Compounds 4g Research Articles

Potent Alkaline Phosphatase Inhibitors, Pyrazolo-Oxothiazolidines: Synthesis, Biological Evaluation, Molecular Docking, and Kinetic Studies.

To develop new alkaline phosphatase inhibitors (ALP), a series of pyrazolo-oxothiazolidine derivatives were synthesized and biologically assessed, and the results showed that all of the synthesized compounds significantly inhibited ALP. Specifically, compound 7g displayed the strongest inhibitory activity (IC50 = 0.045 ± 0.004 μM), which is 116-fold more active than monopotassium phosphate (IC50 = 5.242 ± 0.472 μM) as a standard reference. The most potent compound among the series (7g) was checked for its mode of binding with the enzyme and shown as non-competitively binding with the target enzyme. The antioxidant activity of these compounds was examined to investigate the radical scavenging effect. Moreover, the MTT assay method was performed to evaluate their toxic effects on the viability of MG-63 human osteosarcoma cells, and all compounds have no toxic effect on the cells at 4 μM. Computational research was also conducted to examine the binding affinity of the ligands with alkaline phosphatase, and the results revealed that all compounds showed good binding energy values within the active site of the target. Therefore, these novel pyrazolo-oxothiazolidine derivatives might be employed as promising pharmacophores for potent and selective alkaline phosphatase inhibitors.

Discovery of novel analogs of KHS101 as transforming acidic coiled coil containing protein 3 (TACC3) inhibitors for the treatment of glioblastoma

Transforming acidic coiled coil containing protein 3 (TACC3) is emerging as an attractive anticancer target in recent years, however, few TACC3 small-molecular inhibitors have been reported up to now. In this study, fifteen compounds were designed and synthesized based on the lead compound KHS101 to find more potent TACC3 inhibitors. Among them, the most potent compound 7g exhibited about 10-folds more potent antiproliferative activities than KHS101 in various cancer cell lines. Two different protein-drug binding assays including DARTS, and CETSA revealed TACC3 as a biologically relevant target of compound 7g. In addition, compound 7g induced cell cycle arrest at the G2/M phase and induced cell apoptosis. Furthermore, compound 7g depolarized the MMP and induced ROS generation in a dose-dependent manner in U87 cells. More importantly, 7g reduced tumor weight by 72.7% in U87 xenograft model at a dose of 20 mg/kg/day without obvious toxicity. Altogether, compound 7g deserved further investigations as a novel, safe and efficacious TACC3 inhibitor for the treatment of GBM.

Chitosan-supported FeCl3 catalyzed multicomponent synthesis of tetrahydroisoquinoline-indole hybrids with promising activity against chloroquine resistant Plasmodium falciparum

An operationally simple three-component coupling of tetrahydroisoquinoline (THIQ), aldehydes and indoles or indole-3-carboxylic acids has been achieved using chitosan-ionic liquid supported FeCl3 (chit-IL@FeCl3) as a recyclable heterogeneous catalyst. The developed waste-free approach provided rapid access to biologically important THIQ-indole hybrids without the use of any additive or ligand. The synthesized THIQ-indole hybrids were evaluated as antiplasmodial agents against chloroquine-sensitive (Pf3D7) and chloroquine-resistant (PfINDO) strains of Plasmodium falciparum. Compounds 4b (most potent against Pf3D7) and 4g (most potent against PfINDO) showed IC50 values of 1.32 and 0.26 µg/mL respectively. Also, 4g showed strong cytocidal action against both rings and trophozoite stages. Furthermore, cytotoxic study against human liver HUH 7 cells revealed that the most potent compound 4g with an excellent resistance index of 0.07 is also relatively non-toxic. The results of this study suggest that THIQ-indole hybrids hold an enormous potential for developing new antimalarial agents with novel mechanism of action.

