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G-quadruplex (G4) ligands are investigated to discover new anticancer drugs with increased cell-killing potency. These ligands can induce genome instability and activate innate immune genes at non-cytotoxic doses, opening the discovery of cytostatic immune-stimulating ligands. However, the interplay of G4 affinity/selectivity with cytotoxicity and immune gene activation is not well-understood. We investigated a series of closely related hydrazone derivatives to define the molecular bases of immune-stimulation activity. Although they are closely related to each other, such derivatives differ in G4 affinity, cytotoxicity, genome instability, and immune gene activation. Our findings show that G4 affinity of ligands is a critical feature for immune gene activation, whereas a high cytotoxic potency interferes with it. The balance of G4 stabilization versus cytotoxicity can determine the level of immune gene activation in cancer cells. Thus, we propose a new rationale based on low cell-killing potency and high immune stimulation to discover effective anticancer G4 ligands.

Targeting G-quadruplex structures is currently viewed as a promising anticancer strategy. Searching for potent and selective G-quadruplex binders, here we describe a small series of new monohydrazone derivatives designed as analogues of a lead which was proved to stabilize G-quadruplex structures and increase R loop levels in human cancer cells. To investigate the G-quadruplex binding properties of the new molecules, in vitro biophysical studies were performed employing both telomeric and oncogene promoter G-quadruplex-forming sequences. The obtained results allowed the identification of a highly selective G-quadruplex ligand that, when studied in human cancer cells, proved to be able to stabilize both G-quadruplexes and R loops and showed a potent cell killing activity associated with the formation of micronuclei, a clear sign of genome instability.

A series of new Knoevenagel adducts, bearing two indolinone systems, has been synthesized and evaluated on 60 human cancer cell lines according to protocols available at the National Cancer Institute (Bethesda, MD, USA). Some derivatives proved to be potent antiproliferative agents, showing GI50 values in the submicromolar range. Compound 5b emerged as the most active and was further studied in Jurkat cells in order to determine the effects on cell-cycle phases and the kind of cell death induced. Finally, oxidative stress and DNA damage induced by compound 5b were also analyzed.

The present study aims at the development and validation of a quali-quantitative headspace solid-phase microextraction gas chromatography–mass spectrometry (HS-SPME GC-MS) method for the analysis of odorants in different Chinese and Japanese green teas. A 65 µm PDMS/DVB fiber was used, and GC-MS was performed on a ZB-5 (30 m × 0.25 mm ID, 0.25 μm film) column. The main odorants in green tea samples were identified and the method was fully validated. Linearity (r2 0.981–0.999), sensitivity (LOQ 0.005–0.04 µg/mL), reproducibility (CV% 3.12–10.37), accuracy (recovery% 79.08–99.17) and matrix effect (ME% −9.5 to +4.5) were determined. Quantitation of 2,4-heptadienal, β-damascenone, β-ionone, linalool, indole, 2-ethyl-6-methyl-pyrazine, 2-ethyl-5-methyl-pyrazine, 2-ethyl-3,6-dimethylpirazine, 2-ethyl-3,5-dimethyl-pyrazine and 2-acetyl-pyrazine was carried out in the presence of isotopically labeled compounds as the internal standards. The proposed method was applied to the comparison of the profile of the volatile flavor compounds (VFCs) of green tea subjected to roasting treatment at three different temperatures (160, 180 and 200 °C for 30 min). In particular, the roasting process was monitored by following the quantitative variations of the selected odorant content, considered as the most important contributory components to the Hojicha or black tea (roasted tea) flavor. A temperature of 160 °C was found to be the best roasting temperature.

