Synthesis and biological evaluation of indole derivatives as α-amylase inhibitor

A series of twenty indole hydrazone analogs (1–21) were synthesized, characterized by different spectroscopic techniques such as ¹H NMR and EI-MS, and screened for α-amylase inhibitory activity. All analogs showed a variable degree of α-amylase inhibition with IC₅₀ values ranging between 1.66 and 2.65 μM. Nine compounds that are 1 (2.23 ± 0.01 μM), 8 (2.44 ± 0.12 μM), 10 (1.92 ± 0.12 μM), 12 (2.49 ± 0.17 μM), 13 (1.66 ± 0.09 μM), 17 (2.25 ± 0.1 μM), 18 (1.87 ± 0.25 μM), 20 (1.83 ± 0.63 μM), and 19 (1.97 ± 0.02 μM) showed potent α-amylase inhibition when compared with the standard acarbose (1.05 ± 0.29 μM). Other analogs showed good to moderate α-amylase inhibition. The structure activity relationship is mainly focusing on difference of substituents on phenyl part. Molecular docking studies were carried out to understand the binding interaction of the most active compounds.     

Synthesis and biological evaluation of curcumin derivatives modified with α-amino boronic acid as proteasome inhibitors

Curcumin is a well-known pharmacophore and some of its derivatives are shown to target 20S proteasome recently. In this report, we designed and synthesized two series of curcumin derivatives modified with different α-amino boronic acids as potent proteasome inhibitors. The synthesized compounds were evaluated for their cytotoxic activities against HCT116 cells, and the results showed that all of them exhibited excellent cell growth inhibitory activity comparing with curcumin, with the IC₅₀ values varying from 0.17?μM to 1.63?μM. Compound II-2F with free boronic acid was assayed for its proteasome inhibitory activity and the results indicated that II-2F exhibited more potent inhibitory activity against ChT-L with high subunit selectivity than any other reported curcumin derivatives.     

Synthesis,photophysical properties and biological evaluation of β-alkylaminoporphyrin for photodynamic therapy

A series of β-alkylaminoporphyrins conjugated with different amines at β position (D1–D3) or with electron-donating and electron-withdrawing substituents at phenyl position (D4–D6) were synthesized. Their photophysical and photochemical properties, intracellular localization, photocytotoxicities in vitro and vivo were also investigated. All target compounds exhibited no cytotoxicities in the dark and excellent photocytotoxicities against HeLa cells. Among them, D6 showed the highest phototoxicity and the lowest dark toxicity, which was more phototoxic than Hematoporphyrin monomethyl ether (HMME). In addition, D6 exhibited best photodynamic antitumor efficacy on BALB/c nude mice bearing HeLa tumor. Therefore, D6 is a powerful and promising antitumor photosensitizer for photodynamic therapy.     

Synthesis and biological evaluation of novel cryptophycin analogs with modification in the β-alanine region

Structure modification of the β-alanine region (fragment C) of the potent antimitotic agent cryptophycin was investigated. This includes: (1) introduction of substituents at the previously unsubstituted C7 position of the macrolide ring and (2) replacement of the (2R)-3-amino-2-methyl-propanoic acid (β-alanine) with various (1)-amino acids to give the corresponding 15-membered unnatural cryptophycin analogs.     

Synthesis and biological evaluation of novel 4β-(1,3,4-oxadiazole-2-amino)-podophyllotoxin derivatives

A series of new 4β-(1,3,4-oxadiazole-2-amino)-podophyllotoxin derivatives were designed and synthesized. Their cytotoxicity in vitro against six tumor cell lines (DU-145, SGC-7901, A549, SH-SY5Y, HepG2 and HeLa) were evaluated by standard MTT assay. The pharmacological results showed that most of the newly synthesized podophyllotoxin derivatives displayed potent cytotoxicity against at least one of the tested tumor cells; and among the new derivatives, 11b was more potent than podophyllotoxin against HepG2 and Hela cell lines. Furthermore, 11b exhibited much better selectivity toward the normal cell lines L929 and Vero than etoposide, 5-Fu and podophyllotoxin. The possible antitumor mechanism of 11b is to inhibit the activity of DNA topoisomerase II, result in the S-phase arrest, and then cause apoptotic cell death.     

