays, 1b antagonized the antinociceptive effects of nicotine (mouse tail-flick assay) in a dose-dependent fashion when administered via an intrathecal route.

Several 6-alkyl analogues of nicotine were examined in radioligand binding and in vivo functional assays. Although (−)6-ethylnicotine ( 3 ) binds with high affinity at nACh receptors ( K i =5.6 nM) and produces nicotine-like actions, its n -propyl homologue (−) 4 ( K i =22 nM) failed to produce such effects. In fact, (−) 4 antagonized the antinociceptive effects of (−)nicotine in the tail-flick assay in mice, but not the spontaneous activity or discriminative stimulus effects of (−)nicotine. Compound (−) 4 appears to selectively antagonize only one of the three effects examined and is an interesting cholinergic agent for subsequent investigation.