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.     

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.     

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.     

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.     

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.     

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.     

Bisindolylmethane thiosemicarbazides as potential inhibitors of urease: Synthesis and molecular modeling studies

Bisindolylmethane thiosemicarbazides 1-18 were synthesized, characterized by ¹H NMR and ESI MS and evaluated for urease inhibitory potential. All analogs showed outstanding urease inhibitory potentials with IC₅₀ values ranging between 0.14?±?0.01 to 18.50?±?0.90?μM when compared with the standard inhibitor thiourea having IC₅₀ value 21.25?±?0.90?μM. Among the series, analog 9 (0.14?±?0.01?μM) with di-chloro substitution on phenyl ring was identified as the most potent inhibitor of urease. The structure activity relationship has been also established on the basis of binding interactions of the active analogs. These binding interactions were identified by molecular docking studies.     

Novel leucine ureido derivatives as aminopeptidase N inhibitors using click chemistry

The over-expression of aminopeptidase N on diverse malignant cells is associated with the tumor angiogenesis and metastasis. In this report, one new series of leucine ureido derivatives containing the triazole moiety was designed, synthesized and evaluated as APN inhibitors. Among them, compound 13v showed the best APN inhibition with an IC₅₀ value of 0.089?±?0.007?μM, which was two orders of magnitude lower than that of bestatin (IC₅₀?=?9.4?±?0.5?μM). Compound 13v also showed dose-dependent anti-angiogenesis activities. Even at the lower concentration (10?μM), compound 13v presented similar anti-angiogenesis activity compared with bestatin at 100?μM in both the human umbilical vein endothelial cells (HUVECs) capillary tube formation assay and the rat thoracic aorta rings test. Moreover, compared with bestatin, 13v exhibited comparable, if not better in vivo anti-metastasis activity in a mouse H22 pulmonary metastasis model.     

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.     

Design and synthesis of various quinizarin derivatives as potential anticancer agents in acute T lymphoblastic leukemia

A series of quinizarin derivatives containing quaternary ammonium salts and/or thiourea groups were synthesized and their anticancer activities against leukemia cell lines have been tested. Results showed that most of quinizarin derivatives could inhibit the proliferation of leukemia cells. Among these derivatives, compound 3 showed good inhibition activity against various leukemia cells with IC₅₀ values ranging from 0.90?±?2.55?μM to 10.90?±?3.66?μM. At the same time, compound 3 also inhibited the growth of human embryonic kidney-293 cell (HEK-293). Molt-4 and Jurkat cells, acute T lymphoblastic leukemia (T-ALL) cell lines, were selected to reveal potential anticancer mechanism of compound 3. Compound 3 inhibited the proliferation of Molt-4 and Jurkat cells in a dose- and time-dependent manner and led to a marked G0/G1 phase arrest. Analysis of Annexin V-APC and intracellular reactive oxygen species (ROS) level by flow cytometry showed that compound 3 induced significant apoptosis in Molt-4 and Jurkat cells. Western blotting assay showed that compound 3 activated the caspase-dependent apoptosis pathway and induced the degradation of Bcl-2 and c-myc protein.     

Design,synthesis and biological evaluation of benzofuran appended benzothiazepine derivatives as inhibitors of butyrylcholinesterase and antimicrobial agents

A series of bezofuran appended 1,5-benzothiazepine compounds 7a–v was designed, synthesized and evaluated as cholinesterase inhibitors. The biological assay experiments showed that most of the compounds displayed a clearly selective inhibition for butyrylcholinesterase (BChE), while a weak or no effect towards acetylcholinesterase (AChE) was detected. All analogs exhibited varied BChE inhibitory activity with IC₅₀ value ranging between 1.0?±?0.01 and 72?±?2.8?μM when compared with the standard donepezil (IC₅₀, 2.63?±?0.28?μM). Among the synthesized derivatives, compounds 7l, 7m and 7k exhibited the highest BChE inhibition with IC₅₀ values of 1.0, 1.0 and 1.8?μM, respectively. The results from a Lineweaver-Burk plot indicated a mixed-type inhibition for compound 7l with BChE. In addition, docking studies confirmed the results obtained through in vitro experiments and showed that most potent compounds bind to both the catalytic anionic site (CAS) and peripheral anionic site (PAS) of BChE active site. The synthesized compounds were also evaluated for their in vitro antibacterial and antifungal activities. The results indicated that the compounds possessed a broad spectrum of activity against the tested microorganisms and showed high activity against both gram positive and gram negative bacteria and fungi.     