Synthesis and biological evaluation of indole-chalcone derivatives as β-amyloid imaging probe

A series of chaclone derivatives containing an indole moiety were evaluated in competitive binding assays with Aβ_1-42 aggregates versus [¹²⁵I]IMPY. The affinity of these compounds ranged from 4.46 to >1008 nM, depending on the substitution on the phenyl ring. Fluorescent staining in vitro showed that one compound with a N,N-dimethylamino group intensely stained Aβ plaques within brain sections of AD transgenic mice. The radioiodinated probe [¹²⁵I]-(E)-3-(1H-indol-5-yl)-1-(4-iodophenyl)prop-2-en-1-one, [¹²⁵I]4, was prepared and autoradiography in sections of brain tissue from an animal model of AD showed that it labeled Aβ plaques specifically. However, experiments with normal mice indicated that [¹²⁵I]4 exhibited a low uptake into the brain in vivo (0.41% ID/g at 2 min). Additional chemical modifications of this indole-chalcone structure may lead to more useful imaging agents for detecting β-amyloid plaques in the brains of AD patients.     

Hetarylcoumarins: Synthesis and biological evaluation as potent α-glucosidase inhibitors

In search of better α-glucosidase inhibitors, a series of novel hetarylcoumarins (3a-3j) were designed and synthesized through a facile multicomponent route where p-toluenesulfonic acid (PTSA) was explored as an efficient catalyst. These new scaffolds were further evaluated for their α-glucosidase inhibition potentials. All the derivatives exhibited good to excellent results which were comparable or even better than of standard drug acarbose. Of these compounds, a dihalogenated compound 3f was found to be the most effective one with IC₅₀: 2.53 ± 0.002 µM. Molecular docking has predicted the plausible binding interactions of compounds 3f, 3g and 3j with α-glucosidase.     

Synthesis and biological evaluation of novel N-arylidenequinoline-3-carbohydrazides as potent β-glucuronidase inhibitors

Thirty N-arylidenequinoline-3-carbohydrazides (1–30) have been synthesized and evaluated against β-glucuronidase inhibitory potential. Twenty four analogs showed outstanding β-glucuronidase activity having IC₅₀ values ranging between 2.11 ± 0.05 and 46.14 ± 0.95 than standard d-saccharic acid 1,4 lactone (IC₅₀ = 48.4 ± 1.25 μM). Six analogs showed good β-glucuronidase activity having IC₅₀ values ranging between 49.38 ± 0.90 and 80.10 ± 1.80. Structure activity relationship and the interaction of the active compounds and enzyme active site with the help of docking studies were established. Our study identifies novel series of potent β-glucuronidase inhibitors for further investigation.     

One-pot synthesis of thioxo-tetrahydropyrimidine derivatives as potent β-glucuronidase inhibitor,biological evaluation,molecular docking and molecular dynamics studies

A series of N,N-diethyl phenyl thioxo-tetrahydropyrimidine carboxamide have been synthesized and investigated for their β-glucuronidase inhibitory activities. All molecules exhibited excellent inhibition with IC₅₀ values ranging from 0.35 to 42.05 µM and found to be even more potent than the standard d-saccharic acid. Structure-activity relationship analysis indicated that the meta-aryl-substituted derivatives significantly influenced β-glucuronidase inhibitory activities while the para-substitution counterpart outperforming moderate potency. The most potent compound in this series was 4g bearing thiophene motif with IC₅₀ of 0.35 ± 0.09 µM. To verify the SAR, molecular docking and molecular dynamics studies were also performed.     

Synthesis and biological evaluation of α-methylidene-δ-lactones with 3,4-dihydrocoumarin skeleton

A series of new 3-methylidenechroman-2-ones bearing various aromatic moieties and various substituents at position 4 were synthesized in a three step reaction sequence. Friedel-Crafts alkylation of phenols or naphthols using ethyl 3-methoxy-2-diethoxyphosphorylacrylate in the presence of trifluoromethanesulphonic acid gave 3-diethoxyphosphorylchromen-2-ones. These compounds were employed as Michael acceptors in the reaction with Grignard reagents to give adducts which were finally used as Horner-Wadsworth-Emmons reagents for the olefination of formaldehyde. All obtained 3-methylidenechroman-2-ones were tested against two human leukemia cell lines NALM-6 and HL-60 as well as MCF-7 breast cancer and HT-29 colon cancer adenocarcinomas. Several obtained methylidenechromanones displayed high cytotoxic activity with IC(50) values below 1μM, mainly against leukemia and MCF-7 cell lines. Investigation of structure-activity relationships revealed that the presence of additional, ortho-fused benzene ring and n-butyl or i-propyl group in position 4 enhances the activity. Selected methylidenechromanones were also tested on normal human umbilical vein endothelial cells (HUVEC) and chromanone 14o was found to be eightfold more toxic against MCF-7 than normal cells. Furthermore, antimicrobial assays revealed that chromanone 14n is highly active and bactericidal at concentration equal to MIC or 2MIC against nosocomial and community-associated staphylococci (MRSA) which are resistant to most or all available therapeutic classes of antimicrobial drugs.     