Cystic fibrosis is a genetic disease caused by loss-of-function mutations in the cystic fibrosis transmembrane conductance regulator gene, encoding for CFTR protein. The most frequent mutation is the deletion of phenylalanine at position 508 (F508del), which leads to distinct defects in channel gating and cellular processing. In last years, several thiazole containing small molecules, endowed with dual F508del-CFTR modulator activity, proved to be able to target these defects. In search of new chemical entities able to restore CFTR function, we designed and synthesized a small series of sixteen thiazole derivatives. The designed compounds were studied as correctors and potentiators of F508del-CFTR. Although none of the molecules showed significant corrector activity, compounds 10 and 11 exhibited potentiator effects, thus allowing to determine some basic structural features which enable to obtain F508del-CFTR potentiator activity. In silico ADME studies showed that these derivatives obey Lipinski's rule of five and are expected to be orally bioavailable. Therefore, these molecules may represent a good starting point for the design of analogues endowed with improved CFTR potentiator activity and a good pharmacokinetic profile.

A fluorescent derivative of trehalose with two dansyl groups (DAT) has been synthesized. It is characterised by a large Stokes shift, good permeability in human living cells and a well detectable fluorescent signal within the cells. Notably, in intestinal cells DAT is sequestered in vesicles induced by trehalose pre-treatment and colocalizes with lipid droplets.

A small library of 3-(5-imidazo[2,1-b]thiazolylmethylene)-2-indolinones has been synthesized and screened according to protocols available at the National Cancer Institute (NCI). Some derivatives were potent antiproliferative agents, showing GI 50 values in the nanomolar range. Remarkably, when most active compounds against leukemia cells were tested in human peripheral blood lymphocytes from healthy donors, were 100–200 times less cytotoxic. Some compounds, selected by the Biological Evaluation Committee of NCI, were examined to determine tubulin assembly inhibition. Furthermore, flow cytometric studies performed on HeLa, HT-29, and A549 cells, showed that compounds 14 and 25 caused a block in the G2/M phase. Interestingly, these derivatives induced apoptosis through the mitochondrial death pathway, causing in parallel significant activation of both caspase-3 and -9, PARP cleavage and down-regulation of the anti-apoptotic proteins Bcl-2 and Mcl-1. Finally, compound 25 was also tested in vivo in the murine BL6-B16 melanoma and E0771 breast cancer cells, causing in both cases a significant reduction in tumor volume.

In the present work we describe the synthesis, characterization and evaluation of neuroprotective effects of a focused library of 4-imidazo[2,1-b]thiazole-1,4-dihydropyridines. Furthermore, the new dihydropyridines were subjected to functional in vitro assays in cardiac tissues and vascular smooth muscle to determine their possible selectivity in counteracting the effects of neurodegeneration. In particular the strategy adopted for designing the compounds involves the imidazo[2,1-b]thiazole nucleus. The observed properties show that substituents at C2 and C6 of the bicyclic scaffold are able to influence the cardiovascular parameters and the neuroprotective activity. In comparison to nifedipine, a set of derivatives such as compound 6, showed a neuroprotective profile of particular interest.

The synthesis of new substituted E -3-(3-indolylmethylene)1,3-dihydroindol-2-ones is reported. The antiproliferative activity was evaluated according to protocols available at the National Cancer Institute (NCI), Bethesda, MD. The action of the most active compound 10 was further investigated in HL-60 leukemia cells. Results obtained show that it causes a block in cell cycle progression, with cell arrest in the G2/M phase, associated with activation of apoptosis accompanied with increased oxidative stress and deregulation of the homeostasis of divalent cations, with significant increase in the cellular concentrations of free Ca 2+ and Mg 2+ .

Thiazole is a well-known five-membered heterocyclic compound. Various methods have been worked out for its synthesis. In the last few decades, a lot of work has been done on thiazole ring in order to find new compounds related to this scaffold acting as antioxidant, analgesic, anti-inflammatory, antimicrobial, antifungal, antiviral, diuretic, anticonvulsant, neuroprotective and antitumor or cytotoxic drugs with lesser side effects. This review presents the up to date development of different thiazole derivatives. The present review gives an account of the recent therapeutic patent literature (2008-2012) describing the applications of thiazole and its derivatives on selected activities. In this review many of relevant biological properties and the therapeutic applications of thiazole derivatives reported in international patents from all companies have been discussed; an overview of the chemical matter has also been given. Because of the huge amount of patents registered in this period relative to thiazole derivatives, we focused our attention, in the first part of the review just published, on inhibitors of phosphatidylinositol-3-kinase, inhibitors of protein kinase and derivatives modulating enzymes related to metabolism, whereas in this second part we focused on thiazole derivatives having pharmacological activity towards receptors. Based on the large variety of possible therapeutic applications proposed in patents for thiazole derivatives having pharmacological activity towards receptors, it is possible to point out the unpredictability of pharmacological activity consequent to structural modification, more or less simple, of a prototype drug molecule. In any case the thiazole scaffold remains one of great potential for the chemical pharmaceutical research.

