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, Synthesis and Biological Evaluation of Novel N-Pyridyl-Hydrazone Derivatives as Potential Monoamine Oxidase (MAO) Inhibitors.

A new series of N-pyridyl-hydrazone derivatives was synthesized by using a simple and efficient method. The final compounds obtained were screened for their inhibitory potency against monoamine oxidase (MAO) A and B. The newly synthesized compounds 2a-2n specifically inhibited monoamine oxidases, displaying notably low IC50 values. Compounds 2i and 2j, with a CF3 and OH group on the 4-position of the phenyl ring, respectively, showed considerable MAO-A and MAO-B inhibitory activities. Compounds 2k, 2l and 2n, with N-methylpyrrole, furan and pyridine moieties instead of the phenyl ring, were the most powerful and specific inhibitors of MAO-A, with IC50 values of 6.12 µM, 10.64 µM and 9.52 µM, respectively. Moreover, these active compounds were found to be non-cytotoxic to NIH/3T3 cells. This study supports future studies aimed at designing MAO inhibitors to obtain more viable medications for neurodegenerative disorders, such as Parkinson's disease.

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.

1,2,4-Triazole-3-thione Compounds as Inhibitors of Dizinc Metallo-ß-lactamases.

Metallo-ß-lactamases (MBLs) cause resistance of Gram-negative bacteria to ß-lactam antibiotics and are of serious concern, because they can inactivate the last-resort carbapenems and because MBL inhibitors of clinical value are still lacking. We previously identified the original binding mode of 4-amino-2,4-dihydro-5-(2-methylphenyl)-3H-1,2,4-triazole-3-thione (compound IIIA) within the dizinc active site of the L1 MBL. Herein we present the crystallographic structure of a complex of L1 with the corresponding non-amino compound IIIB (1,2-dihydro-5-(2-methylphenyl)-3H-1,2,4-triazole-3-thione). Unexpectedly, the binding mode of IIIB was similar but reverse to that of IIIA. The 3 D structures suggested that the triazole-thione scaffold was suitable to bind to the catalytic site of dizinc metalloenzymes. On the basis of these results, we synthesized 54 analogues of IIIA or IIIB. Nineteen showed IC50 values in the micromolar range toward at least one of five representative MBLs (i.e., L1, VIM-4, VIM-2, NDM-1, and IMP-1). Five of these exhibited a significant inhibition of at least four enzymes, including NDM-1, VIM-2, and IMP-1. Active compounds mainly featured either halogen or bulky bicyclic aryl substituents. Finally, some compounds were also tested on several microbial dinuclear zinc-dependent hydrolases belonging to the MBL-fold superfamily (i.e., endonucleases and glyoxalase II) to explore their activity toward structurally similar but functionally distinct enzymes. Whereas the bacterial tRNases were not inhibited, the best IC50 values toward plasmodial glyoxalase II were in the 10 µm range.

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.

Antimicrobial and Cytotoxic Evaluation of New Quinazoline Derivatives.

The synthesis of nine new quinazoline derivatives (2a-2i) and evaluation of their antimicrobial and cytotoxic activities were aims of the present work. For the synthesis of the compounds, 2-chloro-6,7-dimethoxyquinazolin-4-amine was used as the initial starting material. The intermediate product, 2-hydrazinyl-6,7- dimethoxyquinazolin-4-amine, was reacted with appropriate aromatic aldehydes to obtain 2-(2-benzylidenehydrazinyl)-6,7-dimethoxyquinazolin-4-amine derivatives as final compounds. The structures of the compounds were elucidated by (1)H- and (13)C-NMR, IR, and-MS analyses. The new pure compounds were evaluated for their potential antimicrobial and cytotoxic activities using in vitro microdilution and cell culture techniques, respectively. The compounds 2e and 2f may be promising candidates for the treatment of fungal infections with their activity and cytotoxicity.

Synthesis and evaluation of new 1,5-diaryl-3-[4-(methyl-sulfonyl)phenyl]-4,5-dihydro-1H-pyrazole derivatives as potential antidepressant agents.

