Synthesis,biological evaluation,and molecular docking studies of novel 1,3,4-oxadiazole derivatives possessing benzotriazole moiety as FAK inhibitors with anticancer activity

1,3,4-Oxadiazole derivatives have drawn continuing interest over the years because of their varied biological activities. In order to search for novel anticancer agents, we designed and synthesized a series of new 1,3,4-oxadiazole derivatives containing benzotriazole moiety as potential focal adhesion kinase (FAK) inhibitors. All the synthesized compounds were firstly reported. Among the compounds, compound 4 shows the most potent inhibitory activity against MCF-7 and HT29 cell lines with IC₅₀ values of 5.68 μg/ml and 10.21 μg/ml, respectively. Besides, all the compounds were assayed for FAK inhibitory activity using the TRAP–PCR–ELISA assay. The results showed compound 4 exhibited the most potent FAK inhibitory activity with IC₅₀ values of 1.2 ± 0.3 μM. Docking simulation by positioning compound 4 into the FAK structure active site was performed to explore the possible binding mode. Apoptosis which was analyzed by flow cytometry, demonstrated that compound 4 induced apoptosis against MCF-7 cells. Therefore, compound 4 may be a potential anticancer agent against MCF-7 cancer cell.     

Synthesis,biological evaluation and molecular modeling of 1,3,4-thiadiazol-2-amide derivatives as novel antitubulin agents

A series of 1,3,4-thiadiazol-2-amide derivatives (6a–w) were designed and synthesized as potential inhibitors of tubulin polymerization and as anticancer agents. The in vitro anticancer activities of these compounds were evaluated against three cancer cell lines by the MTT method. Among all the designed compounds, compound 6f exhibited the most potent anticancer activity against A549, MCF-7 and HepG2 cancer cell lines with IC₅₀ values of 0.03 μM, 0.06 μM and 0.05 μM, respectively. Compound 6f also exhibited significant tubulin polymerization inhibitory activity (IC₅₀ = 1.73 μM), which was superior to the positive control. The obtained results, along with a 3D-QSAR study and molecular docking that were used for investigating the probable binding mode, could provide an important basis for further optimization of compound 6f as a novel anticancer agent.     

Novel 3-arylfuran-2(5H)-one-fluoroquinolone hybrid: Design,synthesis and evaluation as antibacterial agent

3-Arylfuran-2(5H)-one, a novel antibacterial pharmacophore targeting tyrosyl-tRNA synthetase (TyrRS), was hybridized with the clinically used fluoroquinolones to give a series of novel multi-target antimicrobial agents. Thus, twenty seven 3-arylfuran-2(5H)-one-fluoroquinolone hybrids were synthesized and evaluated for their antimicrobial activities. Some of the hybrids exhibited merits from both parents, displaying a broad spectrum of activity against resistant strains including both Gram-negative and Gram-positive bacteria. The most potent compound (11) in antibacterial assay shows MIC₅₀ of 0.11 μg/mL against Multiple drug resistant Escherichia coli, being about 51-fold more potent than ciprofloxacin. The enzyme assays reveal that 11 is a potent multi-target inhibitor with IC₅₀ of 1.15 ± 0.07 μM against DNA gyrase and 0.12 ± 0.04 μM against TyrRS, respectively. Its excellent inhibitory activities against isolated enzymes and intact cells strongly suggest that 11 deserves to further research as a novel antibiotic.     

Substituted thieno[2,3-b]thiophenes and related congeners: Synthesis, β-glucuronidase inhibition activity,crystal structure,and POM analyses

A series of 15 novel compounds incorporating the thieno[2,3-b]thiophene moiety were synthesized. The chemical structures of these compounds were deduced from elemental analyses, ¹H NMR, ¹³C NMR, and ESI-mass spectral data. The enzyme inhibition potential of these compounds was evaluated, in vitro, against β-glucuronidase, xanthine oxidase, and α-chymotrypsin enzymes. The cytotoxicity was evaluated by a cell viability assay utilizing the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) dye. Among the compounds tested, compound 3 was the most potent β-glucuronidase inhibitor with an IC₅₀ value of 0.9 ± 0.0138 μM; it was much more active than the standard, d-saccharic acid 1,4-lactone (IC₅₀ = 45.75 ± 2.16 μM). Compound 12, on the other hand, was the most potent as a xanthine oxidase inhibitor with an IC₅₀ of 14.4 ± 1.2 μM. With the characterization of their mechanism of action and with further testing, these compounds could be useful candidates as anticancer drugs. In addition, the newly synthesized compounds were subjected to POM analyses to get insights about their degree of their toxicity.     

