Yong-Tao Duan

Sulfonamides containing coumarin moieties selectively and potently inhibit carbonic anhydrases II and IX: Design, synthesis, inhibitory activity and 3D-QSAR analysis

A series of sulfonamides containing coumarin moieties had been prepared that showed a very interesting profile for the inhibition of two human carbonic anhydrase inhibitors. These compounds were evaluated for their ability to inhibit the enzymatic activity of the physiologically dominant isozymes hCA II and the tumor-associated isozyme hCA IX. The most potent inhibitor against hCA II and IX were compounds 5d (IC₅₀ = 23 nM) and 5l (IC₅₀ = 24 nM), respectively. These sulfonamides containing coumarin moieties may prove interesting lead candidates to target tumor-associated CA isozymes, wherein the CA domain is located extracellularly. Eighteen compounds were scrutinized by CoMFA and CoMSIA techniques of 3D quantitative structure-activity relationship. Nine of the compounds were evaluated for cytotoxicity against human macrophage.

Design, synthesis and biological evaluation of pyrazolyl-nitroimidazole derivatives as potential EGFR/HER-2 kinase inhibitors.

A series of novel pyrazole-nitroimidazole derivatives had been arranged and evaluated for their EGFR/HER-2 tyrosine kinase inhibitory activity as well as their antiproliferative properties on four kinds of cancer cell lines (MCF-7, Hela, HepG2, B16-F10). The bioassay results showed most of the designed compounds exhibited potential antiproliferation activity, with the IC50 values ranging from 0.13μM to 128.06μM in four tumor cell lines. Among them, compound 5c exhibited remarkable inhibitory activity against EGFR/HER-2 tyrosine kinase with IC50 value of 0.26μM/0.51μM, respectively, comparable to the positive control erlotinib (IC50=0.41μM for HER-2 and IC50=0.20μM for EGFR) and lapatinib (IC50=0.54μM for HER-2 and IC50=0.28μM for EGFR). Molecular modeling simulation studies were performed in order to predict the biological activity of the proposed compounds and activity relationship (SAR) of these pyrazole-nitroimidazole derivatives.

Design, Synthesis and Antitumor Activity of Novel link-bridge and B-Ring Modified Combretastatin A-4 (CA-4) Analogues as Potent Antitubulin Agents.

A series of 12 novel acylhydrazone, chalcone and amide–bridged analogues of combretastatin A-4 were designed and synthesized toward tubulin. All these compounds were determined by elemental analysis, 1H NMR, and MS. Among them, compound 7 with acylhydrazone-bridge, bearing a benzyl at the indole-N position, was identified as a potent antiproliferative agent against a panel of cancer cell lines with IC50 values ranging from 0.08 to 35.6 μM. In contrast, its cytotoxic effects on three normal human cells were minimal. Cellular studies have revealed that the induction of apoptosis by compound 7 was associated with a collapse of mitochondrial membrane potential, accumulation of reactive oxygen species, alterations in the expression of some cell cycle-related proteins (Cyclin B1, Cdc25c, Cdc2, P21) and some apoptosis-related proteins (Bax, PARP, Bcl-2, Caspase3). The docking mode showed the binding posture of CA-4 and compound 7 are similar in the colchicine-binding pocket of tubulin, as confirmed by colchicine-tubulin competitive binding assay, tubulin polymerization inhibitory activity, extracellular protein expression determination assay and confocal immunofluorescence microscopy. In vivo study, compound 7 effectively inhibited A549 xenograft tumor growth without causing significant loss of body weight suggesting that compound 7 is a promising new antimitotic agent with clinical potential.

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

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

Potentiating 1-(2-hydroxypropyl)-2-styryl-5-nitroimidazole derivatives against antibacterial agents: design, synthesis and biology analysis.

A series of novel 1-(2-hydroxypropyl)-2-styryl-5-nitroimidazole derivatives had been designed, synthesized, isolated and evaluated as potentiators of antibacterial agents. All these synthesized compounds were determined by elemental analysis, (1)H NMR, and MS. Their biological activities were also evaluated against two Gram-negative bacterial strains: Escherichia coli and Pseudomonas aeruginosa and two Gram-positive bacterial strains: Bacillus thuringiensis and Bacillus subtilis by MTT method as potential FabH inhibitory. The results showed that compound 30 exhibited the most potent E. coli FabH inhibitory activity with IC50 of 4.6 μM. Molecular modeling simulation studies were performed in order to predict the biological activities of the proposed compounds. All compounds have been tested for toxicity by MTT assay on human macrophage.

