Design,synthesis and evaluation of vilazodone-tacrine hybrids as multitarget-directed ligands against depression with cognitive impairment

Depression, a severe mental disease, is greatly difficult to treat and easy to induce other neuropsychiatric symptoms, the most frequent one is cognitive impairment. In this study, a series of novel vilazodone-tacrine hybrids were designed, synthesized and evaluated as multitarget agents against depression with cognitive impairment. Most compounds exhibited good multitarget activities and appropriate blood-brain barrier permeability. Specifically, compounds 1d and 2a exhibited excellent 5-HT_1A agonist activities (1d, EC₅₀?=?0.36?±?0.08?nM; 2a, EC₅₀?=?0.58?±?0.14?nM) and 5-HT reuptake inhibitory activities (1d, IC₅₀?=?20.42?±?6.60?nM; 2a, IC₅₀?=?22.10?±?5.80?nM). In addition, they showed moderate ChE inhibitory activities (1d, AChE IC₅₀?=?1.72?±?0.217?μM, BuChE IC₅₀?=?0.34?±?0.03?μM; 2a, AChE IC₅₀?=?2.36?±?0.34?μM, BuChE IC₅₀?=?0.10?±?0.01?μM). Good multitarget activities with goodt blood-brain barrier permeability of 1d and 2a make them good lead compounds for the further study of depression with cognitive impairment.     

Multifunctional 5,6-dimethoxybenzo[d]isothiazol-3(2H)-one-N-alkylbenzylamine derivatives with acetylcholinesterase,monoamine oxidases and β-amyloid aggregation inhibitory activities as potential agents against Alzheimer’s disease

A series of 5,6-dimethoxybenzo[d]isothiazol-3(2H)-one-N-alkylbenzylamine derivatives were designed, synthesized and evaluated as potential multifunctional agents for the treatment of Alzheimer’s disease (AD). The in vitro assays indicated that most of these derivatives were selective AChE inhibitors with good multifunctional properties. Among them, compounds 11b and 11d displayed comprehensive advantages, with good AChE (IC₅₀?=?0.29?±?0.01?μM and 0.46?±?0.02?μM, respectively), MAO-A (IC₅₀?=?8.2?±?0.08?μM and 7.9?±?0.07?μM, respectively) and MAO-B (IC₅₀?=?20.1?±?0.16?μM and 43.8?±?2.0% at 10?μM, respectively) inhibitory activities, moderate self-induced Aβ_1–42 aggregation inhibitory potency (35.4?±?0.42% and 48.0?±?1.53% at 25?μM, respectively) and potential antioxidant activity. In addition, the two representative compounds displayed high BBB permeability in vitro. Taken together, these multifunctional properties make 11b and 11d as a promising candidate for the development of efficient drugs against AD.     

A novel series of 4-methyl substituted pyrazole derivatives as potent glucagon receptor antagonists: Design,synthesis and evaluation of biological activities

A novel series of 4-methyl substituted pyrazole derivatives were designed, synthesized and biologically evaluated as potent glucagon receptor (GCGR) antagonists. In this study, compounds 9q, 9r, 19d and 19e showed high GCGR binding (IC₅₀?=?0.09?μM, 0.06?μM, 0.07?μM and 0.08?μM, respectively) and cyclic-adenosine monophosphate (cAMP) activities (IC₅₀?=?0.22?μM, 0.26?μM, 0.44?μM and 0.46?μM, respectively) in cell-based assays. Most importantly, the docking experiment demonstrated that compound 9r formed extensive hydrophobic interactions with the receptor binding pocket, making it justifiable to further investigate the potential of becoming a GCGR antagonist.     