Design and synthesis of novel 2-methyl-4,5-substitutedbenzo[f]-3,3a,4,5-tetrahydro-pyrazolo[1,5-d][1,4]oxazepin-8(7H)-one derivatives as telomerase inhibitors

Eight novel 4,5-tetrahydropyrazolo[1,5-d][1,4]oxazepine derivatives have been synthesized and purified to be screened for anticancer activity. By a modified TRAP assay, some titled compounds were tested against telomerase, and compound 4a showed the most potent inhibitory activity with IC₅₀ value at 0.78 ± 0.22 μM. Western blot assays showed that compounds 4a and 4b could inhibit expression of Cyclin D1, TERT, phospho-AKT and PI3K/AKT pathway.     

Synthesis,molecular modeling and biological evaluation of N-benzylidene-2-((5-(pyridin-4-yl)-1,3,4-oxadiazol-2-yl)thio)acetohydrazide derivatives as potential anticancer agents

A series of new 1,3,4-oxadiazole derivatives (6a–6x) containing pyridine and acylhydrazone moieties were synthesized and developed as potential telomerase inhibitors. The bioassay tests demonstrated that compounds 6n, 6o, 6q, 6s and 6t exhibited significant broad-spectrum anticancer activity with IC₅₀ range from 0.76 to 9.59 μM against the four cancer cell lines (HEPG2, MCF7, SW1116 and BGC823). Moreover, all the title compounds were assayed for telomerase inhibition using the TRAP-PCR-ELISA assay. Compound 6s showed the highest anticancer activity with IC₅₀ of 0.76–1.54 μM against the tested cancer cell lines and exhibited the most potent telomerase inhibitory activity with IC₅₀ of 1.18 ± 0.14 μM. The docking simulation was carried out to investigate a possible binding mode of compound 6s into the active site of telomerase (pdb. 3DU6) while the QSAR model was built to check the previous work as well as to introduce new directions.     

Design,synthesis, and preliminary studies of the activity of novel derivatives of N-cinnamoyl-l-aspartic acid as inhibitors of aminopeptidase N/CD13

A series of novel derivatives of N-cinnamoyl-l-aspartic acid were designed, synthesized, and assayed for their inhibitory activities against aminopeptidase N. The preliminary biological assay showed that compound 8c has the most potent inhibitory activity against APN with an IC₅₀ of 11.1 ± 0.9 μM, this could be used as the lead compound in future research on anticancer agents.     

Synthesis and identification of α-cyano bis(indolyl)chalcones as novel anticancer agents

Microwave-assisted synthesis of 23 α-cyano bis(indolyl)chalcones (6a–w) and their in vitro anticancer activity against three human cancer cell lines have been discussed. Among the synthesized chalcones, compound 6n was found to be the most potent and selective against A549 lung cancer cell line (IC₅₀ = 0.8 μM). In a preliminary mechanism of action studies some α-cyano bis(indolyl)chalcones were found to enhance tubulin polymerization suggesting these compounds could act as microtubule stabilizing agents.     

Facile synthesis of novel substituted aryl-thiazole (SAT) analogs via one-pot multi-component reaction as potent cytotoxic agents against cancer cell lines

In this study, twenty-five (25) substituted aryl thiazoles (SAT) 1–25 were synthesized, and their in vitro cytotoxicity was evaluated against four cancer cell lines, MCF-7 (ER^+ve breast), MDA-MB-231 (ER^−ve breast), HCT116 (colorectal) and HeLa (cervical). The activity was compared with the standard anticancer drug doxorubicin (IC₅₀ = 1.56 ± 0.05 μM). Among them, compounds 1, 4–8, and 19 were found to be toxic to all four cancer cell lines (IC₅₀ values 5.37 ± 0.56–46.72 ± 1.80 μM). Compound 20 was selectively active against MCF7 breast cancer cells with IC₅₀ of 40.21 ± 4.15 μM, whereas compound 19 was active against MCF7 and HeLa cells with IC₅₀ of 46.72 ± 1.8, and 19.86 ± 0.11 μM, respectively. These results suggest that substituted aryl thiazoles 1 and 4 deserve to be further investigated in vivo as anticancer leads.     

