Design, microwave assisted synthesis, and molecular modeling study of some new 1,3,4-thiadiazole derivatives as potent anticancer agents and potential VEGFR-2 inhibitors.

A green and efficient method was developed for the synthesis of 1,3,4-thiadiazole based compounds under microwave (MW) activation. The nucleophile N-(5-amino-1,3,4-thiadiazol-2-yl)thiophene-2-carboxamide (3) was synthesized and reacted with different carbon electrophilic reagents to afford thiadiazolo-pyrimidine or imidazolo-thiadiazoline derivatives (4-6 and 8), respectively. Furthermore, a one-pot reaction of 3 with p-chlorobenzaldehyde and different carbon electrophile/ or nucleophiles under microwave irradiation yields the cyclic thiadiazolo-pyrimidine derivatives 10-15. Additionally, nucleophilic substitution of aromatic amines and/or potassium salts of some heterocyclic compounds with chloroacetamido-thiadiazole 6 yields derivatives 16-20. All the new derivatives were synthesized by both conventional and MW irradiation methods. All the new 1,3,4-thiadiazole derivatives were evaluated against four cancer cell lines, HepG-2, MCF-7, HCT-116, and PC-3. The anti-proliferative activity of most of the synthesized compounds exhibited excellent broad-spectrum cytotoxic activity against the cancer cell lines with IC50 values ranging from 3.97 to 9.62 µM. Moreover, the enzymatic assessment of five derivatives (2,4b, 6, 8, 9a) against VEGFR-2 tyrosine kinase showed significant inhibitory activities with IC50 of 11.5, 8.2, 10.3, 10.5 and 9.4 nM respectively. Further studies revealed the ability of compound 9a to have a strong DNA-binding affinity of 36.06 µM via DNA/methyl green assay. Moreover, molecular docking study was carried out to reveal the binding interactions of compounds in the binding site of VEGFR-2 enzyme explaining the significant inhibitory activity of these derivatives. Finally, ADME/Tox studies was performed to predict the pharmacokinetics of the synthesized compounds.

SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL EVALUATION OF NEW FUSED TRIAZINE DERIVATIVES BASED ON 6-METHYL-3-THIOXO-1,2,4-TRIAZIN-5-ONE.

A one-pot reaction of 6-methyl-3-thioxo-3,4-dihydro-[1,2,4]triazin-5-one 1 with selected aldehydes 2a-d and chloroacetic acid afforded the respective 2-arylidene-6-methyl-thiazolo[3,2-b][1,2,4]triazine-3,7-diones 4a-d. Compunds 4a-d could be also obtained via the reaction of 1 with chloroacetic acid in refluxing acetic acid to give 6-methyl-thiazolo[3,2-b][1,2,4]triazine-3,7-dione 3 then, Knoevenagel condensation of 3 with aldehydes 2a-d gave compounds 4a-d. Heterocyclization of 4a-c with hydrazine hydrate and phenylhy- drazine gave the corresponding pyrazolines 5a-c and 6a-c, respectively. Moreover, 7-amino-9-(aryl)-3-methyl-2-oxo-2H-pyrido[2',3':4,5][1,3]thiazolo[3,2-b][1,2,4]triazine-8-carbonitrles 7a-c were synthesized by the reaction of 4a-c with malononitrile in the presence of ammonium acetate. The structures of newly synthesized compounds were confirmed by analytical and spectroscopic measurements. Some selected new compounds were screened for their cytotoxic activities against three human cancer cell lines (HepG2, MCF-7 and A549) using SRB assay and the structure-activity relationship (SAR) was discussed. The biochemical assays including antioxidant enzyme, oxidative stress and estimation of nucleic acids and proteins have been discussed for some selected compounds. The molecular docking of 4c and 7b has been also studied.

Synthesis and Regioselective Reaction of Some Unsymmetrical Heterocyclic Chalcone Derivatives and Spiro Heterocyclic Compounds as Antibacterial Agents.

