Design, synthesis, in vitro and in silico evaluation of a new series of oxadiazole-based anticancer agents as potential Akt and FAK inhibitors.

In the current work, new 1,3,4-oxadiazole derivatives were synthesized and investigated for their cytotoxic effects on A549 human lung adenocarcinoma, C6 rat glioma and NIH/3T3 mouse embryonic fibroblast cell lines. Compounds 2, 6 and 9 were found to be the most potent anticancer agents against A549 and C6 cell lines and therefore their effects on apoptosis, caspase-3 activation, Akt, FAK, mitochondrial membrane potential and ultrastructural morphological changes were evaluated. N-(5-Nitrothiazol-2-yl)-2-[[5-[((5,6,7,8-tetrahydronaphthalen-2-yl)oxy)methyl]-1,3,4-oxadiazol-2-yl]thio]acetamide (9) increased early and late apoptotic cell population in A549 and C6 cells more than cisplatin and caused more mitochondrial membrane depolarization in both cell lines than cisplatin. On the other hand, N-(6-methoxybenzothiazol-2-yl)-2-[[5-[((5,6,7,8-tetrahydronaphthalen-2-yl)oxy)methyl]-1,3,4-oxadiazol-2-yl]thio]acetamide (6) caused higher caspase-3 activation than cisplatin in both cell lines. Compound 6 showed significant Akt inhibitory activity in both cell lines. Moreover, compound 6 significantly inhibited FAK (Phospho-Tyr397) activity in C6 cell line. Molecular docking simulations demonstrated that compound 6 fitted into the active sites of Akt and FAK with high affinity and substrate-specific interactions. Furthermore, compounds 2, 6 and 9 caused apoptotic morphological changes in both cell lines obtained from micrographs by transmission electron microscopy. A computational study for the prediction of ADME properties of all compounds was also performed. These compounds did not violate Lipinski's rule, making them potential orally bioavailable anticancer agents.

Synthesis and Evaluation of a Series of 1,3,4-Thiadiazole Derivatives as Potential Anticancer Agents.

BACKGROUND AND METHODS: In an attempt to develop potent antitumor agents, the synthesis of a series of N-(6-substituted benzothiazol-2-yl)-2-[(5-(arylamino)-1,3,4-thiadiazol-2-yl)thio]acetamides (1-14) was described and their cytotoxic effects on A549 human lung adenocarcinoma, MCF-7 human breast adenocarcinoma, HepG2 human hepatocellular carcinoma and NIH/3T3 mouse embryonic fibroblast cell lines were investigated using MTT assay. RESULTS: Phenyl-substituted compounds (8-14) were found to be more effective than naphthyl-substituted compounds (1-7) on cancer cells. Compounds 8, 9, 10, 12, 13 and 14 were identified as the most potent anticancer agents on MCF-7 and HepG2 cell lines and therefore their effects on DNA synthesis and apoptosis/necrosis in MCF-7 cell line were evaluated. Among these compounds, N-(6-methoxybenzothiazol-2-yl)-2-[(5- (phenylamino)-1,3,4-thiadiazol-2-yl)thio]acetamide (13) was the most selective anticancer agent against MCF-7 and HepG2 cell lines with a SI value of 100. On the other hand, compounds 8, 9, 10, 12, 13 and 14 inhibited DNA synthesis in MCF-7 cell line in a dose-dependent manner. Flow cytometric analyses clearly indicated that the compounds showed significant anticancer activity against MCF-7 cell line via the induction of apoptosis dose dependently. CONCLUSION: According to in vitro assays, compounds 8, 9, 10, 12, 13 and 14 stand out as promising candidates for further studies.

New Thiazoline-Tetralin Derivatives and Biological Activity Evaluation.

In this study, novel N'-(3-cyclohexyl/phenyl-4-(substituted phenyl)thiazole-2(3H)-ylidene)-2-[(5,6,7,8-tetrahydronaphthalen-2-yl)oxy]acetohydrazide (4a-4k) derivatives were synthesized and their anticancer potency were evaluated on human breast adenocarcinoma cell line (MCF-7), human lung carcinoma cell line (A549) and mouse embryoblast cell line (NIH/3T3) using the MTT method, DNA synthesis inhibition and flow cytometric analysis. Compound 4e bearing 4-methoxyphenyl moiety exhibited the highest antitumor efficiency against MCF-7 cell line with higher DNA synthesis inhibition and apoptotic cell percentages (ealy+late apoptotic cell). On the other hand, compounds 4f, 4g, and 4h bearing 4-bromo, 4-chloro and 4-florophenyl moieties, respectively caused excellent apoptosis levels against A549 cell line when treated with lower concentration even than cisplatin. Anticholinesterase activity of the compounds were also tested, compound 4h showed 49.92% inhibition of acetylcholinesterase (AChE).