G-Quadruplex-binding compounds are currently perceived as possible anticancer therapeutics. Here, starting from a promising lead, a small series of novel hydrazone-based compounds were synthesized and evaluated as G-quadruplex binders. The in vitro G-quadruplex-binding properties of the synthesized compounds were investigated employing both human telomeric and oncogene promoter G-quadruplexes with different folding topologies as targets. The present investigation led to the identification of potent G-quadruplex stabilizers with high selectivity over duplex DNA and preference for one G-quadruplex topology over others. Among them, selected derivatives have been shown to trap G-quadruplex structures in the nucleus of cancer cells. Interestingly, this behavior correlates with efficient cytotoxic activity in human osteosarcoma and colon carcinoma cells.

Estragole, a volatile phenylpropanoid contained in a variety of edible herbs, has been demonstrated to be genotoxic and carcinogenic, and its addition as a flavoring substance to foodstuffs has been banned by the regulatory bodies of the European Union. Fast and accurate analytical methods for its determination in herbs are thus necessary to assess the dietary exposure of this substance in humans and, in particular, to sensitive groups. In the present study, headspace solid-phase microextraction (HS-SPME) combined with gas chromatography–mass spectrometry (GC–MS) was applied for determination of estragole in infusions from different widely used commercial herbal teas based on Foeniculum vulgare (fennel) seeds. The optimized HS-SPME extraction conditions involved the use of a polydimethylsiloxane fiber exposed to the herbal infusion for 20min at 50°C followed by GC–MS analysis. The method was fully validated for linearity, sensitivity, accuracy, and precision and applied to real samples; the level of estragole in infusions of commercial fennel seed teas was found to be within 50–250 uL/L.

Introduction: Thiazole is a well-known five-membered heterocyclic compound. Various methods have been worked out for its synthesis. In the last few decades, a lot of work has been done on thiazole ring in order to find new compounds related to this scaffold acting as an antioxidant, analgesic, anti-inflammatory, antimicrobial, antifungal, antiviral, diuretic, anticonvulsant, neuroprotective and antitumor or cytotoxic drugs with lesser side effects. This review presents the up to date development of different thiazole derivatives. Areas covered: This review gives an account of the recent therapeutic patent literature (2008 - 2012) describing the applications of thiazole and its derivatives on selected activities. In this review, many of the therapeutic applications of thiazole derivatives reported in international patents have been discussed. In addition to selected biological data, some of pharmaceutical applications are also summarized. Because of the large number of patents registered in this period relative to thiazole derivatives the attention was focused, in this first part of the review, on inhibitors of phosphatidylinositol-3-kinase, inhibitors of protein kinase and derivatives modulating enzymes related to metabolism. Expert opinion: This review of patented products presents the thiazole ring as the nucleus of the derivatives considered from a medicinal chemistry perspective. The applications are based firstly on the specific enzyme target with very low development in the disease treatment. Most of the described compounds are shown to have beneficial therapeutic effects but at the same time these compounds, selective for 'multi-signaling pathway' targets, may also increase the side-effect potential.

The synthesis, characterization, and functional in vitro assay in cardiac and smooth muscle (vascular and nonvascular) of a series of 4-imidazo[2,1-b] thiazole-1,4-dihydropyridines are reported. To define the calcium blocker nature of the imidazo[2,1-b]thiazole-1,4-DHPs and their selectivity on Ca v1.2 and Cav1.3 isoforms, we performed binding studies on guinea pig atrial and ventricular membranes on intact cells expressing the cloned Cav1.2a subunit and on rat brain cortex. To get major insights into the reasons for the affinity for Cav1.2 and/or Ca v1.3, molecular modeling studies were also undertaken. Some physicochemical and pharmacokinetic properties of selected compounds were calculated and compared. All the biological data collected and reported herein allowed us to rationalize the structure-activity relationship of the 4-imidazo[2,1-b]thiazole-1,4-DHPs and to identify which of these enhanced the activity at the central level. © 2013 American Chemical Society.