Structure-activity relationships and docking studies of synthetic 2-arylindole derivatives determined with aromatase and quinone reductase 1

In our ongoing effort of discovering anticancer and chemopreventive agents, a series of 2-arylindole derivatives were synthesized and evaluated toward aromatase and quinone reductase 1 (QR1). Biological evaluation revealed that several compounds (e.g., 2d, IC₅₀?=?1.61?μM; 21, IC₅₀?=?3.05?μM; and 27, IC₅₀?=?3.34?μM) showed aromatase inhibitory activity with half maximal inhibitory concentration (IC₅₀) values in the low micromolar concentrations. With regard to the QR1 induction activity, 11 exhibited the highest QR1 induction ratio (IR) with a low concentration to double activity (CD) value (IR?=?8.34, CD?=?2.75?μM), while 7 showed the most potent CD value of 1.12?μM. A dual acting compound 24 showed aromatase inhibition (IC₅₀?=?9.00?μM) as well as QR1 induction (CD?=?5.76?μM) activities. Computational docking studies using CDOCKER (Discovery Studio 3.5) provided insight in regard to the potential binding modes of 2-arylindoles within the aromatase active site. Predominantly, the 2-arylindoles preferred binding with the 2-aryl group toward a small hydrophobic pocket within the active site. The C-5 electron withdrawing group on indole was predicted to have an important role and formed a hydrogen bond with Ser478 (OH). Alternatively, meta-pyridyl analogs may orient with the pyridyl 3′-nitrogen coordinating with the heme group.     

Design and synthesis of plant cyclopeptide Astin C analogues and investigation of their immunosuppressive activity

To further investigate on the structure-activity relationships of immunosuppressive Astin C, seventeen analogues 1–17 were designed and synthetized via amino acid substitution strategy by the solid-phase peptide synthesis method for the first time. In comparison with Astin C (IC₅₀?=?12.6?±?3.3?μM), only compounds 2 (IC₅₀?=?38.4?±?16.2?μM), 4 (IC₅₀?=?51.8?±?12.7?μM), 5 (IC₅₀?=?65.2?±?15.6?μM), and 8 (IC₅₀?=?61.8?±?12.4?μM) exhibited immunosuppressive activity in the Lymph node cells of mice. These results showed that the Astin C analogues containing _D-amino acid residues, hydrophobic long-chain alkyl substituents, and aryl substituents performed better than those carrying hydrophilic amino acid residues and short-chain alkyl substituents. Moreover compounds 15, 16, and 17 had no immunosuppressive activity, which suggested that cis-3,4-dichlorinated proline played an important role in the immunosuppressive activity of Astin C.     

Synthesis, in vitro α-glucosidase inhibitory activity and docking studies of novel chromone-isatin derivatives

A novel series of chromone-isatin derivatives 6a–6p were designed, synthesized and characterized by ¹H NMR, ¹³C NMR and HRMS. These novel synthetic compounds were evaluated for inhibitory activity against yeast α-glucosidase enzyme. The results of biological test have shown that all tested compounds exhibited excellent to potent inhibitory activity in the range of IC₅₀?=?3.18?±?0.12–16.59?±?0.17?μM as compared to the standard drug acarbose (IC₅₀?=?817.38?±?6.27?μM). Compound 6j (IC₅₀?=?3.18?±?0.12?μM) with a hydroxyl group at the 7-position of chromone and a 4-bromobenzyl group at the N1-positions of isatin, was found to be the most active compound among the series. Furthermore, molecular docking study was performed to help understand binding interactions of the most active analogs with α-glucosidase enzyme. These results indicated that this class of compounds had potential for the development of anti-diabetic agents.     

Leucoflavonine,a new bioactive racemic flavoalkaloid from the leaves of Leucosceptrum canum

A new flavoalkaloid racemate, leucoflavonine (1), together with its flavonoid precursor pectolinarigenin (2), was isolated from the leaves of Leucosceptrum canum collected from Tibet. Its structure was established by comprehensive spectroscopic analysis. Chrial separation of the enantiomers of 1 was achieved, and their absolute configurations were determined as S-(+)- and R-(?)-leucoflavonines ((+)-1a and (?)-1b) by comparison of their computational and experimental optical rotations. Biological assays indicated that both (+)-1a and (?)-1b exhibited inhibitory activity against acetylchlorinesterase (AChE) in vitro (IC₅₀?=?68.0?±?8.6 and 18.3?±?1.8?μM, respectively). Moreover, (?)-1b displayed cytotoxicity against human hepatoma cells HepG2 (IC₅₀?=?52.9?±?3.6?μM), and inhibited the production of interleukelin-2 (IL-2) in Jurkat cells (IC₅₀?=?16.5?±?0.9?μM), while (+)-1a showed no obvious activity in these assays.     