Design and Synthesis of New 1,3,4-Oxadiazole - Benzothiazole and Hydrazone Derivatives as Promising Chemotherapeutic Agents.

Looking for new cytotoxic and antimicrobial agents with improved antitumor activity, a series of hydrazide and oxadiazole derivatives were designed and synthesized using 3-methoxyphenol as starting substance. Novel N'-(arylidene)-2-(3-methoxyphenoxy)acetohydrazide derivatives (4a-f)/1-(4-substitutedphenyl)-2-[(5-[(3-methoxyphenoxy)methyl]-1,3,4-oxadiazol-2-yl)thio]ethan-1-one derivatives (6a-f)/N-(6-substitutedbenzothiazol-2-yl)-2-[(5-[(3-methoxyphenoxy)methyl]-1,3,4-oxadiazol-2-yl)thio]acetamide derivatives (7a-e) were obtained and evaluated for their in vitro antimicrobial activity against various gram-positive, gram-negative bacteria and fungi. The antimicrobial activity potential of the compounds against gram-negative bacteria was found to have higher compared to the potential against gram-positive bacteria. Also, compounds were screened for their antiproliferative activity against 2 selected human tumor cell lines, A549 lung, MCF7 breast cancer cell line and mouse embryo fibroblast cell line, NIH/3T3 as healthy cell line. Among the compounds evaluated, compound 7c bearing 1,3,4-oxadiazole ring and 6-methoxy benzothiazole moiety exhibited the highest inhibitory activity against A549 and MCF-7 tumor cell lines in contrary to NIH/3T3 cell line, as desired.

New Adamantyl Chalcones: Synthesis, Antimicrobial and Anticancer Activities.

BACKGROUND: A new variety of adamantyl chalcones (2, 3a-o) were efficiently prepared by Claisen-Schmidt reaction of 4-adamantyl acetophenone 2 with a serie of aromatic aldehydes in good yields. Their structures were confirmed by spectroscopic data, and the relative configuration of 3d was confirmed by X-ray crystallography. All synthesized chalcones were tested against a panel of Grampositive and Gram-negative bacteria and pathogenic fungus and displayed strong antibacterial activity against Enterococcus faecali 29212, Pseudomonas aeruginosa ATCC27853, Escherichia coli and interesting antifungal activity against Candida glabrata ATCC 90030. RESULT: The effect of these compounds was also tested in vitro as antitumor on Miapaca2 cells. Compounds also showed anticancer activity against human pancreas cancer cell MiaPaca2.

Synthesis and evaluation of bis-thiazole derivatives as new anticancer agents.

New bis-thiazole derivatives (1-10) were synthesized via the ring closure of 1,1'-(3,3'-dimethoxybiphenyl-4,4'-diyl)bis(thiourea) with phenacyl bromides and evaluated for their cytotoxic effects on A549 human lung adenocarcinoma, C6 rat glioma, 5RP7 H-ras oncogene transformed rat embryonic fibroblast and NIH/3T3 mouse embryonic fibroblast cell lines using MTT assay. DNA synthesis inhibitory effects of these compounds were investigated. Each derivative was also evaluated for its ability to inhibit AChE and BuChE using a modification of Ellman's spectrophotometric method. Among these compounds, 3,3'-dimethoxy-N(4),N(4)'-bis(4-(4-bromophenyl)thiazol-2-yl)-[1,1'-biphenyl]-4,4'-diamine (5) can be identified as the most promising anticancer agent due to its notable inhibitory effects on A549 and C6 cell lines and low toxicity to NIH/3T3 cell lines. Compound 5 exhibited anticancer activity against A549 and C6 cell lines with IC50 values of 37.3 ± 6.8 µg/mL and 11.3 ± 1.2 µg/mL, whereas mitoxantrone showed anticancer activity against A549 and C6 cell lines with IC50 values of 15.7 ± 4.0 µg/mL and 11.0 ± 1.7 µg/mL, respectively. Furthermore, compound 5 showed DNA synthesis inhibitory activity against A549 cell line.

A novel series of thiazolyl-pyrazoline derivatives: synthesis and evaluation of antifungal activity, cytotoxicity and genotoxicity.