4-Phthalimidobenzenesulfonamide Derivatives as Acetylcholinesterase and Butyrylcholinesterase Inhibitors: DFTs, 3D-QSAR, ADMET, and Molecular Dynamics Simulation

Introduction: Alzheimer’s disease is a form of dementia which affects majority of the people. It is characterized by memory loss and other cognitive function disabilities and is one of the most challenging neurodegenerative disorders to treat because of its progressive nature. The disease affects millions of people all around the world, and the number of those affected is expanding every day. In the previous study, the 4-phthalimidobenzenesulfonamide derivatives were synthesized as AChE and BChE inhibitors, and here, we were aiming to further reporting in silico studies of these compounds for efficient drug discovery process and to find out the potential lead compounds. Methods: In silico characterization included density functional theory (DFT) studies, 3D-QSAR, ADMET properties, molecular docking, and molecular dynamic simulations. The geometries of all derivatives were optimized using B3LYP method and 6-311G basis set. Results: The findings of the current study revealed that 4-phthalimidobenzenesulfonamide derivatives exhibited a reactive electronic property which is essential for anticholinesterase activity. Moreover, optimized structures were subjected to molecular docking studies with targeted protein. The compounds 2c and 2g showed excellent binding score of −37.44 and −33.67 kJ/mol with BChE and AChE, respectively, and exhibited strong binding affinity. The potent derivatives produced stable complex with amino acid residues of active pocket of both BChE and AChE. The stability of protein-ligand complexes was determined by molecular dynamic simulation studies, and results were found in correlation with molecular docking findings. Conclusion: Findings of the current study suggested that these derivatives are potent inhibitors of cholinesterase enzyme.

Synthesis, Structure and Cytotoxic Properties of Copper(II) Complexes of 2-Iminocoumarins Bearing a 1,3,5-Triazine or Benzoxazole/Benzothiazole Moiety.

A series of copper(II) complexes of 2-imino-2H-chromen-3-yl-1,3,5-triazines 2a-h, 3-(benzoxazol-2-yl)-2H-chromen-2-imines 4a-b, and 3-(benzothiazol-2-yl)-2H-chromen-2-imines 6a-c were obtained by reacting of appropriate 2-iminocoumarin ligands L1a-h, L3a-b, and L5a-c with 3-fold molar excess of copper(II) chloride. The structure of these compounds was confirmed by IR spectroscopy, elemental analysis, and single-crystal X-ray diffraction data (2f, 2g, 2h, and 6c). All the synthesized complexes were screened for their activity against five human cancer cell lines: DAN-G, A-427, LCLC-103H, SISO, and RT-4 by using a crystal violet microtiter plate assay and relationships between structure and in vitro cytotoxic activity are discussed. The coordination of 2-iminocoumarins with copper(II) ions resulted in complexes 2a-h, 4a-b, and 6a-c with significant inhibitory properties toward tested tumor cell lines with IC50 values ranging from 0.04 μM to 15.66 μM. In comparison to the free ligands L1a-h, L3a-b, and L5a-c, the newly prepared Cu(II) complexes often displayed increased activity. In the series of copper(II) complexes of 2-imino-2H-chromen-3-yl-1,3,5-triazines 2a-h the most potent compound 2g contained a 4-phenylpiperazine moiety at position 6 of the 1,3,5-triazine ring and an electron-donating diethylamino group at position 7' of the 2-iminocoumarin scaffold. Among the Cu(II) complexes of 3-(benzoxazol-2-yl)-2H-chromen-2-imines 4a-b and 3-(benzothiazol-2-yl)-2H-chromen-2-imines 6a-c the most active was benzoxazole-2-iminocoumarin 4b that also possessed a diethylamino group at position 7' of the 2-iminocoumarin moiety. Moreover, compound 4b was found to be the most prominent agent and displayed the higher potency than cisplatin against tested cell lines.

Synthesis and Chemopreventive Potential of 5-FU/Genistein Hybrids on Colorectal Cancer Cells.