(E)-N-Aryl-2-oxo-2-(3,4,5-trimethoxyphenyl)acetohydrazonoyl cyanides as tubulin polymerization inhibitors: Structure-based bioisosterism design,synthesis, biological evaluation,molecular docking and in silico ADME prediction

A series of (E)-N-Aryl-2-oxo-2-(3,4,5-trimethoxyphenyl)acetohydrazonoyl cyanides have been synthesized and evaluated for their anticancer activity in human hepatocellular liver carcinoma HepG2 and breast adenocarcinoma MCF-7?cell lines. Among all the tested compounds, compound 3a, 3e and 3n displayed more activity than lead compound with IC₅₀ value of 0.26–0.61?μM. Meanwhile, these compounds (3a, 3e and 3n) showed potent antiproliferative activity against a panel of cancer cells and the HCT-8/T multidrug resistant cell line with IC₅₀ values in the range of 0.077– 7.44?μM. Flow cytometric analyses revealed that compound 3n induced cell cycle arrest in G2/M phases in a dose dependent manner. The compound 3n also displayed potent tubulin polymerization inhibition with an IC₅₀ value of 0.9?µM, with ten folds more active than colchicine (IC₅₀?=?9?μM). Molecular docking studies revealed that compound 3n efficiently interacted with the colchicine binding site of tubulin through hydrophobic, cation-π and hydrogen bond interaction. Furthermore, in silico pharmacokinetic prediction shown that these compounds have a good ADME-related physicochemical parameters. These results demonstrate that 3n exhibits potent cytotoxicity in cancer cells by targeting the colchicine binding site of tubulin and potentially acts as a therapeutic lead compound for the development of anticancer drugs.     

Discovery and development of novel rhodanine derivatives targeting enoyl-acyl carrier protein reductase

A series of rhodanine derivatives RB1–RB23 were synthesized through a two-round screening. Their Mycobacterial tuberculosis (Mtb) InhA inhibitory activity and Mtb growth blocking capability were evaluated. The most potent hit compound RB23 indicated comparable InhA inhibiton (IC₅₀?=?2.55?μM) with the positive control Triclosan (IC₅₀?=?6.14?μM) and Isoniazid (IC₅₀?=?8.29?μM). Its improved growth-blocking effect on Mtb and low toxicity were attractive for further development. The docking simulation revealed the possible binding pattern of this series and picked the key interacted residues as Ser20, Phe149, Lys165 and Thr196. The 3D-QSAR model visualized the SAR discussion and hinted new information. Modifying the surroundings near rhodanine moiety might be promising attempts in later investigations.     

Novel oxazolxanthone derivatives as a new type of α-glucosidase inhibitor: synthesis,activities, inhibitory modes and synergetic effect

Xanthone derivatives have shown good α-glucosidase inhibitory activity and have drawn increased attention as potential anti-diabetic compounds. In this study, a series of novel oxazolxanthones were designed, synthesized, and investigated as α-glucosidase inhibitors. Inhibition assays indicated that compounds 4–21 bearing oxazole rings exhibited up to 30-fold greater inhibitory activity compared to their corresponding parent compound 1b. Among them, compounds 5–21 (IC₅₀?=?6.3?±?0.4–38.5?±?4.6?μM) were more active than 1-deoxynojirimycin (IC₅₀?=?60.2?±?6.2?μM), a well-known α-glucosidase inhibitor. In addition, the kinetics of enzyme inhibition measured by using Lineweaver–Burk analysis shows that compound 4 is a competitive inhibitor, while compounds 15, 16 and 20 are non-competitive inhibitors. Molecular docking studies showed that compound 4 bound to the active site pocket of the enzyme while compounds 15, 16, and 20 did not. More interestingly, docking simulations reveal that some of the oxazolxanthone derivatives bind to different sites in the enzyme. This prediction was further confirmed by the synergetic inhibition experiment, and the combination of representative compounds 16 and 20 at the optimal ratio of 4:6 led to an IC₅₀ value of 1.9?±?0.7?μM, better than the IC₅₀ value of 7.1?±?0.9?μM for compound 16 and 8.6?±?0.9?μM for compound 20.     

