Investigating the Promising Anticancer Activity of Cetuximab and Fenbendazole Combination as Dual CBS and VEGFR-2 Inhibitors and Endowed with Apoptotic Potential.

In this work, the cytotoxicity of monoclonal antibody (Cetuximab, Ce) and Fenbendazole (Fen), as well as their combination therapy were tested with the MTT assay. On the other side, Ce, Fen, and a combination between them were subjected to a colchicine-tubulin binding test, which was conducted and compared to Colchicine as a reference standard. Besides, Ce, Fen, and the combination of them were tested against the VEGFR-2 target receptor, compared to Sorafenib as the standard medication. Moreover, the qRT-PCR technique was used to investigate the levels of apoptotic genes (p53 and Bax) and anti-apoptotic gene (Bcl-2) as well. Also, the effect of Ce, Fen, and the combination of them on the level of ROS was studied. Furthermore, the cell cycle analysis and Annexin V apoptosis assay were carried out for Ce, Fen, and a combination of them. In addition, the molecular docking studies were used to describe the molecular levels of interactions for both (Fen and colchicine) or (Fen and sorafenib) within the binding pockets of the colchicine binding site (CBS) and vascular endothelial growth factor-2 receptor (VEGFR-2), respectively.

Chloroacetonitrile reduces rat prenatal bone length and induces oxidative stress, apoptosis, and DNA damage in rat fetal liver.

One of the disinfection byproducts of chlorinating drinking water is chloroacetonitrile (CAN). Thirty-six female rats were used and distributed equally into four groups. The low dose treated group received CAN at a dose of 5.5 mg/kg body weight/day (1/40 LD50 ) orally from the 6th to 12th day of gestation. The high dose treated group received 11 mg/kg body weight/day (1/20 LD50 ) of CAN orally for the same period, the vehicle control group received 1 mL of corn oil, and the water control group received 1 mL of distilled water orally for the same period. High dose exposure to CAN significantly reduced gravid uterine weight, fetal body weights, and length, and caused obvious skeletal deformities, weak mineralization. Fetal tibial growth plates displayed histopathologic changes. Induced oxidative stress and redox imbalance in fetal liver tissues was evidenced by significantly decreased in catalase and superoxide dismutase activity, and elevated malondialdehyde levels. Histopathological, glycogen content changes, and DNA damage were observed in the fetal liver of high dose treated group. Additionally, administration of high dose of CAN induced apoptosis, evidenced by increased caspase-3 concentration in fetal liver. Thus, extensive exposure to CAN induces poor pregnancy outcomes. CAN levels in water should be monitored regularly.

Synthesis, biological evaluation, and molecular docking studies of new pyrazol-3-one derivatives with aromatase inhibition activities.

A new series derived from 4-(2-chloroacetyl)-1,2-dihydro-1,5-dimethyl-2-phenyl-3H-pyrazol-3-one was synthesized, characterized and its pharmacological activity toward aromatase enzyme inhibition was screened and compared to the reference native ligand letrozole. The most active compound of the series was 16, showing IC50 value of 0.0023 ± 0.0002 µm compared to letrozole with IC50 of 0.0028 ± 0.0006 µm. In addition, compounds 26 and 36 exhibit good inhibition activities close to letrozole with IC50 values 0.0033 ± 0.0001 and 0.0032 ± 0.0003 µm, respectively. Moreover, molecular docking studies were conducted to support the findings.

Novel Benzo[d]imidazole-based Heterocycles as Broad Spectrum Anti-viral Agents: Design, Synthesis and Exploration of Molecular Basis of Action.