Novel biphenyl bis-sulfonamides as acetyl and butyrylcholinesterase inhibitors: Synthesis,biological evaluation and molecular modeling studies

A series of new biphenyl bis-sulfonamide derivatives 2a–3p were synthesized in good to excellent yield (76–98%). The inhibitory potential of the synthesized compounds on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) was investigated. Most of the screened compounds showed modest in vitro inhibition for both AChE and BChE. Compared to the reference compound eserine (IC₅₀ 0.04 ± 0.0001 μM for AChE) and (IC₅₀ 0.85 ± 0.0001 μM for BChE), the IC₅₀ values of these compounds were ranged from 2.27 ± 0.01 to 123.11 ± 0.04 μM for AChE and 7.74 ± 0.07 to <400 μM for BuChE. Among the tested compounds, 3p was found to be the most potent against AChE (IC₅₀ 2.27 ± 0.01 μM), whereas 3g exhibited the highest inhibition for BChE (IC₅₀ 7.74 ± 0.07 μM). Structure–activity relationship (SAR) of these compounds was developed and elaborated with the help of molecular docking studies.     

Synthesis,molecular modeling and biological evaluation of dithiocarbamates as novel antitubulin agents

A series of novel dithiocarbamate compounds with the chalcone scaffold have been designed and synthesized, and their biological activities were also evaluated as potential antiproliferation and antitubulin polymerization inhibitors. Compound 2n showed the most potent biological activity in vitro, which inhibited the growth of MCF-7 cells with IC₅₀ of 0.04 ± 0.01 μM and the polymerization of tubulin with IC₅₀ of 6.8 ± 0.6 μM. To understand the tubulin–inhibitor interaction and the selectivity of the most active compound towards tubulin, molecular modeling studies were performed to dock compound 2n into the colchicine binding site, which suggested probable inhibition mechanism.     

Pyridine sulfonamide as a small key organic molecule for the potential treatment of type-II diabetes mellitus and Alzheimer’s disease: In vitro studies against yeast α-glucosidase,acetylcholinesterase and butyrylcholinesterase

This paper presents the efficient high yield synthesis of novel pyridine 2,4,6-tricarbohydrazide derivatives (4a–4i) along with their α-glucosidase, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition activities. The enzymes inhibition results showed the potential of synthesized compounds in controlling both type-II diabetes mellitus and Alzheimer’s disease. In vitro biological investigations revealed that most of compounds were more active against yeast α-glucosidase than the reference compound acarbose (IC₅₀ 38.25 ± 0.12 μM). Among the tested series the compound 4c bearing 4-flouro benzyl group was noted to be the most active (IC₅₀ 25.6 ± 0.2 μM) against α-glucosidase, and it displayed weak inhibition activities against AChE and BChE. Compound 4a exhibited the most desired results against all three enzymes, as it was significantly active against all the three enzymes; α-glucosidase (IC₅₀ 32.2 ± 0.3 μM), AChE (IC₅₀ 50.2 ± 0.8 μM) and BChE (IC₅₀ 43.8 ± 0.8 μM). Due to the most favorable activity of 4a against the tested enzymes, for molecular modeling studies this compound was selected to investigate its pattern of interaction with α-glucosidase and AChE targets.     

Design,synthesis and biological evaluation of novel tripeptidyl epoxyketone derivatives constructed from β-amino acid as proteasome inhibitors

A series of novel tripeptidyl epoxyketone derivatives constructed from β-amino acid were designed, synthesized and evaluated as proteasome inhibitors. All target compounds were tested for their proteasome inhibitory activities and selected compounds were tested for their anti-proliferation activities against two multiple myeloma (MM) cell lines RPMI 8226 and NCI-H929. Among them, eleven compounds exhibited proteasome inhibitory rates of more than 50% at the concentration of 1 μg/mL and nine compounds showed anti-proliferation activities with IC₅₀ values at low micromolar level. Compound 20h displayed the most potent proteasome inhibitory activities (IC₅₀: 0.11 ± 0.01 μM) and anti-proliferation activities with IC₅₀ values at 0.23 ± 0.01 and 0.17 ± 0.02 μM against two tested cell lines. Additionally, the poly-ubiquitin accumulation in the western blot analysis supported that proteasome inhibition in a cellular system was induced by compound 20h. All these experimental results confirmed that β-amino acid can be introduced as a building block for the development of proteasome inhibitors.     