Novel (S)-1,3,4,12a-tetrahydropyrazino[2,1-c][1,4]benzodiazepine-6,12(2H,11H)-dione derivatives: Selective inhibition of MV-4-11 biphenotypic B myelomonocytic leukemia cells’ growth is accompanied by reactive oxygen species overproduction and apoptosis

A series of optically pure (R)- and (S)-1,3,4,12a-tetrahydropyrazino[2,1-c][1,4]benzodiazepine-6,12(2H,11H)-dione derivatives was designed and synthesized as novel anthramycin analogues in a three-step, one-pot procedure, and tested for their antiproliferative activity on nine following cell lines: MV-4-11, UMUC-3, MDA-MB-231, MCF7, LoVo, HT-29, A-549, A2780 and BALB/3T3. The key structural features responsible for exhibition of cytotoxic effect were determined: the (S)-configuration of chiral center and the presence of hydrophobic 4-biphenyl substituent in the side chain. Introduction of bromine atom into the 8 position (8g) or substitution of dilactam ring with benzyl group (8m) further improved the activity and selectivity of investigated compounds. Among others, compound 8g exhibited selective cytotoxic effect against MV-4-11 (IC₅₀?=?8.7?μM) and HT-29 (IC₅₀?=?17.8?μM) cell lines, while 8m showed noticeable anticancer activity against MV-4-11 (IC₅₀?=?10.8?μM) and LoVo (IC₅₀?=?11.0?μM) cell lines. The cell cycle arrest in G₁/S checkpoint and apoptosis associated with overproduction of reactive oxygen species was also observed for 8e and 8m.     

Synthesis and biological evaluation of Complex I inhibitor R419 and its derivatives as anticancer agents in HepG2 cells

In this study, Complex I inhibitor R419 was firstly revealed to have significant anticancer activity against HepG2 cells (IC₅₀?=?5.2?±?0.9?μM). Based on this finding, a series of R419 derivatives were synthesized and biologically evaluated. As results, 9 derivatives were found to have obvious anticancer activity. Among them, H20 exhibited the most potent activity (IC₅₀?=?2.8?±?0.4?μM). Mechanism study revealed that H20 caused severe depletion of cellular ATP, dose-dependently activated AMPK, decreased Bcl-2/Bax ratio and induced necrotic cell death. Most importantly, H20 displayed definite inhibitory activity against Complex I.     

Synthesis and in vitro evaluation of homoisoflavonoids as potent inhibitors of nitric oxide production in RAW-264.7 cells

Syntheses of natural homoisoflavonoids, (±)-portulacanones A–C (4, 8 and 9), portulacanone D (6), isolated from Portulaca oleracea L. (POL) and their derivatives (3, 5 and 7) have been achieved for the first time along with the synthesis of known derivatives (1 and 2) and their in vitro inhibitory effect against NO production in LPS-induced RAW-264.7 macrophages was evaluated as an indicator of anti-inflammatory activity. All the compounds tested had a concentration-dependent inhibitory effect on NO production by RAW-264.7 macrophages without obvious cytotoxicity. Compounds 3 (97.2% at 10?μM; IC₅₀?=?1.26?µM) followed by 6 (portulacanone D) (92.5% at 10?μM; IC₅₀?=?2.09?µM), 1 (91.4% at 10?μM; IC₅₀?=?1.75?µM) and 7 (83.0% at 10?μM; IC₅₀?=?2.91?µM) were the most potent from the series. This finding was further correlated with the suppressed expression of iNOS induced by LPS. Our promising preliminary results may provide the basis for the assessment of compound 3 as a lead structure for a NO production-targeted anti-inflammatory drug development and also could support the usefulness of POL as a folklore medicinal plant in the treatment of inflammatory diseases.     