A series of 5-FU-Genistein hybrids were synthesized and their structures were elucidated by spectroscopic analysis. The chemopreventive potential of these compounds was evaluated in human colon adenocarcinoma cells (SW480 and SW620) and non-malignant cell lines (HaCaT and CHO-K1). Hybrid 4a displayed cytotoxicity against SW480 and SW620 cells with IC50 values of 62.73 ± 7.26 µM and 50.58 ± 1.33 µM, respectively; compound 4g induced cytotoxicity in SW620 cells with an IC50 value of 36.84 ± 0.71 µM. These compounds were even more selective than genistein alone, the reference drug (5-FU) and the equimolar mixture of genistein plus 5-FU. In addition, hybrids 4a and 4g induced time- and concentration-dependent antiproliferative activity and cell cycle arrest at the S-phase and G2/M. It was also observed that hybrid 4a induced apoptosis in SW620 cells probably triggered by the extrinsic pathway in response to the activation of p53, as evidenced by the increase in the levels of caspases 3/8 and the tumor suppressor protein (Tp53). Molecular docking studies suggest that the most active compound 4a would bind efficiently to proapoptotic human caspases 3/8 and human Tp53, which in turn could provide valuable information on the biochemical mechanism for the in vitro cytotoxic response of this compound in SW620 colon carcinoma cell lines. On the other hand, molecular dynamics (MD) studies provided strong evidence of the conformational stability of the complex between caspase-3 and hybrid 4a obtained throughout 100 ns all-atom MD simulation. Molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) analyses of the complex with caspase-3 showed that the interaction between the ligand and the target protein is stable. Altogether, the results suggest that the active hybrids, mainly compound 4a, might act by modulating caspase-3 activity in a colorectal cancer model, making it a privileged scaffold that could be used in future investigations.

Synthesis, Characterization, and Biological Evaluation of Tetrahydropyrimidines: Dual-Activity and Mechanism of Action.

In this paper, the synthesis, characterization, and biological evaluation of the novel tetrahydropyrimidines—THPMs are described. THPMs are well-known for wide pharmacological activities such as antimicrobial, anticancer, antiviral, etc. This research includes obtained results of in vitro antimicrobial, anticancer, and α-glucosidase inhibitory activities of the eleven novel THPMs. An antibiotic assessment was done against five bacteria (two Gram-positive and three Gram-negative) and five fungi by determining the minimal inhibitory concentration (MIC), using the broth tube dilution method. The most active antibacterial compounds were 4a, 4b, and 4d, while the best antifungal activity was shown by 4e, 4f, and 4k. The lowest MIC value (0.20 mg/mL) was measured for 4e, 4f, and 4k against the Trichophyton mentagrophytes. Moreover, examining the α-glucosidase inhibitory activity revealed the compound 4g as the one with the best activity. The cytotoxic activity was performed on the tumor cell lines (HeLa, K562, and MDA-MB-231) and normal cells (MRC-5). The best antitumor activity was shown by compounds 4b and 4k against HeLa cell lines. The influence on cell cycle and mechanism of action of the most active compounds were examined too. Compound 4b had good antibacterial and anticancer activities, while 4k showed promising antifungal and anticancer activities.

Discovery of 5-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)-1H-indole-2-carboxamide derivatives as novel anti-cancer agents targeting Nur77

Encouraged by our previous findings and in continuation of our ongoing study project in designing and synthesis of novel Nur77-targeting anti-cancer agents, a series of 5-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)-1H-indole-2-carboxamide derivatives were designed, synthesized and biologically evaluated as potent Nur77 modulators. Among synthesized compounds, 8b maintained good potency against different liver cancer cell lines and other types of cancer cell lines while exhibiting lower toxicity than the positive compound celastrol. Moreover, 8b displayed excellent Nur77-binding activity, superior to the lead compound 10g and comparable to the reference compound celastrol. The cytotoxic action of 8b towards cancer cells was associated with its induction of Nur77-mitochondrial targeting and Nur77-dependent apoptosis. Notably, 8b has good in vivo safety and anti-hepatocellular carcinoma (HCC) activity. Altogether, this study reveals that 8b is a novel Nur77 modulator with great promise for further research.