In an effort to develop potent antidepressant agents, new pyrazoline derivatives 2a-s were synthesized and evaluated for their antidepressant-like activity by tail suspension test (TST) and modified forced swimming test (MFST). The effects of the compounds on spontaneous locomotor activity were also investigated using an activity cage apparatus. Among these derivatives, compounds 2b, 2d, 2f, 2o, and 2r decreased both horizontal and vertical activity number of the mice. On the other hand, compounds 2a, 2h, 2j, 2k, 2l, 2m, and 2n, which did not induce any significant change in the locomotor activity, significantly shortened the immobility time of mice in TST and MFST, representing the presence of the antidepressant-like effect. Additionally, the same compounds increased the swimming time of mice in MFST without any change in climbing duration, similar to the reference drug fluoxetine (10 mg/kg). In the light of previous papers examining the effects of pyrazolines on central nervous system, this study, once more, pointed out remarkable antidepressant activity potential of pyrazoline derivatives.

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 evaluation of new indole-based chalcones as potential antiinflammatory agents.

In the present work, new indole-based chalcone derivatives were obtained via the reaction of 5-substituted-1H-indole-3-carboxaldehydes/1-methylindole-3-carboxaldehyde with appropriate acetophenones. The synthesized compounds were investigated for their in vitro COX-1 and COX-2 inhibitory activity. The most effective COX inhibitors were also evaluated for their in vivo antiinflammatory and antioxidant activities in LPS induced sepsis model. Furthermore, the CCK-8 assay was carried out to determine cytotoxic effects of all compounds against NIH/3T3 mouse embryonic fibroblast cells. 3-(5-Bromo-1H-indol-3-yl)-1-(4-cyanophenyl)prop-2-en-1-one (6) can be considered as a non-selective COX inhibitor (COX-1 IC50 = 8.1 ± 0.2 µg/mL, COX-2 IC50 = 9.5 ± 0.8 µg/mL), whereas 3-(5-methoxy-1H-indol-3-yl)-1-(4-(methylsulfonyl)phenyl)prop-2-en-1-one (1) inhibited only COX-1 (IC50 = 8.6 ± 0.1 µg/mL). According to in vivo studies, these compounds also displayed antiinflammatory and antioxidant activities.

Synthesis and evaluation of new thiadiazole derivatives as potential inhibitors of human carbonic anhydrase isozymes (hCA-I and hCA-II).

2-[[5-(2,4-Difluoro/dichlorophenylamino)-1,3,4-thiadiazol-2-yl]thio] acetophenone derivatives (3a--s) were designed as human carbonic anhydrase isozymes (hCA-I and hCA-II) inhibitors and synthesized. hCA-I and hCA-II were purified from erythrocyte cells by the affinity chromatography. The inhibitory effects of 18 newly synthesized acetophenones on hydratase activity of these isoenzymes were studied in vitro. The average IC50 values of the new compounds for hydratase activity ranged from 0.033 to 0.14 µM for hCA-I and from 0.030 to 0.11 µM for hCA-II. Among the newly synthesized compounds, 2-[[5-(2,4-dichlorophenylamino)-1,3,4-thiadiazol-2-yl]thio]-4'-bromoacetophenone (3n) can be considered as a promising hCA-II inhibitor owing to its selective and potent inhibitory effect on hCA-II.

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, anticandidal activity and cytotoxicity of some tetrazole derivatives.

In this study, 14 different 2-[(1-methyl-1H-tetrazole-5-yl)thio]-1-(phenyl)ethanone derivatives (1-14) were synthesized. The structures of the obtained compounds were elucidated using IR, (1)H-NMR, (13)C-NMR and FAB(+)-MS spectral data and elemental analyses results. The compounds were screened for their anticandidal activity using the microbroth dilution method and for their cytotoxic effects using the MTT assay against NIH/3T3 cells. Some of the compounds were found to be potent anticandidal agents with weak cytotoxicities.

Synthesis and biological evaluation of pyrazoline derivatives bearing an indole moiety as new antimicrobial agents.

1-(p-Methylphenyl)-3,5-diaryl-2-pyrazoline derivatives (2a-f) were synthesized via the treatment of 1-(1H-indol-3-yl)-3-aryl-2-propen-1-ones (1a-f) with p-methylphenylhydrazine hydrochloride in hot acetic acid. The structures of these compounds were elucidated by IR, ¹H NMR, and mass spectral data and elemental analysis. These compounds were investigated for their antimicrobial activity. Brine-Shrimp lethality assay was carried out to determine the toxicity of the compounds. Compound 2e, which is the pyrazoline derivative bearing the 2,5-dichlorophenyl moiety, can be identified as the most promising agent against Klebsiella pneumoniae (ATCC 13883) and Candida glabrata (ATCC 36583) due to its inhibitory effects on K. pneumoniae and C. glabrata with a MIC value of 100 µg/mL as a non-toxic agent (LC50 > 1000 µg/mL).