Bis-indolinone derivatives having either 2,6-disubstituted pyridine core (1a and 1b) or 1,10-disubstituted phenanthroline core (2a and 2b), already known to have antitumor activity, have been tested as potential G-quadruplex binders. Compounds 2a and 2b are able to selectively stabilize G-quadruplex over duplex DNA, and also to discriminate among different G-quadruplex structures, having a particular affinity for the parallel form of the human telomeric G-quadruplex. Both compounds are also able to induce telomeric DNA damage that may explain the activity of these compounds.

Background Fused five-membered heterocyclic rings containing bridgehead nitrogen atom are particularly versatile in the field of medicinal chemistry because of their different biological activities. Among them, the imidazo[2,1-b]thiazole is an attractive fused heterocyclic core that has been extensively studied. Objective The aim of the current study was to study the therapeutic applications of imidazo[2,1- b]thiazole derivatives as antimicrobial agents for the treatment of genitourinary infections. Method A traditional synthetic methodology was involved to obtain a small series of imidazothiazole derivatives. Results Herein, we report the antimicrobial activity of the imidazo[2,1-b]thiazole or imidazo[2,1- b]thiazolidine derivatives against selected fungi, Gram-positive and Gram-negative bacteria. Moreover, experiments were carried out to investigate the interference towards the endogenous microbiota. Conclusion The most interesting of the series are the thiocyano derivatives (19, 23) showing a good profile for the treatment of genitourinary infections: a spectrum of activity covering both bacteria and fungi together with a reduced impact versus critical lines of Lactobacillus exerting defense against pathogens.

none 8 no The rhizome of the Zingiber officinale Roscoe, a biennial herb growing in South Asia, is commonly known as ginger. Ginger is used in clinical disorders, such as constipation, dyspepsia, diarrhoea, nausea and vomiting and its use is also recommended by the traditional medicine for cardiopathy, high blood pressure, palpitations and as a vasodilator to improve the circulation. The decoction of ginger rhizome is widely used in Ayurvedic medicine. In this papery by high-performance liquid chromatography, we have seen that its main phytomarkers were 6-gingerol, 8-gingerol and 6-shogaol and we report the effects of the decoction of ginger rhizome on cardiovascular parameters and on vascular and intestinal smooth muscle. In our experimental models, the decoction of ginger shows weak negative inotropic and chronotropic intrinsic activities but a significant intrinsic activity on smooth muscle with a potency on ileum is greater than on aorta: EC50 = 0.66 mg/mL versus EC50 = 1.45 mg/mL. mixed Leoni, Alberto; Budriesi, Roberta; Poli, Ferruccio; Lianza, Mariacaterina; Graziadio, Alessandra; Venturini, Alice; Broccoli, Massimiliano; Micucci, Matteo Leoni, Alberto; Budriesi, Roberta; Poli, Ferruccio; Lianza, Mariacaterina; Graziadio, Alessandra; Venturini, Alice; Broccoli, Massimiliano; Micucci, Matteo

Imidazo[2,1-b]thiazole is a fused heterobicyclic system containing bridgehead nitrogen atom. Derivatives of this scaffold are especially attractive in the field of medicinal chemistry because of their broad spectrum of biological activities. The imidazo[2,1-b]thiazole system constitutes the core unit of the well-known anthelminthic and immunomodulatory agent Levamisole, marketed under the trade name Ergamisol© and discovered at Janssen Pharmaceutica in 1966.