In the current work, new thiazolyl-pyrazoline derivatives (1-22) were synthesized and evaluated for their antifungal effects against pathogenic yeasts and molds using a broth microdilution assay. Ames assay was carried out to determine the genotoxicity of the most effective antifungal derivatives. The cytotoxicity of the compounds (1-22) was also investigated against A549 human lung adenocarcinoma and NIH/3T3 mouse embryonic fibroblast cells. Among these derivatives, 2-[5-(4-fluorophenyl)-3-(5-methylthiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl]-4-(4-methylsulfonylphenyl)thiazole (18) can be identified as the most promising anticandidal derivative due to its notable inhibitory effect on Candida zeylanoides with a MIC value of 250 µg/mL when compared with ketoconazole (MIC = 250 µg/mL), low cytotoxicity against NIH/3T3 cells and non-mutagenic effect. On the other hand, 2-[5-(4-fluorophenyl)-3-(5-chlorothiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl]-4-(4-bromophenyl)thiazole (4) can be considered as the most promising anticancer agent against A549 cancer cells owing to its notable inhibitory effect on A549 cells with an IC50 value of 62.5 µg/mL when compared with cisplatin (IC50 = 45.88 µg/mL) and low cytotoxicity against NIH/3T3 cells.

Synthesis and in vitro evaluation of new nitro-substituted thiazolyl hydrazone derivatives as anticandidal and anticancer agents.

Fourteen new thiazolyl hydrazone derivatives were synthesized and evaluated for their anticandidal activity using a broth microdilution assay. Among the synthesized compounds, 2-[2-((5-(4-chloro-2-nitrophenyl)furan-2-yl)methylene)hydrazinyl]-4-(4-fluorophenyl)thiazole and 2-[2-((5-(4-chloro-2-nitrophenyl)furan-2-yl)methylene) hydrazinyl]-4-(4-methoxyphenyl)thiazole were found to be the most effective antifungal compounds against Candida utilis, with a MIC value of 250 µg/mL, when compared with fluconazole (MIC=2 µg/mL). Additionally, the synthesized compounds were evaluated for their in vitro cytotoxic effects on the MCF-7 and NIH/3T3 cell lines. As a result, 2-[2-((5-(4-chloro-2-nitrophenyl)furan-2-yl)methylene)hydrazinyl]-4-(4-chlorophenyl)thiazole was identified as the most promising anticancer compound against MCF-7 cancer cells due to its inhibitory effects (IC50=125 µg/mL) and relatively low toxicity towards the NIH/3T3 cell line (IC50>500 µg/mL).

Synthesis of 1-acetyl-3-(2-thienyl)-5-aryl-2-pyrazoline derivatives and evaluation of their anticancer activity.

In the present study, 1-acetyl-3-(2-thienyl)-5-aryl-2-pyrazoline derivatives (1-6) were synthesized via the ring closure reaction of 1-(2-thienyl)-3-aryl-2-propen-1-ones with hydrazine hydrate in acetic acid. The chemical structures of the compounds were elucidated by IR, (1)H-NMR, (13)C-NMR and mass spectral data and elemental analyses. MTT assay, analysis of DNA synthesis and caspase-3 activation assay were carried out to determine anticancer effects of the compounds on A549 and C6 cancer cell lines. They exhibited dose-dependent anticancer activity against A549 and C6 cancer cell lines. Anticancer activity screening results revealed that compounds 1, 2 and 4 were the most potent derivatives among these compounds. But anticancer effects of these compounds may result from different death mechanisms in A549 and C6 cell lines.

Synthesis and biological evaluation of some hydrazone derivatives as new anticandidal and anticancer agents.

New hydrazone derivatives were synthesized via the nucleophilic addition-elimination reaction of 2-[(1-methyl-1H-tetrazol-5-yl)thio)]acetohydrazide with aromatic aldehydes/ketones. The compounds were tested in vitro against various Candida species and compared with ketoconazole. Genotoxicity of the most effective anticandidal compounds was evaluated by umuC and Ames assays. All compounds were also investigated for their cytotoxic effects on NIH3T3 and A549 cell lines. Compound 8 was the most effective antifungal derivative against C. albicans (ATCC-90028) with a MIC value of 0.05 mg/mL. Compound 5 can be identified as the most promising anticancer agent against A549 cancer cell lines due to its inhibitory effect on A549 cell lines and low toxicity to NIH3T3 cells.