Exploration of Structure-Based on Imidazole Core as Antibacterial Agents

Imidazole, a five-membered heterocycle having three carbon atoms, and two double bonds, having efficient antibacterial Escherichia coli, Bacillus subtili, Bacillus proteus, Staphylococcus aureus, Pseudomonas aeruginosa, and Helicobacter pyloriurease etc, shows a broad-spectrum of antibacterial activities. To Search new antibacterial drugs to overcome resistance of microorganisms to antibiotics, to date hundreds of this sort of derivatives have been synthesized and possess potent antibacterial activity. As the structure of imidazole derivatives is various, the target of antibacterial is also diverse including β-Lactamases, β-ketoacyl-acyl carrier protein synthase III (FabH), DNA gyrase and topoisomerase, glutamate racemase and urease. In this review, we will discuss the emergence of resistance to antibiotics and attempt to summarize the main developments of imidazole derivatives in the past ten years. We hope that increasing knowledge of the structure-activity relationship (SAR) will be beneficial to the rational design of new generation of small molecule antibacterial drugs.

Synthesis, biological evaluation, and molecular docking studies of novel 2-styryl-5-nitroimidazole derivatives containing 1,4-benzodioxan moiety as FAK inhibitors with anticancer activity

A series of 2-styryl-5-nitroimidazole derivatives containing 1,4-benzodioxan moiety (3a-3r) has been designed, synthesized and their biological activities were also evaluated as potential antiproliferation and focal adhesion kinase (FAK) inhibitors. Among all the compounds, 3p showed the most potent activity in vitro which inhibited the growth of A549 with IC50 value of 3.11 μM and Hela with IC50 value of 2.54 μM respectively. Compound 3p also exhibited significant FAK inhibitory activity (IC50=0.45 μM). Docking simulation was performed for compound 3p into the FAK structure active site to determine the probable binding model.

Synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives: assessment of their antimicrobial, antituberculosis and antioxidant activity

A new series of pyrazolo[1,2-b]phthalazine derivatives (4a–p) bearing the 5-aryloxypyrazole nucleus was synthesized by one-pot, three-component, base-catalyzed cyclo condensation reaction of 3-methyl-5-aryloxy-1-aryl-1H-pyrazole-4-carbaldehyde (1a–d), malononitrile or ethyl cyanoacetate (2a–b) and 2,3-dihydro-1,4-phthalazinedione (3a–b) in ethanol containing an eco friendly base, NaOH, in good to excellent yields. All synthesized compounds (4a–p) were duly characterized by physico-chemical parameters, 1H NMR, 13C NMR, FT-IR and LCMS techniques. In vitro antimicrobial activity of the synthesized compounds was investigated against a representative panel of pathogenic strains. Compounds 4e, 4g, 4h, 4k and 4o exhibited excellent antimicrobial activity compared with first line drugs. In vitro antituberculosis activity was evaluated against Mycobacterium tuberculosis H37Rv, and compounds 4g and 4o emerged as the promising antimicrobial members with better antituberculosis activity. A brine shrimp bioassay was carried out to study the in vitro cytotoxic properties of the synthesized compounds. In vitro antioxidant activity was evaluated by the ferric-reducing antioxidant power method. Compounds 4c, 4d, 4g and 4h showed the highest antioxidant potencies.

Synthesis and biological evaluation of quinoline–imidazole hybrids as potent telomerase inhibitors: a promising class of antitumor agents

A series of 1-isoquinoline-2-styryl-5-nitroimidazole derivatives has been synthesized and screened for telomerase inhibitory as well as antiproliferative properties on four variant cancer cell lines (U251, Hela, HepG-2 and A549). The bioassay results showed that most of the designed compounds exhibited moderate to potent in vitro inhibitory activity in the enzymatic and cellular assays, of which compounds 3u and 3v were revealed the most potent telomerase inhibitors, with IC50 values of 0.98 μM and 1.92 μM, respectively, compared to staurosporine. Docking simulation was performed to position compounds 3u and 3v into the telomerase active site to determine the probable binding pose. Twenty three compounds were scrutinized by the CoMFA and CoMSIA techniques of 3D Quantitative Structure–Activity Relationship (QSAR). These new findings along with molecular docking observations could provide important information that compounds 3u and 3v with potent inhibitory activity in tumor growth inhibition may be potential anticancer agents.

Novel metronidazole-sulfonamide derivatives as potent and selective carbonic anhydrase inhibitors: design, synthesis and biology analysis

Metronidazole–sulfonamide derivatives 4a–4l, a new class of human carbonic anhydrase inhibitors (hCA), were designed, synthesized, isolated, and evaluated for their ability to inhibit the enzymatic activity of the physiologically dominant isozymes hCA II and the tumor-associated isozyme hCA IX (h = human). Many of these compounds inhibited CA II and IX in the range of 16–137 and 38–169 nM, respectively. Among all the compounds, the most potent inhibitor against hCA II and IX were compounds 4b (IC50 = 16 nM) and 4h (IC50 = 38 nM). Conversely compounds 4e and 4d displayed the most potent growth inhibitory activity against B16-F10 and MCF-7 cancer cell lines in vitro, respectively, with an IC50 value of 150 nM for B16-F10 and 6.5 nM for MCF-7. These metronidazole–sulfonamide derivatives may prove interesting lead candidates to target tumor-associated CA isozymes, wherein the CA domain is located extracellularly. All the new compounds were evaluated for cytotoxicity against human macrophages by MTT assay.