Electronic nose and capillary electrophoresis were applied in quality control of green tea samples subjected to long-term storage. Twelve representative green teas were considered, available as an "aged" (tea leaves stored during a long-term period of two years) and/or "not aged" (fresh products) samples. Their infusions were analyzed by an electronic nose, equipped with an array of six metal oxide semiconductor (MOS) sensors to obtain olfactive fingerprints of the volatile compounds in the infusions headspace. Upon training and chemometric analysis of acquired data (linear discriminant analysis), the electronic nose was found to be able in correctly classifying unknown samples as "aged" or "not aged". Concomitantly, the infusion samples were analyzed by Cyclodextrin-modified Micellar Electrokinetic Chromatography (CD-MEKC) for determination of catechins. The analysis of seven most represented catechins and the methylxanthines theobromine and caffeine revealed a general loss of the polyphenols in each of the considered aged samples (up to 45%, w/w). In addition, the applied enantioselective method based on (2-hydroxypropyl)-beta-cyclodextrin (HP-beta CD) as chiral selector, was exploited for the estimation of (+)-Gallocatechin in the presence of (-)-Gallocatechin; the latter, as the non-native enantiomer, can be associated to the epimerisation of (-)-Epigallocatechin and was assumed as a marker occurring in case of uncorrected storage conditions of tea leaves. Interestingly, it was observed that epimerization did not significantly occur during aging. The application of CD-MEKC and electronic nose allowed for a fast characterization of green teas taking into account that the aroma is a decisive parameter for the acceptance of the product, whereas the catechins content is associated to the biological value.

A series of 2,5,6-substituted imidazo2,1-b]1,3,4]thiadiazole derivatives have been prepared and were tested for antiproliferative activity on cancer cells at the National Cancer Institute. Results showed that molecules with a benzyl group at position 2, exhibited an increase in activity for the introduction of a formyl group at the 5 position. The compound 2-benzyl-5-formyl-6-(4-bromophenyl)imidazo 2,1-b]1,3,4]thiadiazole 22 has been chosen for understanding the mechanism of action by various molecular and cellular biology studies. Results obtained from cell cycle evaluation analysis, analysis of mitochondrial membrane potential and Annexin V-FITC by flow cytometric analysis, ROS production and expression of apoptotic and DNA-repair proteins suggested that compound 22 induced cytotoxicity by activating extrinsic pathway of apoptosis, however, without affecting cell cycle progression. (C) 2014 Elsevier Ltd. All rights reserved.

Micellar electrokinetic chromatography was applied to the determination of the major phytomarkers, namely 2-hydroxy-4-methoxybenzaldehyde, 2-hydroxy-4-methoxybenzoic acid, and 3-hydroxy-4-methoxybenzaldehyde, of Hemidesmus indicus root, an Indian medicinal plant. H. indicus bioactive preparations were analyzed by reverse flow micellar electrokinetic chromatography (MEKC) using sodiumtaurodeoxycholate as the surfactant. A pH 2.5 phosphate buffer (50mM) was supplemented with 65mM of sodium taurodeoxycholate to produce the MEKC pseudostationary phase; because of the suppression of the electroosmotic flow, the migration of the partitioned analytes was toward the capillary anodic end. The use of a short fused-silica capillary (8.5 cm effective length; 50 µm i.d.) allowed the separation of phytomarkers, including vanillin and salicylaldehyde (reported as additional metabolites of H. indicus roots), in less than 8 min. The method showed good validation parameters and was applied to the analysis of methanol extracts and a root decoction of H. indicus, a promising botanical drug. The obtained results were compared to those from an independent high-performance liquid chromatography–mass spectrometry method. The 2-Hydroxy-4-methoxybenzaldehyde, 2-hydroxy-4-methoxybenzoic acid, and 3-hydroxy 4-methoxybenzaldehyde were found in all samples confirming their roles as phytomarkers. The absence of vanillin and salicylaldehyde suggested that these latter compounds should not be regarded as characteristic components of the bioactive preparations from the plant roots.