Synthesis, characterization and inhibitor properties of benzimidazolium salts bearing 4-(methylsulfonyl)benzyl side arms

Herein, a series of N-heterocyclic carbene (NHC) precursors bearing sulfonyl moieties was prepared. 1-(4-(methylsulfonyl)benzyl)-3-alkylbenzimidazolium chloride salts were synthesized with the reaction of 1-alkylbenzimidazoles with 4-(methylsulfonyl)benzyl chloride. These compounds were characterized by using 1H NMR, 13C NMR, FT-IR spectroscopy and elemental analysis techniques. Molecular and crystal structures of compounds 2e and 2j were determined by using the single-crystal X-ray diffraction method. Furthermore, enzyme inhibitory properties of benzimidazolium salt were tested against xanthine oxidase (XO) and acetylcholinesterase (AChE), then determined the IC50 value range of XO were determined from 0.218 to 1.927 µM, while the IC50 for AChE were determined from 1.328 to 5.22. Docking applications were used by using AutoDock4 in order to define the binding pose of the selected compounds, (2c, 2d and 2g) and also to visualize the correlation of the generated optimal complexes. It is found that the compound 2g has good binding affinity (-11.24 kcal/mol) against AChE, on the other side, compound 2c shows the lowest binding energy (-8.32 kcal/mol) for the XO target. These findings and the defined compounds could be as potential agents to develop effective medicine for AChE and XO in the future.

Discovery of Novel N-Pyridylpyrazole Thiazole Derivatives as Insecticide Leads

To develop effective insecticides against Lepidoptera pests, 25 novel N-pyridylpyrazole derivatives containing thiazole moiety were designed and synthesized based on the intermediate derivatization method (IDM). The insecticidal activities of these target compounds against Plutella xylostella (P. xylostella), Spodoptera exigua (S. exigua), and Spodoptera frugiperda (S. frugiperda) were evaluated. Bioassays indicated that compound 7g−7j exhibited good insecticidal activities. Compound 7g showed especially excellent insecticidal activities against P. xylostella, S. exigua, and S. frugiperda with LC50 values of 5.32 mg/L, 6.75 mg/L, and 7.64 mg/L, respectively, which were adequate for that of commercial insecticide indoxacarb. A preliminary structure-activity relationship analysis showed that the insecticidal activities of thiazole amides were better than that of thiazole esters, and the amides with electron-withdrawing groups on the benzene ring were better than the ones with electron-donating groups. This work provides important information for designing novel N-pyridylpyrazole thiazole candidate compounds and suggests that the 7g is a promising insecticide lead for further studies.

Synthesis, Antifungal Activity, and Molecular Docking Study of Novel 3-Carene-Derived 4-Substituted Phenyl-1,2,4-Triazolinthiones Bearing gem-Dimethylcyclopropane Moiety.

For exploring new natural product-based leading compounds with antifungal activity, 15 novel 3-carene-derived 4-substituted phenyl-1,2,4-triazolinthiones 7a∼7o bearing gem-dimethylcyclopropane moiety were synthesized and structurally characterized by UV/VIS, FT-IR, 1 H-NMR, 13 C-NMR, ESI-MS and elemental analysis. The preliminary bioassay at 50 μg/mL showed that all of the target compounds exhibited certain in vitro inhibitory activities against the eight tested fungi, in which compound 7g (R=m, p-Cl) displayed better inhibition activity (85.0 %) against P. piricola than that of the positive control Chlorothalonil. Furthermore, a reasonable and effective 3D structure of phytofungal CYP51 was constructed by homology modeling. Molecular docking study revealed that the total scores of all the target compounds were higher than that of Prothioconazole. In addition, it was found that compound 7g could readily embed into the binding site, and therein shared similar interactions with the case of Prothioconazole. Thus, compound 7g deserved further study as an antifungal leading compound.

Water mediated TBAB catalyzed synthesis of spiro-indoline-pyrano[3,2-c]quinolines as α-amylase inhibitor and in silico studies