Synthesis and anti-Candida activity of novel 2-hydrazino-1,3-thiazole derivatives.

Eighteen new hydrazino-1,3-thiazole derivatives were evaluated against 8 strains of multi-resistant Candida spp. Introduction of an indolyl moiety linked to the hydrazone function enhanced the in vitro anti-Candida activity, with an activity spectrum towards Candida albicans strains. Introduction of a (S)-2-aminoethyl chain on the thiazole nucleus largely enhanced the in vitro antifungal activity, with a selectivity oriented towards non-C. albicans species.

Synthesis and biological evaluation of some pyrazoline derivatives bearing a dithiocarbamate moiety as new cholinesterase inhibitors.

In the present study, new pyrazoline derivatives were synthesized via the reaction of 1-(chloroacetyl)-3-(2-furyl)-5-aryl-2-pyrazolines with sodium salts of N,N-disubstituted dithiocarbamic acids. Each derivative was evaluated for its ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) using a modification of Ellman's spectrophotometric method. The compounds were also investigated for their cytotoxic properties using the MTT assay. The most potent AChE inhibitor was found as compound 7 followed by compounds 27 and 17, when compared with eserine. Compounds effective on AChE carry the 2-dimethylaminoethyl moiety, which resembles the trimethylammonium group and the ethylene bridge of acetylcholine. Among all compounds, compound 7 bearing 2-dimethylaminoethyl and 3,4-methylenedioxyphenyl moieties was also found to be the most effective inhibitor of BuChE. The MTT assay indicated that the effective concentration of compound 7 was lower than its cytotoxic concentration.

Synthesis and biological evaluation of some thiazole derivatives as new cholinesterase inhibitors.

In the present study, some thiazole derivatives were synthesized via the ring closure reaction of 1-[2-(2-oxobenzo[d]thiazol-3(2H)-yl)acetyl]thiosemicarbazide with various phenacyl bromides. The chemical structures of the compounds were elucidated by (1)H NMR, (13)C NMR and mass spectral data and elemental analyses. Each derivative was evaluated for its ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) using a modification of Ellman's spectrophotometric method. The compounds were also investigated for their cytotoxic properties using MTT assay. The most potent AChE inhibitor was found as compound 4e (IC(50) = 25.5 ± 2.12 µg/mL) followed by compounds 4i (IC(50) = 38.50 ± 2.12 µg/mL), 4c (IC(50) = 58.42 ± 3.14 µg/mL) and 4g (IC(50) = 68 ± 2.12 µg/mL) when compared with eserine (IC(50) = 0.025 ± 0.01 µg/mL). Effective compounds on AChE exhibited weak inhibition on BuChE (IC(50) > 80 µg/mL). MTT assay indicated that the cytotoxic dose (IC(50) = 71.67 ± 7.63 µg/mL) of compound 4e was higher than its effective dose.

Synthesis and antifungal activity of new hydrazide derivatives.

In this study, nine new hydrazide derivatives were synthesized. The reaction of 2-[(5,6,7,8-tetrahydronaphthalen-2-yl)oxy]acetohydrazide with various benzaldehydes or acetophenones resulted in N'-substituted-2-[(5,6,7,8-tetrahydronaphthalen-2-yl)oxy]acetohydrazide derivatives. The structure elucidation of the synthesized and purified compounds was performed by using IR, (1)H-NMR, and FAB(+)-MS spectral data and elemental analyses, respectively. Furthermore, the compounds were screened and evaluated for their antifungal activity against a panel of different human pathogenic Candida strains such as C. albicans, C. glabrata, C. utilis, C. tropicalis, C. krusei, C. zeylanoides and C. parapsilosis using agar diffusion and broth microdilution assays, respectively. Some of the tested compounds showed comparable antifungal activity (MIC = 0.0156->2 mg/mL) with ketoconazole.