The design and synthesis of a novel series of benzo[d]imidazole-based heterocycles and their biological evaluation as antiviral agents are reported herein. 1-(1-Methyl-1H-benzo[d]imidazol- 2-yl)-2-thiocyanatoethanone 2 was used as a key intermediate for the synthesis of the thiazolylhydrazine 4, the thiazolylamine 5 and the methylthiazole 7. Coupling of compounds 5 or 7 with the appropriate diazotized aromatic amines gave the diazenyl derivatives 6a-c and 8a-c, respectively. The quinazoline derivative 12 was also synthesized. On the other hand, the phenylthio 20 and the phenylsulphonyl 22 bioisosteresand their respective diazenyl derivatives 21a-c and 23a-c were prepared. The synthesized compounds were evaluated for their HIV-1, HCV, SSPE and H1N1 inhibitory activities and were found to display very promising results. Furthermore, to investigate the underlying possible mechanism of action, in vitro and in silico screening of this series of benzo[d]imidazoles was performed against the viral enzymes HIV-1 RT, HCV NS3/4A serine protease and H1N1 NA1. Overall findings of the executed investigations highlight these novel compounds as very promising potent, broad spectrum antiviral agents.

Synthesis and antiviral activity of some new bis-1,3-thiazole derivatives.

Treatment of 3-phenyl-1,3-thiazolidin-4-one derivative 1 with phenylisothiocyanate in DMF, in the presence of potassium hydroxide, at room temperature gave the non-isolable potassium salt 2. The in-situ reaction of 2 with differently substituted N-aryl hydrazonoyl chlorides 3, 7a-d and 14a-d afforded the corresponding 2-(pyrazolyl)thiazolylimino-5-(thiadiazolylidene)thiazolidin-4-one derivatives 6, 10a-d and 17a-d, respectively. Reaction of 2 with further α-haloketones yielded the 4-(pyrazolyl)thiazolylimino-bis-thiazolidine derivatives 22, 25 and 26. Single crystal X-ray analysis was used in structure elucidation of the products. The in-vitro antiviral screening against four viruses (Poliovirus, Influenza A (H1N1) virus, Hepatitis B virus and Hepatitis C virus) for the obtained compounds was examined. Structure activity relationship (SAR) was also studied. The goal of the work was achieved in discovering a very active compound 10a as anti HCV agent (EC50 0.56 µM).

Novel 4-heteroaryl-antipyrines as DPP-IV inhibitors.

Type 2 diabetes mellitus is a vast growing progressive disease that almost affects one person among every twelve globally. Regardless the availability of wide variety of oral hypoglycemics, only one-third of patients achieves proper glycemic control. With the advantage of the low risk of hypoglycemia, DPP-IV attracted the attention of medicinal chemists as a new target for oral hypoglycemics. In this report, a lead compound 1, with antipyrine scaffold, was obtained, and its binding mode was calculated. Several derivatives with bridged nitrogenous heterocycles have been synthesized via multicomponent reaction under controlled microwave heating conditions. The antidiabetic activity versus DPP-IV protein was evaluated and compared with sitagliptin. Compounds with smaller- or medium-sized nitrogenous bridges were comparable with sitagliptin in terms of DPP-IV inhibitory activity, potentially via targeting Glu203 and Glu204. The oral hypoglycemic activities of compounds with submicromolar IC50 values were further evaluated using diabetic mouse model.

Diphenylpyrroles: Novel p53 activators.

Cellular tumor antigen p53 is crucial for cancer prevention via different mechanisms. E3 ubiquitin-protein ligase HDM2 binds to p53, blocks its ability to activate transcription, and therefore acts as a negative regulator. Blocking p53 binding site on HDM2 was believed to generate efficient antitumor agents. So far, limited scaffolds were reported with HDM2 antagonist activity. Herein, diphenylpyrroles were introduced and evaluated as a novel scaffold in the field of p53 activators. An efficient synthesis of novel 3-heteroaryl-pyrroles is described via reactions of E-3-(dimethylamino)-1-(2-methyl-4,5-diphenyl-1H-pyrrol-3-yl)prop-2-en-1-one or E-1-(2-methyl-4,5-diphenyl-1H-pyrrol-3-yl)-3-morpholinoprop-2-en-1-one with hydrazine hydrate, phenyl hydrazine, hydroxylamine, various heterocyclic amines and active methylene compounds.

Synthesis of some new pyrazole-based 1,3-thiazoles and 1,3,4-thiadiazoles as anticancer agents.