Background: Despite the fact that in recent years, a substantial progress has been made in the treatment of pulmonary hypertension, it is still a severe disease characterized by poor prognosis, and the search for new drugs remains a priority. Current remedies address mainly the vasoconstrictor/ vasodilator imbalance in the pulmonary circulation, while the causes of the disease are only moderately affected. Recently, the role of receptor and non receptor kinases in pulmonary hypertension has emerged and these targets were extensively considered for the development of new therapeutic strategies. This review discusses the patents on small-molecules targeting kinases involved in the proliferation/apoptosis imbalance, typically present in pulmonary hypertension. Methods: Bibliographic research for the inventions was carried out using Espacenet and Sci-Finder databases, “pulmonary hypertension and kinases” as research query and the range from 2010 to 2015. Only patents published in English were considered. A qualitative analysis of the contents of each patent was made to examine the reported compounds, the studies performed and the resulting conclusions. Results: The review includes about thirty applications. Moreover, in order to illustrate the pathophisiology of the disease and the mechanisms of the targets, about forty additional papers were reported. Considering that imatinib, a PDGF receptor inhibitor, entered the clinical trials for the treatment of pulmonary hypertension, the first patents were devoted to inhibitors of tyrosine kinase receptors, such as PDGFR and c-Kit. Subsequently, in addition to kinase receptors, the role of other pathways involved in pulmonary hypertension has emerged, and some research groups have focused their attention also on non-receptor kinases. Fifteen patents on this topic reported these new targets and new derivatives. However, in most of the inventions, although the pulmonary hypertension is among the treatable diseases, the compounds were subjected only to antiproliferative assays and not to specific tests on animal models. Conclusion: The studies reported in this review confirm the continuous research efforts aimed to identify new targets and new drugs for the treatment of pulmonary hypertension. Several inhibitors of kinase were described. These compounds could inhibit mainly important branching processes and pathological growth of blood vessels, thereby might increase the lifespan of patients.

2-Indolinone is a well-known aromatic heterocyclic organic compound. A lot of work has been done on this bicyclic structure by academic and company researchers to synthesize compounds directed to a plethora of molecular targets in order to discover new drug leads. This review presents up-to-date information in the field of cancer therapy research based on this small building block. Areas covered: The present review gives an account of the recent patent literature (2008–2014) describing the discovery of 2-indolinone derivatives with selected therapeutic activities. In this period, a large amount of patents were published on this topic. We have limited the analysis to 37 patents on 2-indolinone derivatives having potential clinical application as chemotherapeutic agents. In this review, the therapeutic applications of 2-indolinone derivatives for the treatment of cancer reported in international patents have been discussed. Expert opinion: 2-Indolinone is the scaffold of the compounds considered from a medicinal chemistry perspective. Many of them have been developed and marketed for therapeutic use. In cancer chemotherapy, progress has been made in designing selective 2- indolinone derivatives. Some of them show preclinical efficacy. However, 2-indolinone has not exhausted all of its potential in the development of new compounds for clinical applications and remains a great tool for future research.

The activity of a series of imidazo[2,1-b]thiazole guanylhydrazones as inhibitors of p90 ribosomal S6 kinase 2 (RSK2) is described. It was found that a small subset of compounds show both potent inhibition of RSK2 kinase activity and tumor cell growth in vitro. Detailed study of one of the most active compounds indicates a high degree of selectivity for inhibition of RSK2 compared to a spectrum of other related kinases. Selective inhibition of the MCF-7 breast tumor cell line compared to MCF-10A non-transformed cells, as well as selective inhibition of the biomarker GSK3 provides evidence that the compounds can affect the RSK2 target in cells.

The use of 2,5-dimethyl-1H-pyrrole-3,4-dicarbaldehyde as a precolumn derivatization reagent for LC analysis of amino acids is proposed. The compound reacts at mild conditions (10 min at ambient temperature) with primary amino groups. The derivatization conditions were optimised by considering different parameters (temperature, pH and reagent concentration) using L-Val. The reaction was found to be quantitative. The synthesized L-Val derivative was characterized by 1H-NMR and UV, whereas the adducts obtained by derivatization of 19 amino acids were separated by LC under reversed-phase conditions and detected at λ=320 nm. The method was applied successfully to the quali-quantitative analysis of commercial polyaminoacid preparations.

