2-Thioxo-3,4-dihydropyrimidine and thiourea endowed with sulfonamide moieties as dual EGFRT790M and VEGFR-2 inhibitors: Design, synthesis, docking, and anticancer evaluations.

The effectiveness of a new series of thiopyrimidine and thiourea containing sulfonamides moieties was tested on HCT-116, MCF-7, HepG2, and A549. HepG2 cell line was the one that all the new derivatives affected the most. The greatest potent compounds against the four HepG2, HCT116, MCF-7, and A549 cell lines were 8f and 8g with IC50 = 4.13, 6.64, 5.74, 6.85 µM and 4.09, 4.36, 4.22, 7.25 µM correspondingly. Compound 8g exhibited higher activity than sorafenib against HCT116 and MCF-7 but exhibited lower activity against HepG2 and A549. Moreover, compounds 8f and 8g exhibited higher activities than erlotinib on HepG2, HCT116, and MCF-7 but demonstrated lower activity on A549. The most potent cytotoxic derivatives 6f, 6g, 8c, 8d, 8e, 8f, and 8g were examined on normal VERO cell lines. Our derivatives have low toxicity on VERO cells with IC50 values ranging from 32.05 to 53.15 µM. Additionally, all compounds were assessed for dual VEGFR-2 and EGFRT790M inhibition effects. Compounds 8f and 8g were the most potent derivatives inhibited VEGFR-2 at IC50 value of 0.88 and 0.90 µM, correspondingly. As well, derivatives 8f and 8g could inhibit EGFRT790M demonstrating strongest effects with IC50 = 0.32 and 0.33 µM sequentially. Additionally, the greatest active derivatives ADMET profile was evaluated in relationship with sorafenib and erlotinib as reference agents. The data attained from docking were greatly related to that achieved from the biological testing.

Synthesis of Novel Nano-Sulfonamide Metal-Based Corrosion Inhibitor Surfactants.

The synthesis of novel corrosion inhibitors and biocide metal complex nanoparticle surfactants was achieved through the reaction of sulfonamide with selenious acid to produce a quaternary ammonium salt. Platinum and cobalt surfactants were then formed by complexing the first products with platinum (II) or cobalt (II) ions. The surface properties of these surfactants were then investigated, and the free energy of form micelles (ΔGomic) and adsorption (ΔGoads) was determined. The obtained cationic compounds were evaluated as corrosion inhibitors for carbon steel dissolution in 1N HCl medium. The results of gravimetric and electrochemical measurements showed that the obtained inhibitors were excellent corrosion inhibitors. The anti-sulfate-reducing bacteria activity known to cause corrosion of oil pipes was obtained by the inhibition zone diameter method for the prepared compounds, which were measured against sulfate-reducing bacteria. FTIR spectra, elemental analysis, H1 NMR spectrum, and 13C labeling were performed to ensure the purity of the prepared compounds.

Design, Molecular Docking, Synthesis, Anticancer and Anti-Hyperglycemic Assessments of Thiazolidine-2,4-diones Bearing Sulfonylthiourea Moieties as Potent VEGFR-2 Inhibitors and PPARγ Agonists.

Newly designed thiazolidine-2,4-diones 3-7a-c were synthesized, and their anticancer activities were screened against three cancer lines. They showed potent activities against HepG2 compared to the other HCT116 and MCF-7 tumor cell lines. Compounds 7c and 6c were detected as highly effective derivatives against MCF-7 (IC50 = 7.78 and 8.15 µM), HCT116 (IC50 = 5.77 and 7.11 µM) and HepG2 (IC50 = 8.82 and 8.99 µM). The highly effective derivatives 6a-c and 7a-c were tested against VERO normal cell lines. All derivatives were evaluated for their VEGFR-2 inhibitory actions and demonstrated high to low activities, with IC50 values varying from 0.08 to 0.93 µM. Moreover, derivatives 5a-c, 6a-c and 7a-c were assessed to verify their in vitro binding affinities to PPARγ and insulin-secreting activities. Finally, docking studies were performed to explore their affinities and binding modes toward both VEGFR-2 and PPARγ receptors.