Design,synthesis and molecular modeling of biquinoline–pyridine hybrids as a new class of potential EGFR and HER-2 kinase inhibitors

A new series of biquinoline–pyridine hybrids were designed and synthesized by a base-catalyzed cyclocondensation through one-pot multicomponent reaction. All compounds were tested for in vitro anticancer activities against two cancer cell lines A549 (adenocarcinomic human alveolar basal epithelial) and Hep G2 (liver cancer). Enzyme inhibitory activities of all compounds were carried out against EGFR and HER-2 kinase. Of the compounds studied, majority of the compounds showed effective anticancer activity against used cancer cell lines. Compound 9i (IC₅₀ = 0.09 μM) against EGFR and (IC₅₀ = 0.2 μM) against HER-2 kinase displayed the most potent inhibitory activity as compared to other member of the series. In the molecular modelling study, compound 9i was bound in to the active pocket of EGFR with four hydrogen bonds and two π–cation interactions having minimum binding energy ΔG_b = −54.4 kcal/mol.     

Chalcones,inhibitors for topoisomerase I and cathepsin B and L,as potential anti-cancer agents

In order to diversify the pharmacological activity of chalcones and extend the scaffold of topoisomerase and cathepsins B and L inhibitors, we have designed and synthesized total 18 chalcone compounds and tested their biological activity. In the topoisomerase inhibition test, most analogues in group III and IV except compound 11 exhibited more efficient topoisomerase I inhibitory activity than camptothecin at 20 μM. Compounds 15, 16 and 18 in group IV showed significant cathepsin B and L inhibitory activity. Among the compounds, compound 15 was most active with IC₅₀ values of 1.81 ± 0.05 μM on cathepsin B and 3.15 ± 0.07 μM on cathepsin L, respectively. Compound 15 also showed most potent cytotoxic activity against T47D and SNU638 cells with IC₅₀ values of 1.37 ± 0.05 μM and 0.62 ± 0.01 μM, respectively. Overall, although more compounds should be tested and analyzed for clear SAR against topoisomerase I and cathepsin B and L, compound 15 showed consistent inhibitory ability on the tested assays, which can implicate the cytotoxic activity of compound 15 on topoisomerase I and cathepsin B and L inhibitory pathways.     

Active compounds from a diverse library of triazolothiadiazole and triazolothiadiazine scaffolds: Synthesis,crystal structure determination,cytotoxicity, cholinesterase inhibitory activity,and binding mode analysis

In an effort to identify novel cholinesterase candidates for the treatment of Alzheimer’s disease (AD), a diverse array of potentially bioactive compounds including triazolothiadiazoles (4a–h and 5a–f) and triazolothiadiazines (6a–h) was obtained in good yields through the cyclocondensation reaction of 4-amino-5-(pyridin-3-yl)-4H-1,2,4-triazole-3-thiol (3) with various substituted aryl/heteroaryl/aryloxy acids and phenacyl bromides, respectively. The structures of newly prepared compounds were confirmed by IR, ¹H and ¹³C NMR spectroscopy and, in case of 4a, by single crystal X-ray diffraction analysis. The purity of the synthesized compounds was ascertained by elemental analysis. The newly synthesized conjugated heterocycles were screened for cholinesterase inhibitory activity against electric eel acetylcholinesterase (EeAChE) and horse serum butyrylcholinesterase (hBChE). Among the evaluated hybrids, several compounds were identified as potent inhibitors. Compounds 5b and 5d were most active with an IC₅₀ value of 3.09 ± 0.154 and 11.3 ± 0.267 μM, respectively, against acetylcholinesterase, whereas 5b, 6a and 6g were most potent against butyrylcholinesterase, with an IC₅₀ of 0.585 ± 0.154, 0.781 ± 0.213, and 1.09 ± 0.156 μM, respectively, compared to neostigmine and donepezil as standard drugs. The synthesized heteroaromatic compounds were also tested for their cytotoxic potential against lung carcinoma (H157) and vero cell lines. Among them, compound 6h exhibited highest antiproliferative activity against H157 cell lines, with IC₅₀ value of 0.96 ± 0.43 μM at 1 mM concentration as compared to vincristine (IC₅₀ = 1.03 ± 0.04 μM), standard drug used in this study.     

New nemadectin congeners with acaricidal and nematocidal activity from Streptomyces microflavus neau3 Y-3

Two nemadectin congeners 1 and 2 were isolated from the fermentation broth of a mutant strain (Y-3) of Streptomyces microflavus neau3. Their structures were determined on the basis of extensive spectroscopic analysis and comparison with data from the literature. Compound 2 possessed a 5-membered ring lactone that is unprecedented among known milbemycins and avermectins. Both compounds 1 and 2 exhibited potent acaricidal activity and nematocidal activity. Especially, compound 2 demonstrated impressive acaricidal activity against adult mites with an IC₅₀ of 2.3 ± 0.9 μg/mL and mite eggs with an IC₅₀ of 17.5 ± 2.1 μg/mL and nematocidal activity against Caenorhabditis elegans with an IC₅₀ of 0.7 ± 0.2 μg/mL, which are higher than those of nemadectin and the known commercial acaricide and nematocide milbemycin A3/A4.     