Artemisinin-indole and artemisinin-imidazole hybrids: Synthesis,cytotoxic evaluation and reversal effects on multidrug resistance in MCF-7/ADR cells

A series of artemisinin derivatives with MDR reversal activity were designed and synthesized. All hybrids were screened to anticancer activities against four human cancer cell lines (A549, MCF-7, HepG-2, MDA-MB-231) and normal human hepatic cell (L02) in vitro. Most of the new compounds showed higher anticancer activities than artemisinin, among which compounds 11a and 11c displayed superior potency with IC₅₀ 6.78?μM and 5.25?μM against MCF-7, respectively. The further research indicated that the most potent 11c induced cell cycle arrest at G2 phase in MCF-7. Additionally, compound 11c showed remarkable MDR reversal activity which reversed adriamycin against MCF-7/ADR cells with IC₅₀ 0.76?μM.     

Semi-synthesis and anti-tumor activity of novel 25-OCH3-PPD derivatives incorporating aromatic moiety

Previously we have reported that 25-OCH₃-PPD could suppress the reproduction of cancer cells and cause apoptosis without obvious toxicity. Herein, we aimed to enhance its bioactivity by introducing aromatic groups to its dammarane-type skeleton. These synthesized derivatives were tested for their inhibitory activities against five cancer cell lines. Of them, compounds 3a, 14a and 18a had the strongest antiproliferative activities against tumor cells (IC₅₀?<?15?µM, 5-fold to 10-fold increases than 25-OCH₃-PPD). Especially compound 14a displayed the most potent activity against DU145, MCF-7 and HepG2 cells (IC₅₀?=?6.7?±?0.8, 4.3?±?0.8 and 5.8?±?0.6?µM, respectively). Structure-activity relationships demonstrated that having aromatic ester at the C3 position could improve the bioactivity. The data provided new insights into exploring novel antiproliferative lead compounds.     

Synthesis and biological evaluation of irreversible EGFR tyrosine kinase inhibitors containing pyrido[3,4-d]pyrimidine scaffold

In the present study, a new class of compounds containing pyrido[3,4-d]pyrimidine scaffold with an acrylamide moiety was designed as irreversible EGFR-TKIs to overcome acquired EGFR-T790M resistance. The most promising compound 25h inhibited HCC827 and H1975 cells growth with the IC₅₀ values of 0.025?μM and 0.49?μM, respectively. Meanwhile, 25h displayed potent inhibitory activity against the EGFR^L858R (IC₅₀?=?1.7?nM) and EGFR^L858R/T790M (IC₅₀?=?23.3?nM). 25h could suppress EGFR phosphorylation in HCC827 and H1975 cell lines and significantly induce the apoptosis of HCC827 cells. Additionally, compound 25h could remarkably inhibit cancer growth in established HCC827 xenograft mouse model at 50?mg/kg in vivo. These results indicated that the 2,4-disubstituted 6-(5-substituted pyridin-2-amino)pyrido[3,4-d]pyrimidine derivatives can serve as effective EGFR inhibitors and potent anticancer agents.     

Ultrasonic synthesis of tyramine derivatives as novel inhibitors of α-glucosidase in vitro

Tyramine derivatives 3–27 were synthesized by using conventional and environmental friendly ultrasonic techniques. These derivatives were then evaluated for the first time for their α-glucosidase (Sources: Saccharomyces cerevisiae and mammalian rat-intestinal acetone powder) inhibitory activity by using in vitro mechanism-based biochemical assays. Compounds 7, 14, 20, 21 and 26 were found to be more active (IC₅₀?=?49.7?±?0.4, 318.8?±?3.7, 23.5?±?0.9, 302.0?±?7.3 and 230.7?±?4.0?μM, respectively) than the standard drug, acarbose (IC₅₀?=?840.0?±?1.73?μM (observed) and 780?±?0.028?μM (reported)) against α-glucosidase obtained from Saccharomyces cerevisiae. Kinetic studies were carried out on the most active members of the series in order to determine their mode of inhibition and dissociation constants. Compounds 7, 20 and 26 were found to be the competitive inhibitors of α-glucosidase. These compounds were also screened for their protein antiglycation, and dipeptidyl peptidase-IV (DPP-IV) inhibitory activities. Only compounds 20, 22 and 27 showed weak antiglycation activity with IC₅₀ values 505.27?±?5.95, 581.87?±?5.50 and 440.58?±?2.74?μM, respectively. All the compounds were found to be inactive against DDP-IV enzyme. Inhibition of α-glucosidase, DPP-IV enzymes and glycation of proteins are valid targets for the discovery of antidiabetic drugs. Cytotoxicity of compounds 3–27 was also evaluated by using mouse fibroblast 3T3 cell lines. All the compounds were found to be noncytotoxic. The current study describes the synthesis α-glucosidase inhibitory activity of derivatives, based on a natural product tyramine template. The compounds reported here may serve as the starting point for the design and development of novel α-glucosidase inhibitors as antidiabetic agents.     