Design, synthesis, anticancer, and docking of some S- and/or N-heterocyclic derivatives as VEGFR-2 inhibitors.

Novel heterocyclic derivatives (4-22) were designed, synthesized, and evaluated against hepatocellular carcinoma type (HepG2) and breast cancer (MCF-7) cells, targeting the VEGFR-2 enzyme. Compounds 18, 10, 13, 11, and 14 were found to be the most potent derivatives against both the HepG2 and MCF-7 cancer cell lines, with GI50 = 2.11, 2.54 µM, 3.16, 3.64 µM, 3.24, 6.99 µM, 7.41, 6.49 µM and 8.08, 10.46 µM, respectively. Compounds 18 and 10 showed higher activities against both HepG2 and MCF-7 cells than sorafenib (GI50 = 9.18, 5.47 µM, respectively) and doxorubicin (GI50 = 7.94, 8.07 µM, respectively). Compounds 13, 11, and 14 showed higher activities than sorafenib against HepG2 cancer cells, but lower activities against MCF-7 cells. Compounds 18, 13, and 10 were more potent than sorafenib, inhibiting vascular endothelial growth factor receptor-2 (VEGFR-2) at GI50 values of 0.05, 0.06, and 0.08 µM, respectively. Compound 11 inhibited VEGFR-2 at an IC50 value of 0.10 µM, which is equipotent to sorafenib. Compound 14 inhibited VEGFR-2 at an IC50 value of 0.11 µM, which is nearly equipotent to sorafenib. The tested compounds have more selectivity against cancer cell lines. Compounds 18, 10, 13, 11, and 14 are, respectively, 16.76, 9.24, 6.06, 2.78, and 2.85 times more toxic in HePpG2 cancer cells than in VERO normal cells. Also, compounds 18, 10, 13, 11, and 14 are, respectively, 14.07, 8.02, 2.81, 3.18, and 2.20 times more toxic in MCF-7 than in VERO normal cells. The most active compounds, 10, 13, and 18, showed a good ADMET (absorption, distribution, metabolism, excretion, and toxicity) profile.

Pyridine-derived VEGFR-2 inhibitors: Rational design, synthesis, anticancer evaluations, in silico ADMET profile, and molecular docking.

Novel pyridine-derived compounds (5-19) were designed and synthesized, and their anticancer activities were evaluated against HepG2 and MCF-7 cells, targeting the VEGFR-2 enzyme. Compounds 10, 9, 8, and 15 were found to be the most potent derivatives against the two cancer cell lines, HepG2 and MCF-7, respectively, with IC50 = 4.25 and 6.08 µM, 4.68 and 11.06 µM, 4.34 and 10.29 µM, and 6.37 and 12.83 µM. Compound 10 displayed higher activity against HepG2 cells than sorafenib (IC50 = 9.18 and 5.47 µM, respectively) and doxorubicin (IC50 = 7.94 and 8.07 µM, respectively). It also showed higher activity than doxorubicin against MCF-7 cells, but lower activity than sorafenib. Compounds 9, 8, and 15 displayed higher activities than sorafenib and doxorubicin against HepG2 cells but exhibited lower activities against MCF-7 cells. Compound 10 potently inhibited VEGFR-2 at an IC50 value of 0.12 µM, which is nearly equipotent to sorafenib (IC50 = 0.10 µM). Compounds 8 and 9 exhibited very good activity with the same IC50 value of 0.13 µM. The six most potent derivatives, 6, 9, 8, 10, 15, and 18, were tested for their cytotoxicity against normal Vero cells. Compounds 6, 8, 9, 10, 15, and 18 are, respectively, 1.13, 3.74, 4.18, 3.64, 2.81, and 2.00 times more toxic to HepG2 and 2.06, 1.58, 1.76, 2.54, 1.40, and 2.69 times more toxic to MCF-7 breast cancer cells than in normal Vero cells.

Design, synthesis, molecular docking, in silico ADMET profile and anticancer evaluations of sulfonamide endowed with hydrazone-coupled derivatives as VEGFR-2 inhibitors.