Herein, an efficient synthesis of spiro-indoline-pyrano[3,2-c]quinolines derivatives of spiroxindolines by the water-mediated three-component condensation reaction of 2-hydroxyquinoline-4-one 1(a-b), isatin derivatives 2(a-n), and malononitrile 3 in the presence of water-soluble and phase transfer Tetrabutylammonium bromide (TBAB) catalyst is described. The present protocol shows features such as excellent yield of product, mild reaction condition, reusable reaction medium with catalyst and low E-factor. This blossomed the reaction with the green synthetic condition and provide a safe and clean alternative for the synthesis of spiropyrano[3,2-c] quinolines derivatives. All the synthesized compounds were screened against the pancreatic α-amylase. Many of those synthesized compounds possess noticeably good α-amylase inhibitory action. From the activity profile, analogous 4g and 4h were found to be more active than the others with IC50 values ranges for α-amylase inhibition (IC50 = 73.82 -76.65 µg/ml) in comparison with the standard acarbose (IC50 = 79.64 ± 0.46 µg/ml). Molecular docking results showed key interactions of 4g, 4h and acarbose with α-amylase, compound 4g shows H-bonding interaction with GLN63, HIS101 and compound 4h shows H-bonding interaction with ASP300. In silico ADMET prediction was carried out to check the physicochemical properties of the synthesized compound.

New Oxazolo[5,4-d]pyrimidines as Potential Anticancer Agents: Their Design, Synthesis, and In Vitro Biological Activity Research.

Cancer is a large group of diseases in which the rapid proliferation of abnormal cells generally leads to metastasis to surrounding tissues or more distant ones through the lymphatic and blood vessels, making it the second leading cause of death worldwide. The main challenge in designing a modern anticancer therapy is to develop selective compounds that exploit specific molecular targets. In this work, novel oxazolo[5,4-d]pyrimidine derivatives were designed, synthesized, and evaluated in vitro for their cytotoxic activity against a panel of four human cancer cell lines (lung carcinoma: A549, breast adenocarcinoma: MCF7, metastatic colon adenocarcinoma: LoVo, primary colon adenocarcinoma: HT29), along with their P-glycoprotein-inhibitory ability and pro-apoptotic activity. These oxazolo[5,4-d]pyrimidine derivatives, which are structurally similar to nucleic purine bases in general, are characterized by the presence of a pharmacologically favorable isoxazole substituent at position 2 and aliphatic amino chains at position 7 of the condensed heterocyclic system. In silico analysis of the obtained compounds identified their potent inhibitory activity towards human vascular endothelial growth factor receptor-2 (VEGFR-2). Molecular docking was performed to assess the binding mode of new derivatives to the VEGFR-2 active site. Then, their physicochemical, pharmacokinetic, and pharmacological properties (i.e., ADME—administration, distribution, metabolism, and excretion) were also predicted to assess their druglikeness. In particular, compound 3g (with a 3-(N,N-dimethylamino)propyl substituent) was found to be the most potent against the HT29 cell line, with a 50% cytotoxic concentration (CC50) of 58.4 µM, exceeding the activity of fluorouracil (CC50 = 381.2 μM) and equaling the activity of cisplatin (CC50 = 47.2 µM), while being less toxic to healthy human cells (such as normal human dermal fibroblasts (NHDFs)) than these reference drugs. The results suggest that compound 3g is a potentially promising candidate for the treatment of primary colorectal cancer.

Synthesis, molecular docking, ADME study, and antimicrobial potency of piperazine based cinnamic acid bearing coumarin moieties as a DNA gyrase inhibitor.

A series of novel piperazine based cinnamic acid bearing coumarin derivatives were designed and synthesized by piperazine based cinnamic acids esterification with 4-hydroxycoumarin and characterized by various spectral techniques like infrared, 1 H nuclear magnetic resonance (NMR), 13 C NMR, and mass. The novel bioactive compounds (7a-7m) screen their potential against different bacterial and fungal strains. Compound 7g (minimum inhibitory concentration [MIC] = 12.5 µg/ml) exhibited potent antibacterial activity against Escherichia colistrain. Compounds 7d, 7f, 7g, 7k, 7l, and 7m showed potent antibacterial activity against all bacterial strains. Compounds 7a, 7g, 7h, 7k, 7l, and 7m exhibited potent antifungal activity against all fungal strains. Furthermore, a molecular docking study revealed that compounds 7d, 7f, 7g, and 7k could bind to the active site of E. coli DNA gyrase subunit B protein and form hydrogen bonding with crucial amino acid residues Arg136 in the active sites. Comprehensively, our study recommends that 7d, 7f, 7g, and 7k could be a promising lead for developing more efficient antimicrobial drug candidates and DNA gyrase inhibitors.