N-(4-(Pyrazol-4-yl)thiazol-2-yl)-N'-phenylthiourea derivative 2 was synthesized and then treated with variety of hydrazonoyl chlorides under basic condition at reflux to afford the corresponding 2-(4-(pyrazol-4-yl)thiazol-2-ylimino)-1,3,4-thiadiazole derivatives 6, 10a-e and 17a-e. Reaction of 2 with ethyl chloroacetate and with 3-chloro-2,4-pentanedione gave the thiazolidin-4-one 22 and 1,3-thiazole 25 derivatives, respectively. Condensation of thiazolidin-4-one 22 with aldehydes gave their 5-arylidene derivatives 23a-f. Most of the synthesized compounds were tested for anticancer activity against human hepatocelluar carcinoma HepG2, human breast cancer MCF-7 and human lung cancer A549. Their SAR was studied and variously affected by the electronic factor of electron donating and withdrawing groups. Many of the tested compounds showed moderate to high anticancer activity.

Ultrasound assisted one-pot, three-components synthesis of pyrimido[1,2-a]benzimidazoles and pyrazolo[3,4-b]pyridines: A new access via phenylsulfone synthon.

A simple, facile, efficient and three-components procedure for the synthesis of pyrimido[1,2-a]benzimidazoles and pyrazolo[3,4-b]pyridines utilizing phenylsulfone synthon, under ultrasonic irradiation was developed.

Synthesis, spectral characterization, solution equilibria, in vitro antibacterial and cytotoxic activities of Cu(II), Ni(II), Mn(II), Co(II) and Zn(II) complexes with Schiff base derived from 5-bromosalicylaldehyde and 2-aminomethylthiophene.

Schiff base namely 2-aminomethylthiophenyl-4-bromosalicylaldehyde (ATS)(4-bromo-2-(thiophen-2-yl-imino)methylphenol) and its metal complexes have been synthesized and characterized by elemental analyses, IR, 1H NMR, solid reflectance, magnetic moment, molar conductance, mass spectra, ESR and thermal analysis (TGA). The analytical data of the complexes show the formation of 1:2 [M:L] ratio of the formula [ML2], where M represents Ni(II), Zn(II) and Cu(II) ions, while L represents the deprotonated Schiff base. IR spectra show that ATS is coordinated to the metal ions in a bidentate manner through azomethine-N and phenolic-oxygen groups. The ligand and their metal chelates have been screened for their antimicrobial activities using the disc diffusion method against the selected bacteria. A cytotoxicity of the compounds against colon (HCT116) and larynx (HEP2) cancer cells have been studied. Protonation constants of (ATS) ligand and stability constants of its Cu2+, Co2+, Mn2+, Zn2+ and Ni2+ complexes were determined by potentiometric titration method in 50% (v/v) DMSO-water solution at ionic strength of 0.1 M NaNO3.

Synthesis and structure-activity relationship studies of pyrazole-based heterocycles as antitumor agents.

Several 4-cyano-1,5-diphenylpyrazoles attached to different heterocyclic ring systems at position 3 were synthesized starting from ethyl 4-cyano-1,5-diphenyl-1H-pyrazole-3-carboxylate 1. The newly synthesized compounds were tested in vivo for their anti-estrogenic effects and evaluated in vitro for their cytotoxic properties against estrogen-dependent tumors. 3-(5-Mercapto-1,3,4-oxadiazole-2-yl)-1,5-diphenyl-1H-pyrazole-4-carbonitrile 13 revealed the highest cytotoxic activity with a GI(50) value equal to 40 nM against the IGROVI ovarian tumor cell line. It also showed an anti-estrogen activity 1.6 more effective than the reference drug, in addition to a high tolerable dose. 3-(5-(Methylthio)-4-phenyl-4H-1,2,4-triazol-3-yl)-1,5-diphenyl-1H-pyrazole-4-carbonitrile 7 was found to have the highest anti-estrogenic activity, while 1,5-diphenyl-3-[5-(phenylamino)-1,3,4-thiadiazol-2-yl]-1H-pyrazole-4-carbonitrile 11 showed the lowest activity. The oral LD(50) values revealed that most of the tested compounds are relatively nontoxic.