Design,synthesis, and docking studies of phenylpicolinamide derivatives bearing 1H-pyrrolo[2,3-b]pyridine moiety as c-Met inhibitors

Four series of phenylpicolinamide derivatives bearing 1H-pyrrolo[2,3-b]pyridine moiety (12a–e, 13a–f, 14a–f and 15a–i) were designed, synthesized and evaluated for the IC₅₀ values against three cancer cell lines (A549, PC-3 and MCF-7) and c-Met kinase. Five selected compounds (13b, 15b, 15d, 15e and 15f) were further evaluated for the activity against HepG2 and Hela cell lines. Eighteen of the compounds showed excellent cytotoxicity activity and selectivity with the IC₅₀ valuables in single-digit μM to nanomole range. Seven of them are equal to more active than positive control Foretinib against one or more cell lines. The most promising compound 15f showed superior activity to Foretinib, with the IC₅₀ values of 1.04 ± 0.11 μM, 0.02 ± 0.01 μM and 9.11 ± 0.55 μM against A549, PC-3 and MCF-7 cell lines, which were 0.62 to 19.5 times more active than Foretinib (IC₅₀ values: 0.64 ± 0.26 μM, 0.39 ± 0.11 μM, 9.47 ± 0.22 μM), respectively. Structure–activity relationships (SARs) and docking studies indicated that replacement of quinoline nucleus of the previous active compounds with 1H-pyrrolo[2,3-b]pyridine moiety maintained even improved the potent cytotoxic activity. The results suggested that the introduction of fluoro atoms to the aminophenoxy part of target compounds or the phenyl group of pyrimidine substituted on C-4 position was benefit for the activity.     

Design,synthesis and anticancer activity of novel nopinone-based thiosemicarbazone derivatives

A series of new nopinone-based thiosemicarbazone derivatives were designed and synthesized as potent anticancer agents. All these compounds were identified by ¹H NMR, ¹³C NMR, HR-MS spectra analyses. In the in vitro anticancer activity, most derivatives showed considerable cytotoxic activity against three human cancer cell lines (MDA-MB-231, SMMC-7721 and Hela). Among them, compound 4i exhibited most potent antitumor activity against three cancer cell lines with the IC₅₀ values of 2.79 ± 0.38, 2.64 ± 0.17 and 3.64 ± 0.13 μM, respectively. Furthermore, the cell cycle analysis indicated that compound 4i caused cell cycle arrest of MDA-MB-231 cells at G2/M phase. The Annexin V-FITC/7-AAD dual staining assay also revealed that compound 4i induced the early apoptosis of MDA-MB-231 cells.     

Design,synthesis, and docking studies of afatinib analogs bearing cinnamamide moiety as potent EGFR inhibitors

Two series of afatinib derivatives bearing cinnamamide moiety (10a–n and 11a–h) were designed, synthesized and evaluated for the IC₅₀ values against four cancer cell lines (A549, PC-3, MCF-7 and Hela). Two selected compounds (10e, 10k) were further evaluated for the inhibitory activity against EGFR and VEGFR2/KDR kinases. Seven of the compounds showed excellent cytotoxicity activity and selectivity with the IC₅₀ values in single-digit μM to nanomole range. Three of them are equal to more active than positive control afatinib against one or more cell lines. The most promising compound 10k showed the best activity against A549, PC-3, MCF-7 and Hela cancer cell lines and EGFR kinase, with the IC₅₀ values of 0.07 ± 0.02 μM, 7.67 ± 0.97 μM, 4.65 ± 0.90 μM and 4.83 ± 1.28 μM, which were equal to more active than afatinib (0.05 ± 0.01 μM, 4.1 ± 2.47 μM, 5.83 ± 1.89 μM and 6.81 ± 1.77 μM), respectively. Activity of compounds 10e (IC₅₀ 9.1 nM) and 10k (IC₅₀ 3.6 nM) against EGFR kinase were equal to the reference compound afatinib (IC₅₀ 1.6 nM). Structure–activity relationships (SARs) and docking studies indicated that replacement of the aqueous solubility 4-(dimethylamino)but-2-enamide group by cinnamamide moiety didn’t decrease the antitumor activity. The results suggested that methoxy substitution had a significant impact on the activity and methoxy substituted on C-4 or C-2,3,4 position was benefit for the activity.