Design, synthesis and biological evaluation of isoxazole bearing N-Arylpyrazole derivatives as anticancer agents

A novel library of isoxazole bearing N-arylpyrazole ( 12a-j ) derivatives has been designed synthesized and their structures were confirmed by 1 HNMR, 13 CNMR and mass spectral analysis. Further, these compounds were evaluated for their anticancer activity towards four human cancer cell line including MCF-7: human breast, A549: human lung, DU-145: human prostrate and MDA MB-231: human breast) and etoposide used standard drug. Most of the synthesized compounds showed good to moderate activity. Among them, these compounds 12b, 12c, 12d, 12f, 12g and 12h displayed more potent than etoposide. Particularly, compound 12h has showed most promising activity compare to all compounds (MCF-7 = 0.31±0.044µM, A549 = 0.47±0.059µM, Du-145 = 0.19±0.053µM and MDA MB-231 = 0.37±0.098µM)

Design, Synthesis, and Biological Evaluation of quinoxaline bearing tetrahydropyridine derivatives as anticancer, antioxidant, and anti-tubercular agents.

Quinoxaline and Tetrahydropyridine derivatives showed various biological properties. The combination of these two scaffolds may contribute to good biological activity and may give novel and efficacious bioactive candidates. The present study aimed to identify bioactive agents with quinoxaline bearing tetrahydropyridine derivatives possessing anticancer, antioxidant, and anti-tubercular agents. A series of novel quinoxaline bearing tetrahydropyridine derivatives have been designed and synthesized in good yields. The synthetic protocol involves three-component Povarov reactions of 6-amino quinoxaline, propenyl guaethol, and substituted aldehydes using BF3•OEt2 as catalyst. The newly synthesized molecules were evaluated for their anticancer activity against four cell lines, i.e. A-549, MCF-7, PC-3, and HepG2. The results from in vitro assay indicated that compound 4a proved to be as potent as the standard drug adriamycin against all cell lines with GI50 values <10 μg/ml. Compounds 4b, 4f, and 4i exhibited good cytotoxicity against A-549 cell line. All synthesized molecules were evaluated for their antioxidant activity and the results revealed that the compounds 4a, 4b, and 4i showed promising antioxidant activities against DPPH and H2O2 scavenging. In addition, the anti-mycobacterial activity of the synthesized compounds against MTB H37Rv strain was determined using MABA method. The results indicate that the compounds 4a, 4b, 4g, and 4i showed better anti-mycobacterial activity than the standard drugs pyrazinamide, ciprofloxacin and streptomycin with MIC value 1.6 μg/ml. Furthermore, molecular docking studies and ADME properties showed good pharmacokinetic profile and drug-likeness properties. These studies showed that a series of novel quinoxaline bearing tetrahydropyridine derivatives exhibit anticancer, anti-mycobacterial, and antioxidant activities.

Inhibitory Efficacy of Thiosemicarbazones for Carbonic Anhydrase II (Bovine and Human) as a Target of Calcification and Tumorigenicity.

Carbonic anhydrase II (CA-II) is associated with calcification, tumorigenicity, epilepsy, osteoporosis, and several other physiological or pathological processes. CA-II inhibitors can be used to reduce the intraocular pressure usually associated with glaucoma. In search for potent CA-II inhibitors, a series of thiosemicarbazone derivatives (3a-u) was synthesized. This series was evaluated against bovine and human carbonic anhydrase II (bCA-II and hCA-II) and their docking studies were carried out. In the preliminary screening, most of the compounds exhibited significant inhibition of bCA-II and hCA-II. The predictive structure-activity relationship suggested that the thiosemicarbazide moiety plays a key role in the inhibition of enzyme activity and substitution at R position and has a remarkable contribution to the overall activity. The kinetic studies of the most active inhibitors of bCA-II (3d, 3e, 3l, 3f, and 3p) and hCA-II (3g) were performed against bCA-II and hCA-II, respectively to investigate their mode of inhibition and dissociation constants (Ki). Subsequently, (3e, 3f, 3l and 3p) were identified as competitive inhibitors of bCA-II with Ki values of 5.02-14.70 μM, while (3d) as a noncompetitive inhibitor of bCA-II (Ki = 2.5 ± 0.015 μM), however, (3g) demonstrated competitive inhibition of hCA-II with a Ki value of 5.95 ± 0.002 μM. The selectivity index reflects that compound (3g) is more selective for hCA-II. The binding modes of these compounds with bCA-II and hCA-II were investigated by structure-based molecular docking, and the docking results are in complete agreement with the experimental findings.