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.     

Novel cycloalkylthiophene–imine derivatives bearing benzothiazole scaffold: Synthesis,characterization and antiviral activity evaluation

A series of novel cycloalkylthiophene–imine derivatives containing benzothiazole unit were designed, synthesized and evaluated for their anti-viral activities. The bio-evaluation results indicated that some of the target compounds (such as 5g, 5i, 5u) exhibited good to moderate antiviral effect on CVB5, ADV7 and EV71 viruses, however, these compounds did not have inhibition activity against H1N1 virus. Especially, the compounds 4c and 4d also exhibited high antiviral activities, which provide a new and efficient approach to evolve novel multi-functional antiviral agents by rational integration of active pharmacophores.     

Synthesis, biological evaluation and molecular modeling of novel triazole-containing berberine derivatives as acetylcholinesterase and β-amyloid aggregation inhibitors

A series of novel triazole-containing berberine derivatives were synthesized via the azide-alkyne cycloaddition reaction. Their biological activity as inhibitors of both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) were evaluated. Among them, compound 16d, which featured a diisopropylamino substitution at the 4-position of triazole ring, was found to be a potent inhibitor of AChE, with IC(50) value of 0.044 μM. Compound 18d, which beares a butyl at the 4-position of the triazole ring, showed the highest potency of β-amyloid aggregation inhibition (77.9% at 20 μM). Molecular modeling studies indicated that the triazole moiety of berberine derivatives displayed a face-to-face π-π stacking interaction in a 'sandwich' form with the Trp84 (4.09 ?) and Phe330 (4.33 ?) in catalytic sites of AChE.     

Synthesis,biological evaluation and SAR studies of ursolic acid 3β-ester derivatives as novel CETP inhibitors

Cholesteryl ester transfer protein (CETP) is an attractive therapeutic target for the prevention and treatment of cardiovascular diseases by lowering low-density lipoprotein cholesterol levels as well as raising high-density lipoprotein cholesterol levels in human plasma. Herein, a series of ursolic acid 3β-ester derivatives were designed, synthesized and evaluated for the CETP inhibiting activities. Among these compounds, the most active compound is U12 with an IC₅₀ value of 2.4 μM in enzymatic assay. The docking studies showed that the possible hydrogen bond interactions between the carboxyl groups at both ends of the molecule skeleton and several polar residues (such as Ser191, Cys13 and Ser230) in the active site region of CETP could significantly enhance the inhibition activity. This study provides structural insight of the interactions between these pentacyclic triterpenoid 3β-ester derivatives and CETP protein for the further modification and optimization.     

Synthesis and biological evaluation of 4β-acrylamidopodophyllotoxin congeners as DNA damaging agents

A series of new 4β-acrylamidopodophyllotoxin derivatives (13a-o) were synthesized by coupling of substituted acrylic acids (10a-l and 11m-o) to the 4β-aminopodophyllotoxin. The synthesized derivatives 13a-o were evaluated for their cytotoxicity against five human cancer cell lines (breast, oral, colon, lung and ovarian). These podophyllotoxin conjugates have shown promising activity with GI?? values ranging from <0.1 to 0.29 μM. Some of the compounds 13j, 13k and 13l that showed significant antiproliferative activity were also evaluated for related cytotoxic effects in MCF-7 cells, and compared to etoposide. These compounds (13j, 13k and 13l) showed G2/M cell cycle arrest and the apoptotic event was found to be due to both the single-strand DNA breaks as observed by comet assay as well as double-strand breaks as observed by the large accumulation of gamma H2AX foci.     