This paper reports the synthesis of new derivatives (formed by two indole systems separated by a central moiety) analogous of potent antitumor agents previously described. The activity of the bis-indoles bearing a pyridine core confirms the good result described in the previous paper and compound 4c was chosen for the first in vivo experiment (Hollow Fiber Assay). COMPARE analysis and structure–activity relationships were also considered. Contrary to data reported by other Authors, no correlations were found between antitumor activity and NQO1 induction.

The reaction between isatin and 2,5-dimethoxyaniline is described. The main product was identified as 3,3-bis(4-amino-2,5-dimethoxyphenyl)-1,3-dihydroindol-2-one. The antioxidant activity of the compounds isolated was evaluated with two methods. Three published antitumor E-3-(2-chloro-3-indolylmethylene)1,3-dihydroindol-2-ones entered the same tests to search whether they are endowed with antioxidant activity too. 3,3-Bis(4-amino-2,5-dimethoxyphenyl)-1,3-dihydroindol-2-one and the three antitumor agents showed a good chemical antioxidant activity.

A series of hydrochloride derivatives 2a – 9a and quaternary ammonium derivatives 3b – 9b of diphenidol have been synthesized and characterized in receptor binding and cellular functional assays versus human muscarinic M 1 –M 5 receptors expressed in CHO cells. Compound 8b , a methiodide derivative with a bipiperidinyl moiety and a second diphenidol framework, showed a potent and selective M 4 activity as competitive antagonist. Moreover 8b , acting as an allosteric modulator, was able to retard the dissociation rate of [ 3 H]- N -methylscopolamine from CHO-M 4 cell membranes exposed to atropine. Taken together, these data suggest that 8b might open new avenues to the discovery of novel multivalent antagonists for the muscarinic receptors.

The synthesis of a new series of imidazo[2,1-b]thiazole derivatives is described. They were tested as potential acetylcholinesterase and butyrylcholinesterase inhibitors by means of a chemiluminescent microassay. Although most of the new compounds did not show significant cholinesterase inhibition potency, three of them displayed selective antiacetylcholinesterase activity in the micromolar range.

The synthesis, characterization, and functional in vitro assays in cardiac tissues and smooth muscle (vascular and nonvascular) of a number of 4-imidazo[2,1-b]thiazole-1,4-dihydropyridines are reported. The binding properties for the novel compounds have been investigated and the interaction with the binding site common to other aryl-dihydropyridines has been demonstrated. Interestingly, the novel 4-aryl-dihydropyridines are L-type calcium channel blockers with a peculiar pharmacological behavior. Indeed, the imidazo[2,1-b]thiazole system is found to confer to the dihydropyridine scaffold an inotropic and/or chronotropic cardiovascular activity with a high selectivity toward the nonvascular tissue. Finally, molecular modeling studies were undertaken for the most representative compounds with the aim of describing the binding properties of the new ligands at molecular level and to rationalize the found structure-activity relationship data. Due to the observed pharmacological behavior of our compounds, they might be promising agents for the treatment of specific cardiovascular pathologies such as cardiac hypertrophy and ischemia. © 2008 American Chemical Society.

The synthesis of new imidazo[2,1-b]thiazoles bearing phenolic groups is reported. These compounds and some previously described analogs were evaluated as antioxidant agents with three chemical model systems, and cancer chemopreventive potential was examined by inhibition of NO production, TNF-a activated NFkB activity, and aromatase activity, as well as induction of QR1 and RXRE binding. Two of the test compounds, 9 and 12, displayed promising activity by inhibiting iNOS, NFkB and aromatase in dose edependent manner, with IC50 values in low micromolar range. The same compounds activated QR1 in a bifunctional manner. When incubated with human liver microsomes, the active compounds were further hydroxylated on the parent ring system, suggesting the next logical step in the development of these promising leads will entail synthetic production of metabolites followed by additional assessment of biological activity.