Design, synthesis and activity evaluation of Hedgehog inhibitor Itraconazole derivatives in A549 cells

Hedgehog signal channel, a channel that plays a role in the occurrence and development of a variety of cancers. We introduce the composition and mechanism of Hedgehog signal channel, and the anti-tumor mechanism. A series of derivatives were designed and synthesized with the Hedgehog signal channel inhibitor Itraconazole in clinical phase II as the precursor. Compared with the other inhibitors, Itraconazole has a weaker inhibitory effect on Hedgehog, and there are few studies on improving the anti proliferation ability of Itraconazole on cells. Therefore, using Itraconazole as the lead, we obtained a series of derivatives that can effectively inhibit Hedgehog channels. Compared with Itraconazole, compounds 12g and 12n had stronger inhibitory effects in A549 cells.

Novel Morpholine-Bearing Quinoline Derivatives as Potential Cholinesterase Inhibitors: The Influence of Amine, Carbon Linkers and Phenylamino Groups.

A series of novel 4-N-phenylaminoquinoline derivatives containing a morpholine group were designed and synthesized, and their anti-cholinesterase activities and ABTS radical-scavenging activities were tested. Among them, compounds 11a, 11g, 11h, 11j, 11l, and 12a had comparable inhibition activities to reference galantamine in AChE. Especially, compound 11g revealed the most potent inhibition on AChE and BChE with IC50 values of 1.94 ± 0.13 μM and 28.37 ± 1.85 μM, respectively. The kinetic analysis demonstrated that both the compounds 11a and 11g acted as mixed-type AChE inhibitors. A further docking comparison between the 11a- and 12a-AChE complexes agreed with the different inhibitory potency observed in experiments. Besides, compounds 11f and 11l showed excellent ABTS radical-scavenging activities, with IC50 values of 9.07 ± 1.34 μM and 6.05 ± 1.17 μM, respectively, which were superior to the control, Trolox (IC50 = 11.03 ± 0.76 μM). It is worth noting that 3-aminoquinoline derivatives 12a–12d exhibited better drug-like properties.

Ring-fused 3β-acetoxyandrost-5-enes as novel neuroprotective agents with cholinesterase inhibitory properties

Alzheimer´s disease (AD) is an intellectual disorder caused by organic brain damage and cerebral atrophy, characterized by the loss of memory, judgment, and abstract thinking followed by declining cognitive functions, language, and the ability to perform daily living activities. Many efforts have been made to decrease the effects of the disease but also to block the neurodegenerative process. Cholinesterase inhibitors (ChEIs) are a group of medicines that act at the neurotransmission of acetylcholine, preventing its excessive breakdown and helping to improve cognitive functions in patients with AD. In this work, 16 chiral steroids, namely ring-fused 3β-acetoxyandrost-5-ene derivatives, their precursor and two 16-dehydroprogesterone-derived dioximes, were assessed as cholinesterase inhibitors and neuroprotective agents. The results demonstrated that some of the tested steroids are cholinesterase inhibitors and the majority selective for acetylcholinesterase inhibition. Albeit, one ring-fused 3β-acetoxyandrost-5-ene containing N-methylpiperidine ring (compound 2g) demonstrated to be a selective and potent inhibitor of the butyrylcholinesterase enzyme. (S)− 4,4a,5,6,7,8-(hexahydronaphthalen-2-one)-fused 3β-acetoxyandrost-5-ene (compound 6) showed high neuroprotective effect, high ability to restore the mitochondrial membrane potential from glutamate intoxication, and dramatic improvement in cell morphology. The described results provided relevant structure-activity relationship data.