A number of novel heterocyclic chalcone derivatives can be synthesized by thermal and microwave tools. Treatment of 4-(4-Acetylamino- and/or 4-bromo-phenyl)-4-oxobut-2-enoic acids with hydrogen peroxide in alkaline medium were afforded oxirane derivatives 2. Reaction of the epoxide 2 with 2-amino-5-aryl-1,3,4-thiadiazole derivatives yielded chalcone of imidazo[2,1-b]thiadiazole derivative 4 via two thermal routes. In one pot reaction of 4-bromoacetophenone, diethyloxalate, and 2-amino-5-aryl-1,3,4-thiadiazole derivatives in MW irradiation (W 250 and T 150 °C) under eco-friendly conditions afforded an unsuitable yield of the desired chalcone 4d. The chalcone derivatives 4 were used as a key starting material to synthesize some new spiroheterocyclic compounds via Michael and aza-Michael adducts. The chalcone 4f was similar to the aryl-oxo-vinylamide derivatives for the inhibition of tyrosine kinase and cancer cell growth. The electron-withdrawing substituents, such as halogens, and 2-amino-1,3,4-thiadiazole moeity decreasing the electron density, thereby decreasing the energy of HOMO, and the presence of imidazothiadiazole moiety should improve the antibacterial activity. Thus, the newly synthesized compounds were evaluated for their anti-bacterial activity against (ATCC 25923), (ATCC 10987), (ATCC 274,) and (SM514). The structure of the newly synthesized compounds was confirmed by elemental analysis and spectroscopic data.

A convenient synthesis and molecular modeling study of novel pyrazolo[3,4-d]pyrimidine and pyrazole derivatives as anti-tumor agents.

An efficient method to obtain ethyl 5-amino-1-tosyl-1H-pyrazole-4-carboxylate (3) was outlined using condensation reactions of 4-methylbenzenesulfonylhydrazide with (E)-ethyl 2-cyano-3-ethoxyacrylate. The cyclocondensation reaction of this substrate and its hydrazide derivative with urea, thiourea, formamide, formic acid, d-glucose, o-phenylenediamine, 4-dimethylaminobenzaldehyde, anthracene-9-carbaldehyde, thioglycolic acid and carbon disulphide then with hydrazine hydrate analogues furnished a series of pyrazolo[3,4-d]pyrimidine, pyrazolo[3,4-d]oxazin-4-one, pyrazole-4-glucoside, 4-benzo[d]imidazole, 1,3-thiazolidinone, 1,3,4-oxadiazol-2(3H)-thione and 1,2,4-triazol-5(4H)-thione derivatives respectively. The structure of the compound 3 was supported by X-Ray crystallographic data. Orally administrated, one of each of the series of pyrazoles showed significant effects in mouse tumor model cancer cell lines (EAC) and two human cancer cell lines of Colon cancer (HCT-29) and Breast cancer (MCF-7) with docking studies.

Three-dimensional quantitative structure activity relationship (QSAR) of cytotoxic active 3,5-diaryl-4,5-dihydropyrazole analogs: a comparative molecular field analysis (CoMFA) revisited study.

UNLABELLED: In vitro antitumor evaluation of the synthesized 46 compounds of 3,5-diaryl-4,5-dihydropyrazoles against EAC cell lines and 3D QSAR study using pharmacophore and Comparative Molecular Field Analysis (CoMFA) methods were described. CoMFA derived QSAR model shows a good conventional squared correlation coefficient r2 and cross validated correlation coefficient r2cv 0.896 and 0.568 respectively. In this analysis steric and electrostatic field contribute to the QSAR equation by 70% and 30% respectively, suggesting that variation in biological activity of the compounds is dominated by differences in steric (van der Waals) interactions. To visualize the CoMFA steric and electrostatic field from partial least squares (PLS) analysis, contour maps are plotted as percentage contribution to the QSAR equation and are associated with the differences in biological activity. BACKGROUND: Pyrazole derivatives exhibit a wide range of biological properties including promising antitumor activity. Furthermore, Aldol condensation assisted organic synthesis has delivered rapid routes to N-containing heterocycles, including pyrazoles. Combining these features, the use of chalconisation-assisted processes will provide rapid access to a targeted dihydropyrazoles library bearing a hydrazino 3D QSAR study using pharmacophore and Comparative Molecular Field Analysis (CoMFA) methods were described for evaluation of antioxidant properties. RESULTS: Chalcones promoted 1 of the 2 steps in a rapid, convergent synthesis of a small library of hydrazinyl pyrazole derivatives, all of which exhibited significant antitumor activity against Ehrlich Ascites Carcinoma (EAC) human tumor cell line comparable to that of the natural anticancer doxorubicin, as a reference standard during this study. In order to understand the observed pharmacological properties, quantitative structure-activity relationship (3D QSAR) study was initiated. CONCLUSIONS: Chalcones heating provides a rapid and expedient route to a series of pyrazoles to investigate their chracterization scavenging properties. Given their favorable properties, in comparison with known anticancer, these pyrazole derivatives are promising leads for further development and optimization.