Anticancer activities of novel Mannich bases against prostate cancer cells Abstract This study was designed to synthesize hybridizing molecules starting from compound of 6-(4-phenyl-piperazin-1-yl)pyridine-3-ylamine by enhancing its biological activity with other heterocycles and to determine anticancer activity of the resulting compounds. To this end, 6-(4-phenylpiperazin-1-yl)pyridin-3-ylamine (4) was used as the leading compound, which is known to exert anticancer activities. The synthesis of the leading compound was carried out using 1-(5-nitropyridin-2-yl)-4-phenylpiperazine (3) which was obtained by a novel method with the reaction of N-phenylpiperazine (2) and 2-chloro-5-nitropyridine. 6-(4-phenylpiperazin-1-yl)pyridin-3-ylamine (4) was converted to compound 5, an active intermediate compound, by substitution of one of the amine hydrogens with ethyl bromoacetate. The resulting ester product (5) followed by the hydrazidation (6) was added arylisocyanate to obtain the active intermediate (8). Then, by a series of substitution through cyclization and condensation reactions, thiazolidinone (9), 1,3,4-oxadiazole (7), and 1,2,4-triazole (10) were synthesized. Novel Mannich bases (11a–11f and 12a–12f) were obtained using oxazole (7) and triazole (10) hetero rings with primer or secondary amine compounds. The characterization of the compounds was completed using FT IR, 1H-NMR, 13C-NMR, HRMS spectroscopic methods and elemental analysis technique. The chemicals, then, were tested for their anticancer activities against prostate cancer cell lines PC3 [ATCC, CRL-1435], LNCaP [ATCC, CRL-1740], and DU145 [ATCC, HTB-81]. The results revealed that the Mannich bases exhibited moderate cytotoxic activity against cancer cells tested.

Synthesis, antimicrobial activity, and determination of the lipophilicity of ((cyclohex-3-enylmethylene)hydrazinyl)thiazole derivatives Abstract Synthesis and investigation of antimicrobial activity of fifteen novel thiazoles containing cyclohexene moiety are presented. Among the derivatives, compounds 3a–3d, 3f, 3n, and 3o showed very strong activity against the reference Candida spp. strains with MIC = 0.015–3.91 µg/ml. The activity of these compounds is similar and even higher than the activity of nystatin used as positive control. Compounds 3d, 3f, 3n, 3o showed the highest activity with very strong effect towards most of yeasts isolated from clinical materials with MIC = 0.015–7.81 µg/ml. The cytotoxicity studies for the most active compounds showed that Candida spp. growth was inhibited at noncytotoxic concentrations for the mammalian L929 fibroblast. In addition, a good correlation was obtained between lipophilicity of compounds determined using reversed phase thin-layer chromatography and their antifungal activity.

Aryl azide-sulfonamide hybrids induce cellular apoptosis: synthesis and preliminary screening of their cytotoxicity in human HCT116 and A549 cancer cell lines Abstract Simple, small, drug-like molecules bearing aryl azide and aryl sulfonamide moieties were designed and synthesized. The cytotoxic activity of these compounds was measured on colon cancer HCT116, lung cancer A549, and normal fibroblast cells F180 cell lines. All the synthesized compounds showed a significant cytotoxic activity below 100 µM in both HCT116 and A549 cells. Compounds 10e and 10f exhibited the most potent activity with IC50 values of 2.20 and 6.27 µM on A549 and HCT116 cells, respectively. Also, compounds 10e and 10f showed significant tumor selectivity on HCT116 and A549 cell lines when compared with the reference cytotoxic agent staurosporine. This indicated the promising safety of these compounds on normal cells. In addition, flow cytometry studies showed that HCT116 cell lines treated with the most active compound 10f were arrested in the G2/M phase of the cell cycle. 10f boosted both early and late apoptosis at HCT116 cells. A hypothetical pharmacophore model was built using 14 reported potent carbonic anhydrase I inhibitors. The pharmacophoric study revealed that the tested sulfonamide derivatives 10e and 10f showed significant fitting on the pharmacophore query with reasonable RMSD values. Molecular docking study showed a chelation reaction with the key Zn atom, in addition to different hydrogen bonding, and van der Waals interactions with several important amino acids inside the CA Ι active site.