Synthesis and molecular docking studies of some 4-phthalimidobenzenesulfonamide derivatives as acetylcholinesterase and butyrylcholinesterase inhibitors

A series of 4-phthalimidobenzenesulfonamide derivatives were designed, synthesized and evaluated for the inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Structures of the title compounds were confirmed by spectral and elemental analyses. The cholinesterase (ChE) inhibitory activity studies were carried out using Ellman’s colorimetric method. The biological activity results revealed that all of the title compounds (except for compound 8) displayed high selectivity against AChE. Among the tested compounds, compound 7 was found to be the most potent against AChE (IC₅₀=?1.35?±?0.08?μM), while compound 3 exhibited the highest inhibition against BuChE (IC₅₀=?13.41?±?0.62?μM). Molecular docking studies of the most active compound 7 in AChE showed that this compound can interact with both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE.     

Investigation of chemical reactivity of 2-alkoxy-1,4-naphthoquinones and their anticancer activity

To establish the structure-activity relationship of 5-hydroxy-1,4-naphthoquinones toward anticancer activity, a series of its derivatives were prepared and tested for the activity (IC₅₀ in µM) against three cell lines; colo205 (colon adenocarcinoma), T47D (breast ductal carcinoma) and K562 (chronic myelogenous leukemia). Among them 2 (IC₅₀: 2.3; 2.0; 1.4?µM), 6 (IC₅₀: 1.9; 2.2; 1.3?µM), 9 (IC₅₀: 0.7; 1.7; 0.9?µM) and 10 (IC₅₀:1.7; 1.0; 1.2?µM) showed moderate to excellent activity. Our perception toward the DNA substitution of alkoxy groups at the C2 position of these naphthoquinones for the anticancer activity led us to investigate their reactivity of substitution toward dimethylamine as a nucleophile. The ease of the substitution of alkoxy groups at the C2 position with dimethylamine is strongly accelerated by hydroxyl group at C5 position and is well correlated with the found anticancer activity results.     

Developing potential Helicobacter pylori urease inhibitors from novel oxoindoline derivatives: Synthesis,biological evaluation and in silico study

By recruiting the important moiety from Shikonin, a series of novel oxoindoline derivatives S1–S20 have been synthesized for inhibiting H. pylori urease. The most potent compound S18 displayed better activity (IC₅₀?=?0.71?μM; MIC?=?0.48?μM) than the positive controls AHA (IC₅₀?=?17.2?μM) and Metronidazole (MIC?=?31.3?μM). With low cytotoxicity, it showed considerable potential for further development. Docking simulation revealed the possible binding pattern of this series. 3D QSAR model was built to discuss SAR and give useful hints for future modification.     

Synthesis and bioevaluation study of novel N-methylpicolinamide and thienopyrimidine derivatives as selectivity c-Met kinase inhibitors

Four series of N-methylpicolinamide moiety and thienopyrimidine moiety bearing pyridazinone were designed and synthesized and evaluated for the IC₅₀ values against three cancer cell lines (A549, HepG2 and MCF-7) and some selected compounds were further evaluated for the activity against c-Met, Flt-3, VEGFR-2, c-Kit and EGFR kinases. Three compounds (35, 39 and 43) showed more active than positive control Foretinib against A549, HepG2 and MCF-7 cell lines. The most promising compound 43 showed superior activity against A549, HepG2 and MCF-7, with the IC₅₀ values of 0.58?±?0.15?µM, 0.47?±?0.06?µM and 0.74?±?0.12?µM, which were 3.73–5.39-fold more activity than Foretinib, respectively. The experiments of enzyme-based showed that 43 restrain the c-Met selectively, with the IC₅₀ values of 16?nM, which showed equal activity to Foretinib (14?nM) and better than the compound 5 (90?nM). Moreover, AO and Annexin V/PI staining and docking studies were carried out.     

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.