A new series of sulfonamide endowed with hydrazone coupled to dimethyl and/or diethyl malonates were prepared. Various sulfa drugs were diazotized and followed by coupling with active methylene of dimethyl and/or diethyl malonate to afford the new intermediates hydrazones 3a-c and 4a-c. The reactivity of hydrazone derivatives towards hydrazines was investigated. Thus, a novel series of 3,5-dioxopyrazolidine7a-cwere obtained by treatment with hydrazine hydrate. When hydrazones were allowed to react with phenyl hydrazine, the alkyl 2-((4-(N-(substituted)sulfamoyl)phenyl)diazenyl)-3-oxo-3-(2-phenylhydrazinyl)propanoateswere obtained 8a-c and/or 10a-c. Their anticancer activities were evaluated against HepG2, HCT-116 and MCF-7. HepG2 was the most sensitive one. In particular, compounds 7c, 7b and 10c were found to be the most potent derivatives with IC50 = 6.43 ± 0.5, 9.66 ± 0.8, 10.57 ± 0.9 µM, 8.65 ± 0.7, 7.49 ± 0.6, 14.29 ± 1.3 µM and 8.97 ± 0.7, 10.13 ± 0.9, 13.82 ± 1.1 µM respectively. Sorafenib and doxorubicin were used as reference drugs. The most potent derivatives 7a, 7b, 7c, 8c and 10c were tested for their cytotoxicity against normal VERO cell lines. Compounds 7a, 7b, 7c, 8c and 10c are respectively, 2.41, 4.85, 4.08, 3.23 and 5.89 fold times more toxic in HCT116 than in VERO normal cells. Moreover, the most active anti-proliferative derivatives 7a, 7b, 7c, 8c and 10c were subjected to further biological study to evaluate their inhibitory potentials against VEGFR-2. The tested compounds displayed high to good inhibitory activity with IC50 values ranging from 0.14 ± 0.02 to 0.23 ± 0.03 µM. Among them, compounds 7c, 7b and 10c were found to be the most potent derivative that inhibited VEGFR-2 at IC50 values of 0.14 ± 0.02, 0.15 ± 0.02 and 0.15 ± 0.02 µM respectively. sorafenib was used as reference drug. Furthermore, ADMET profile was evaluated for the four most active compounds in comparison to doxorubicin as a reference drug. The data obtained from docking studies were highly correlated with that obtained from the biological screening.

Design, green synthesis, molecular docking and anticancer evaluations of diazepam bearing sulfonamide moieties as VEGFR-2 inhibitors.

Novel series of diazepam bearing sulfonamide moieties 5a-f and 7a-c were designed, synthesized and evaluated for anticancer activity against HepG2, HCT-116 and MCF-7 cell lines. MCF-7 was the most sensitive cell line to the influence of the new derivatives. In particular, compound 5d was found to be the most potent derivative overall the tested compounds against the three HepG2, HCT116 and MCF-7 cancer cell lines with IC50 = 8.98 ± 0.1, 7.77 ± 0.1 and 6.99 ± 0.1 µM respectively. Compound 5d exhibited higher activity than sorafenib, (IC50 = 9.18 ± 0.6, 5.47 ± 0.3 and 7.26 ± 0.3 µM respectively), against HepG2 and MCF-7 but exhibited lower activity against HCT116 cancer cell lines respectively. Also, this compound displayed lower activity than doxorubicin, (IC50 = 7.94 ± 0.6, 8.07 ± 0.8 and 6.75 ± 0.4 µM respectively), against HepG2 and MCF-7 but higher activity against HCT116 cell lines respectively. Compounds 5b, 5c, 5d, 5e, 5f and 7c are respectively, 5.77, 8.58, 9.54, 5.71, 4.68 and 2.31 fold times more toxic in breast cancer cell lines (MCF-7, the most sensitive cells) than in VERO normal cells. All the synthesized compounds 5a-f and 7a-c were evaluated for their inhibitory activities against VEGFR-2. Among them, compound 5d was found to be the most potent derivative that inhibited VEGFR-2 at IC50 value of 0.10 ± 0.01 µM, which is equipotent to sorafenib IC50 value (0.10 ± 0.02 µM). Compound 5c exhibited excellent activity with IC50 value of 0.12 ± 0.01 µM which nearly equipotent to that of sorafenib. Compounds 5b, 5e and 5f exhibited very good activity with the same IC50 value of 0.14 ± 0.02 µM. Also, compounds 7c and 7b possessed good VEGFR-2 inhibition with IC50 values of 0.16 ± 0.06 and 0.17 ± 0.06 µM respectively which are more than the half activity of that of sorafenib. The data obtained from docking studies were highly correlated with that obtained from the biological screening.