Design,synthesis and evaluation of N2,N4-diaminoquinazoline based inhibitors of phosphodiesterase type 5

We describe the design, synthesis and evaluation of a series of N²,N⁴-diaminoquinazoline analogs as PDE5 inhibitors. Twenty compounds were prepared and these were assessed in terms of their PDE5 and PDE6 activity, ex-vivo vasodilation response, mammalian cytotoxicity and aqueous solubility. Molecular docking was used to determine the binding mode of the series and this was demonstrated to be consistent with the observed SAR. Compound 15 was the most active PDE5 inhibitor (IC₅₀?=?0.072?±?0.008?µM) and exhibited 4.6-fold selectivity over PDE6. Ex-vivo assessment of 15 and 22 in a rat pulmonary artery vasodilation model demonstrated EC₅₀s of 1.63?±?0.72?µM and 2.28?±?0.74?µM respectively.     

Design,synthesis and biological evaluation of novel spiro-pentacylamides as acetyl-CoA carboxylase inhibitors

Acetyl-CoA carboxylase (ACC) catalyzes the rate-determining step in de novo lipogenesis and plays an important role in the regulation of fatty acid oxidation. Therefore, ACC inhibition offers a promising option for intervention in nonalcoholic fatty liver disease (NAFLD), type 2 diabetes (T2DM) and cancer. In this paper, a series of spiropentacylamide derivatives were synthesized and evaluated for their ACC1/2 inhibitory activities and anti-proliferation effects on A549, H1975, HCT116, SW620 and Caco-2 cell lines in vitro. Compound 6o displayed potent ACC1/2 inhibitory activity (ACC1 IC₅₀?=?0.527?μM, ACC2 IC₅₀?=?0.397?μM) and the most potent anti-proliferation activities against A549, H1975, HCT116, SW620 and Caco-2 cell lines, with IC₅₀ values of 1.92?μM, 0.38?μM, 1.22?μM, 2.05?μM and 5.42?μM respectively. Further molecular docking studies revealed that compound 6o maintained hydrogen bonds between the two carbonyls and protein backbone NHs (Glu-B2026 and Gly-B1958). These results indicate that compound 6o is a promising ACC1/2 inhibitor for the potent treatment of cancer.     

Discovery of novel 2,3-dihydro-1H-inden-1-amine derivatives as selective monoamine oxidase B inhibitors

Inhibition of MAO-B has been an effective strategy for the treatment of Parkinson’s disease. To find more potent and selective MAO-B inhibitors with novel chemical scaffold, we designed and synthesized a series of new 2,3-dihydro-1H-inden-1-amine derivatives on basis of our previous study. Furthermore, the corresponding structure-activity relationship (SAR) of these compounds is detailedly discussed. Compounds L4 (IC₅₀?=?0.11?μM), L8 (IC₅₀?=?0.18?μM), L16 (IC₅₀?=?0.27?μM) and L17 (IC₅₀?=?0.48?μM) showed similar MAO-B inhibitory activity as Selegiline. Moreover, L4, L16 and L17 also exhibited comparable selectivity with Selegiline, indicating that L4, L16 and L17 could be promising selective MAO-B inhibitors for further study.     

Dihydropyrazothiazole derivatives as potential MMP-2/MMP-8 inhibitors for cancer therapy

MMP-2/MMP-8 is established as one of the most important metalloenzymes for targeting cancer. A series of dihydropyrazothiazole derivatives (E1–E18) bearing a salicylaldehyde group linked to Pyrazole ring were designed, synthesized, and evaluated for their pharmacological activity as MMP-2/MMP-8 inhibitors. Among them, compound E17 exhibited most potent inhibitory activity (IC₅₀?=?2.80?μM for MMP-2 and IC₅₀?=?5.6?μM for MMP-8), compared to the positive drug CMT-1 (IC₅₀?=?1.29?μM). Compounds (E1–E18) were scrutinized by CoMFA and CoMSIA techniques of Three-dimensional quant. structure-activity relationship (3D-QSAR), as well as a docking simulation. Moreover, treatment with compound E4 could induce MCF-7 cell apoptosis. Overall, the biological profile of E1–E18 may provide a research basis for the development of new agents against cancer.     