Current drug therapies for Alzheimer's disease (AD) are mainly based on acetylcholinesterase (AChE) inhibitors. However, such inhibitors may possess non-optimal pharmacological properties or cause adverse effects, therefore research for the development of new drugs is still in progress. In this paper, a rapid and simple chemiluminescent (CL) assay for the in vitro evaluation of AChE inhibitors in which the activity of AChE is measured through a series of coupled enzymatic reactions leading to light emission is described. The assay is performed in microtiter plates, both in the 96- and 384-well formats. In the latter format up to 30 compounds can be simultaneously analyzed in a very short time (the chemiluminescence measurement lasts 5 min) and using small volumes of samples and reagents (the assay volume is less than 60 μL), thus allowing high-throughput screening (HTS). The assay proved to be reliable, as demonstrated by the analysis of known AChE inhibitors, and the reproducibility of the results was satisfying for a screening assay (CV% in the order of 20%). It could therefore represent a valuable alternative to other methods for the preliminary evaluation of new potential AChE inhibitors.

In this work we describe the synthesis of a series of imidazo[2,1- b ]thiazoles and 2,3-dihydroimidazo[2,1- b ]thiazoles connected by means of a methylene bridge to CoQ 0 . These compounds were tested as specific inhibitors of the NADH:ubiquinone reductase activity in mitochondrial membranes. The imidazothiazole system when bound to the quinone ring in place of the isoprenoid lateral side chain, may increase the inhibitory effect (with an IC 50 for NADH-Q 1 activity ranging between 0.25 and 0.96 μM) whereas the benzoquinone moiety seems to lose the capability to accept electrons from complex I as indicated by very low maximal velocity elicited by the compounds tested. Moreover the low rotenone sensitivity for almost all of these compounds suggests that they are only partially able to interact with the physiological ubiquinone-reduction site. The compounds were investigated for the capability of increasing the permeability transition of the inner mitochondrial membrane in isolated mitochondria. Unlike CoQ 0 , which is considered a mitochondrial membrane permeability transition inhibitor, the new compounds were inducers.

The synthesis and antitumor activity of a new series of E-3-(2-chloro-3-indolylmethylene)1,3-dihydroindol-2-ones is described. Several compounds were active on the primary test (three human cell lines) and entered the second level (60 human cell lines). All of them were potent growth inhibitors with GI(50) ranging from -5.32 to -7.27. Four are now under review by BEC (Biological Evaluation Committee of the NCI). The most potent antitumor derivatives were also evaluated as cardiotonic agents (in view of a possible coanthracyclinic activity). In order to find a possible mechanism of action their effects on cell cycle progression in an adenocarcinoma cell line (HT29) were tested, evidencing that these molecules are able to block HT29 in mitosis. The introduction of new substituents in the indolinone moiety while maintaining the same chloroindole portion generated interesting derivatives. 3-(2-Chloro-5-methoxy-6-methyl-3-indolylmethylene)5-hydroxy-1,3-dihydroindol-2-one was the most active of the whole series. It was more potent than vincristine against seven of the nine tumors considered. Moreover it was selective towards some cell lines such as MDA-MB-435 (breast), OVCAR-3 (ovarian) and SK-MEL-28 (melanoma). Even the introduction of a benzyl ring at the nitrogen of the chloroindole portion, gave rise to potent compounds.

In this work we describe the synthesis and the biological activity of 2-[(E)-3-(6chloroimidazo[2,1-b]thiazol-5-yl)prop-2-enyl]-5,6-dimethoxy-3-methyl-1,4-benzoquinone i.e. an imidazothiazole derivative connected to the benzoquinone ring of Q0. This compound was tested as specific inhibitor of the NADH:ubiquinone (UBQ) reductase activity of NADH dehydrogenase in mitochondrial membranes. Binding of the imidazothiazole moiety to the quinone site normally occupied by the isoprenoid lateral side chain increases the inhibitory effect (with an IC50 for NADH-Q1 activity of 0.24 μM) whereas the benzoquinone moiety seems to lose the capability as electron acceptor from Complex I. The new compound was also tested as potential antitumor agent at the National Cancer Institute.

One of our projects devoted to the synthesis of potential antitumor agents is called “Cancer Fighting Cancer”. This brought us to synthesize the new heterocyclic system, diimidazo-[1,2a:1,2-c]-pyrimidine, which is a key intermediate for the synthesis of antitumor derivatives. The structure of this compound was demonstrated by means of NMR and MS experiments.