Novel Anticancer Fused Pyrazole Derivatives as EGFR and VEGFR-2 Dual TK Inhibitors.

EGFR and VEGFR-2 represent promising targets for cancer treatment as they are very important in tumor development as well as in angiogenesis and metastasis. In this work, 6-amino-4-(2-bromophenyl)-3-methyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile 1 and (E)-4-(2-Bromobenzylidene)-5-methyl-2,4-dihydro-3H-pyrazol-3-one 11 were selected as starting materials to synthesize different fused pyrazole derivatives; dihydropyrano[2,3-c]pyrazole 1, 2, 7-9, and 15, pyrazolo[4',3':5,6]pyrano[2,3-d]pyrimidine 3-6, pyrazolo[3,4-d]pyrimidine 12 and 13, and pyrazolo[3,4-c]pyrazole 14 derivatives were synthesized to evaluate their anticancer activity against HEPG2 human cancer cell lines compared to erlotinib and sorafenib as reference drugs. Seven compounds 1, 2, 4, 8, 11, 12, and 15 showed nearly 10 fold higher activity than erlotinib (10.6 µM) with IC50 ranging from 0.31 to 0.71 µM. In vitro EGFR and VEGFR-2 inhibitory activity were performed for the synthesized compounds, and the results identified compound 3 as the most potent EGFR inhibitor (IC50 = 0.06 µM) and compound 9 as the most potent VEGFR-2 inhibitor (IC50 = 0.22 µM). Moreover, compounds 9 and 12 revealed potent dual EGFR and VEGFR-2 inhibition, and these results were supported by docking studies of these two compounds within the active sites of both enzymes.

Design and synthesis of some new thiophene, thienopyrimidine and thienothiadiazine derivatives of antipyrine as potential antimicrobial agents.

4-acetamide Pyrazolone 2 was synthesized by acetylation of 4-amino antipyrine 1 in excellent yield. 4-acetamide pyrazolone 2 was exploited as a starting material for the syntheses of hitherto unknown different types of new heterocyclic compounds incorporating the antipyrine moiety which expect highly biological activity against various microorganisms. Thus, Claisen condensation of 4-acetamide pyrazolone 2 with diethyl oxalate have been utility to afford new 4-oxaloacetyl antipyrine 3, which upon hydrazinolysis of the ester function to obtain the acetohydrazide derivative 18 which used as starting material to synthesize 1,2,4-triazol 19 and hydrazone 20 derivatives. 4-aminothiophene carboxylate derivatives 6, 7 were synthesized by utility of Gewald reaction. On the other hand, Michael type addition of the enolate ion of acetyl functions in acetamide pyrazolone 2 to the activated double bond in arylidenemalonoester to furnish pyrane derivative 9 was done. Finally, 4-acetamide pyrazolone 2 was treated with aromatic substituted aldehyde to exhibit thiophenacrylamide derivative 10. Compound 6 gave characteristic reaction for enaminonitriles, thus, the behavior of o-aminoester of 4-aminothiophene carboxylate derivative 6 toward electrophilic reagent, one carbon donars, amide and acid was also investigated to afford the correspondence thiophene derivatives 11,12,13,15 and 16. In addition, treatment of carboxamide derivative 16 with thionyl chloride afforded the thienothiadiazine derivative 17. The characterization of all synthesized compounds was done by elemental analysis and spectral studies. Moreover, all the synthesized compounds were tested against antimicrobial activities by the disc diffusion method, which exhibited higher promising biological activities.