Design,synthesis and preliminary activity evaluation of novel 3-amino-2-hydroxyl-3-phenylpropanoic acid derivatives as aminopeptidase N/CD13 inhibitors

Aminopeptidase N (APN/CD13) over expressed on tumour cells, plays a critical role in tumour invasion, metastasis and tumour angiogenesis. In this article, we described the design, synthesis and preliminary activity studies of novel 3-amino-2-hydroxyl-3-phenylpropanoic acid derivatives as APN inhibitors. The in vitro enzymatic inhibitions on APN from porcine kidney showed that compound 7e had the most potent inhibitory activity against APN with the IC₅₀ value to 1.26?±?0.01 μM, which is better than that of bestatin (IC₅₀?=?2.55?±?0.11 μM). In addition, compound 7e also showed better inhibitory activity against APN on human ovary clear cell carcinoma cell ES-2 than bestatin with the IC₅₀ value to 30.19?±?1.02 μM versus 60.61?±?0.1 μM. Compound 7e could be used as the lead compound in the future for anti-cancer agent research.     

Microwave-assisted synthesis of novel 5-substituted benzylidene amino-2-butyl benzofuran-3-yl-4-methoxyphenyl methanones as antileishmanial and antioxidant agents

A series of 5-substitutedbenzylideneamino-2-butylbenzofuran-3-yl-4-methoxyphenyl methanones is synthesized and evaluated for antileishmanial and antioxidant activities. Compounds 4f (IC₅₀?=?52.0?±?0.09?µg/ml), 4h (IC₅₀?=?56.0?±?0.71?µg/ml) and 4l (IC₅₀?=?59.3?±?0.55?µg/ml) were shown significant antileishmanial when compared with standard sodium stibogluconate (IC₅₀?=?490.0?±?1.5?µg/ml). Antioxidant study revealed that compounds 4i (IC₅₀?=?2.44?±?0.47?µg/ml) and 4l (IC₅₀?=?3.69?±?0.44?µg/ml) have shown potent comparable activity when compared with standard ascorbic acid (IC₅₀?=?3.31?±?0.34?µg/ml). Molecular docking study was carried out which replicating results of biological activity in case of initial hits 4f and 4h suggesting that these compounds have a potential to become lead molecules in drug discovery process. In silico ADME study was performed for predicting pharmacokinetic profile of the synthesised antileishmanial agents and expressed good oral drug like behaviour.     

Design,synthesis, and biological evaluation of pyrazole derivatives containing acetamide bond as potential BRAFV600E inhibitors

With the increasingly acquired resistance, relapse and side effects of known marketed BRAF^V600E inhibitors, it’s significant to design the more effective and novel drugs. In this study, a series of novel pyrazole derivatives containing acetamide bond had been designed and synthesized on the basis of analysis of the endogenous ligands extracted from the known B-Raf co-crystals in the PDB database. Then, the compounds were evaluated for biological activities as potential BRAF^V600E inhibitors. The bioassay results in vitro against three human tumor cell lines revealed that some of the compounds showed very impressed antiproliferative property. Among them, the compound 5r with IC₅₀ values of 0.10?±?0.01?μM against BRAF^V600E and 0.96?±?0.10?μM against A375 cell line, showed the most potent inhibitory effect, compared with the positive-controlled agents vemurafenib (IC₅₀?=?0.04?±?0.004?μM for BRAF^V600E, IC₅₀?=?1.05?±?0.10?μM against A375). Further investigation confirmed that the compound 5r could induce A375 cell apoptosis, induce A375 cell death through changing mitochondrial membrane potential, and result in A375 cell arrest at the G1 phase of the cell cycle. Docking simulations results indicated that the compound 5r could bind tightly at the BRAF^V600E active site. Meanwhile, 3D-QSAR model suggested that these compounds may be potential anticancer inhibitors. Overall, the article provided some new molecular scaffolds for the further BRAF^V600E inhibitors.