Synthesis, cytotoxicity against cancer and normal cell lines of novel hydrazide–hydrazone derivatives bearing 5H-chromen-5-one Abstract The reaction of cyclohexan-1,3-dione with either of malononitrile or ethyl cyanoacetate gave the 4-amino-6,7-dihydro-5H-chromen-5-one derivatives 3a and 3b, respectively. The reaction of the latter compounds with cyanoacetylhydrazine gave the hydrazide–hydrazone derivatives 5a and 5b, respectively. Compounds 5a,b were used as the key starting materials for the synthesis of thiophen, coumarin, and pyridine derivatives. The newly synthesized compounds were evaluated against three human cancer cell lines, including HCT116 (colon carcinoma cell), MGC803 (gastric carcinoma cell), and Huh7 (hepatoma carcinoma cell). The results showed that 3b, 5b, 6b, 6d, 8b, 8c, 8d, 8f, 10b. 12a–h, 14a–d, 15a–h, and 16b–h displayed higher cytotoxic activity than 5-FU against HCT116 and MGC803 cell lines. Compounds 14d and 16f were the most promising compounds with IC50’s 0.25 and 0.09 μM against HCT116 cell line. The most potent compounds were selected for the in vitro against peripheral blood lymphocytes (PBL) from healthy donors. All compounds were practically devoid of significant cytotoxic activity in quiescent lymphocytes, with GI50’s of 42–68 μM, while with the mitogenic stimulus phytohaemagglutinin (PHA), the GI50’s were reduced to about 20–32 μM.

Zunyimycin C inhibits the proliferation of lung cancer cells by inducing apoptosis through an AKT-related mechanism Abstract Objective Zunyimycin C is a novel halogenated type II polyketide derived from the fermentation product of the Streptomyces species with notable antibiotic activity. However, it is still unclear whether zunyimycin C could inhibit the activity of cancer cells. In this study, human lung adenocarcinoma cell line A549, the large-cell lung cancer cell line NCI-H460 and the non-small-cell lung cancer cell line NCI-H1299 were employed to determine the in vitro anticancer properties of zunyimycin C and underlying molecular mechanisms. Materials and methods The cellular viability and proliferative properties of lung cancer cells were investigated using the Cell Counting Kit-8 and colony formation assay, respectively. The mRNA expression of apoptotic genes related to lung cancer was studied using reverse-transcription polymerase chain reaction. The apoptotic ratio was measured through flow cytometry. The protein expression was visualized via western blotting using specific antibodies. Results Zunyimycin C could inhibit cell proliferation and induce apoptosis in a dose-dependent manner. The expression levels of apoptosis-related proteins (i.e., BAX, cleaved-caspase-3, and cleaved-caspase-9) were increased compared with the control group. However, the levels of Bcl-2 and phosphorylated AKT were decreased by administration by zunyimycin C. Conclusions Collectively, these results implied that zunyimycin C could inhibit cell proliferation and induce apoptosis via AKT phosphorylation.

Macrocyclic effect on inhibitory activity: a modeling study on MerTK inhibitors Abstract Macrocyclic ring structures could have drug-like properties such as membrane permeability, metabolic stability, binding affinity, selectivity, and high-biological activities. Synthesized macrocyclic inhibitors have been studied and the effect of ring size has gained attention from drug design community. Marsault et al. showed a positive correlation between ring size and inhibitory activity against rennin. On the other hand, De Clercq et al. suggested that there would be some optimum ring size for histone deacetylase inhibitory activity. Therefore, macrocyclic effects appear elusive while intriguing. In this study, we have selected a large set of macrocyclic inhibitors (14–20-membered rings) to study macrocyclic effect on MerTK using molecular modeling techniques. We carefully positioned all the cyclic inhibitors into the binding pocket utilizing available information obtained from both experimental and theoretical means. Then, from the resultant binding poses, the ligand–receptor interactions were analyzed. Unlike previous reports, we could not observe any relevance between ring size and inhibitory activity. However, there is a correlation between the number of hydrogen bonds and inhibitory activity. Among these hydrogen-bonding interactions, active site residues Arg727, and Asn728 as well as two signature interactions at the hinge region were found to be crucial for MerTK inhibition. Furthermore, the importance of number of hydrogen bonding was further validated statistically by means of 3D-QSAR techniques such as CoMFA and CoMSIA. The involvement of Arg727 and Asn728 was checked graphically by CoMSIA hydrogen-bonding donor map. This outcome could be helpful for more potent MerTK inhibitor design. In addition, more detailed studies on ring size effect would be desirable to understand macrocyclic effects.