Synthesis and biological evaluation of 4-styrylcoumarin derivatives as inhibitors of TNF-α and IL-6 with anti-tubercular activity

A series of 4-styrylcoumarin have been synthesized by Knoevenagel condensation between substituted 4-methylcoumarin-3-carbonitrile and different heterocyclic or aromatic aldehydes. 4-Methylcoumarin-3-carbonitrile has been synthesized by the base catalyzed reaction between substituted 2-hydroxyacetophenone and ethyl cyanoacetate. The structures of the newly synthesized compounds were confirmed by ¹H NMR, IR and mass spectral analysis. All the compounds were evaluated for their anti-inflammatory activity (against TNF-α and IL-6) and anti-tubercular activity. Compounds 6a, 6h and 6j exhibited promising activity against IL-6 with 72-87% inhibition and compound 6v showed potent activity against TNF-α with 73% inhibition at 10 μM concentration. Whereas compounds 6n, 6o, 6r and 6u showed very good anti-tubercular activity against Mycobacterium tuberculosis H37Rv strain at <6.25 μM.     

Novel tumor-targeted RGD peptide–camptothecin conjugates: Synthesis and biological evaluation

Five RGD peptide–camptothecin (CPT) conjugates were designed and synthesized with the purpose to improve the therapeutic index of this antitumoral drug family. New RGD cyclopeptides were selected on the basis of their high affinity to α_v integrin receptors overexpressed by tumor cells and their metabolic stability. The conjugates can be divided in two groups: in the first the peptide was attached to the drug through an amide bond, in the second through a hydrazone bond. The main difference between the two spacers lies in their acid stability. Affinity to the receptors was maintained for all conjugates and their internalization into tumor cells was demonstrated. The first group conjugates showed lower in vitro and in vivo activity than the parent drug, probably due to the excessive stability of the amide bond, even inside the tumor cells. Conversely, the hydrazone conjugates exhibited in vitro tumor cell inhibition similar to the parent drug, indicating high conversion in the culture medium and/or inside the cells, but their poor solubility hampered in vivo experiments. On the basis of these results, information was acquired for additional development of derivatives with different linkers and better solubility for in vivo evaluation.     

Synthesis,modification, and cytotoxic evaluation of 2,3-secotriterpenic β-ketoesters

A set of β-ketoesters was synthesized from 2,3-seco-18αH-oleanane and 2,3-secolupane bromomethyl ketones. Additionally, hydroxy derivatives with the A-seco- or five-membered A ring were obtained as a result of the reduction or of alkaline hydrolysis of acetic acid β-ketoesters 4, 9. Cytotoxic screening revealed the compound 4 with marked activity (IC₅₀ 3.07–3.61?µM) against the HCT 116, MS, RD TE32 cancer cells. The studies of the cytotoxic mechanism enabled elucidating the fact that treatment of the HCT 116 cells with compound 4 for 18?h leads to induction of apoptosis in a dose-dependent manner. This observation was confirmed by registration of chromatin condensation, by the fluorescence increased during Annexin V-FITC staining, and by appearance of a sub-G0 peak in the cell cycle analysis with DAPI. Compound 4 also inhibited migration of cancer cells in the wound healing assay.     

Structure-based design, synthesis, and biological evaluation of dihydroquinazoline-derived potent β-secretase inhibitors

Structure-based design, synthesis, and biological evaluation of a series of dihydroquinazoline-derived β-secretase inhibitors incorporating thiazole and pyrazole-derived P2-ligands are described. We have identified inhibitor 4f which has shown potent enzyme inhibitory (K(i)=13nM) and cellular (IC(50)=21nM in neuroblastoma cells) assays. A model of 4f was created based upon the X-ray structure of 3a-bound β-secretase. The model suggested possible interactions in the active site.     

Synthesis and biological evaluation of tyrosine modified analogues of the α4β7 integrin inhibitor biotin-R(8)ERY

The α4β7 integrin is a well-known target for the development of drugs against various inflammatory disease states including inflammatory bowel disease, type 1 diabetes and multiple sclerosis. The synthesis of a small library of cell-permeable β7 integrin inhibitors based on the peptide biotin-R(8)ERY is reported, in which the tyrosine residue has been modified by using the Suzuki-Miyaura cross-coupling reaction. The synthesised peptidomimetics were evaluated in a cell adhesion assay and shown to inhibit Mn(2+)-activated adhesion of mouse TK-1 T cells to mouse MAdCAM-1. All of the synthesised peptidomimetics are more active than our previously reported lead compound biotin-R(8)ERY with two of the analogues, 6 and 7, exhibiting IC(50) values of <15μM.