Antioxidant, antiproliferative and anti-inflammatory effects of Glaucium flavum fractions enriched in phenolic compounds Abstract Glaucium flavum (Papaveraceae) is a halophyte which is known for its high importance in phytomedicine and ecology. In this work, phytochemical analysis, as well as antioxidant, antiproliferative and anti-inflammatory effects were investigated for EOH, EA and PE fractions of G. flavum shoots. Results showed that total polyphenol amounts were highest in EOH fraction (158.3 mg GAE/g DR) followed by EA and PE. This latter fraction was rich in flavonoids (128.43 mg CE/g DR), however EA produced more condensed tannins (19.83 mg CE/g DR) than other fractions. In addition, seven molecules (phenolics) have been identified: kaempferol, caffeic acid, catechin hydrate, syringic acid, chlorogenic acid, isoquercitrin, and trans-hydroxycinnamic acid. Concerning antioxidant effects, ethanol fraction was distinguished by a high total antioxidant activity (432.58 mg GAE/g DR), a lower iron reducing power (EC50 = 800 µg/ml), a capacity to inhibit the β-carotene bleaching (IC50 = 48.78 µg/ml), and an important antiradical activity (IC50 = 140 µg/ml). In addition, PE, EA and EOH fractions have strong antiproliferative effect against MCF-7 cells but with superiority of EA fraction (IC50 = 135 µg/ml). EA showed also a high anti-inflammatory effect with an amount of NO which is equal to around 29 and 20 µM/ml NO at 50 and 100 µg/ml, respectively.

Synthesis, α-amylase inhibition and molecular docking study of bisindolylmethane sulfonamide derivatives Abstract We have synthesized nineteen (1–19) bisindolylmethane sulfonamide analogs, characterized by different spectroscopic techniques such as 1HNMR and EI-MS and tested for α-amylase inhibitory potential. All compounds showed excellent to moderate degree of α-amylase inhibitory potential with IC50 values ranging between 1.192 ± 0.51 to 3.057 ± 0.18 μM as equated with standard acarbose (IC50 values 0.83 ± 0.36 μM). Among the series, six analogs such as 1, 4, 5, 6, 10, and 14 showed potent α-amylase inhibition with IC50 values 1.747 ± 0.2, 1.208 ± 0.15, 1.192 ± 0.51, 1.858 ± 0.08, 1.358 ± 0.27 and 1.527 ± 0.17 μM, respectively, as equated with standard acarbose. The structure-activity relationship based upon different substituents on phenyl part. Molecular docking studies performed to recognize the binding interaction of the most active compounds.

Anxiolytic and anticonvulsant activity followed by molecular docking study of ceramides from the Red Sea sponge Negombata sp Abstract The chemical investigation of the Red Sea sponge Negombata sp. led to isolation and structure elucidation of five new ceramides N ((2S,3R,4E,8E)-1,3-dihydroxyhexacosa-4,8-dien-2-yl)pentadecanamide (1), N-((2S,3R,E)-1,3-dihydroxynonadec-4-en-2-yl)stearamide (2), N-[(2S,3R,E)-1,3 dihydroxyhexacos-4-en-2-yl]palmitamide (3), N-((2S,3R)-1,3-dihydroxydodecan-2-yl)tetradecanamide (4), N-[(2S,3S,4R)-1,3,4- trihydroxypentadecan-2-yl] palmitamide (5). Structure elucidation was achieved using spectroscopic techniques, including 1D and 2D NMR and HRMS. The isolated ceramides were tested for anti-anxiety action in the elevated plus maze and the light-dark transition box. Mice given diazepam or compounds number 1, 2, 3, and 5 spent longer time in the light area of the light-dark box. However, compound 4 did not produce a similar effect. Similarly, testing anti-anxiety action in the elevated plus maze test showed that the compounds number 2, 3, and 5 or diazepam were able to prolong the open arm time %. Meanwhile, compounds 1 and 4 failed to produce a similar response. In addition, the anticonvulsant action of the ceramides was assessed employing pentylenetetrazole-induced seizures, where some ceramides prolonged the time to death due to pentylenetetrazole in vivo. In silico testing of the isolated ceramides displayed reasonable GABA receptor modulator binding at the benzodiazepines site. Ceramide 1 showed slightly stronger interaction with the GABA receptor over other ceramides which is compatible with the results of their anxiolytic activity.

Synthesis of novel α-aminophosphonates under microwave irradiation, biological evaluation as antiproliferative agents and apoptosis inducers Abstract The synthesis of two series of α-aminophosphonates was achieved by Microwave Irradiation (MW), using the one-pot Kabachnik–Fields reaction. Based on a green chemistry approach, the reactions were carried out using ethanol as the only solvent and without any catalyst, and short reaction times (20–40 min), in variable yields. Both series were tested to determine their cell proliferation inhibition activity in MDA-MB-231, MCF-7 and MCF-10A cell lines. Ethyl 4-(((diphenoxyphosphoryl)(4-(diphenylamino)phenyl)methyl)amino) benzoate 4e and diphenyl (((4-(((S)-2-hydroxy-1-phenylethyl)carbamoyl)phenyl)amino)(4-hydroxyphenyl)methyl)phosphonate 6b, showed cell proliferation inhibition activity only in the cancer cell line MCF-7 and no effect on the normal cell line MFC-10A, both compounds caused cell death by inducing apoptosis.