5D Activity Research Articles

Discovery of New Heterocyclic/Benzofuran Hybrids as Potential Anti-Inflammatory Agents: Design, Synthesis, and Evaluation of the Inhibitory Activity of Their Related Inflammatory Factors Based on NF-κB and MAPK Signaling Pathways.

NF-κB and MAPK are classic inflammation signaling pathways which regulate inflammation signal transmission and induce the expression of many inflammatory factors. Based on the potent anti-inflammatory activity of benzofuran and its derivatives, several new heterocyclic/benzofuran hybrids were first designed and synthesized by molecular hybridization. Their structure was confirmed by 1H NMR, 13C NMR, HRMS or X-single crystal diffraction. The anti-inflammatory activity of these new compounds was screened by compounds; compound 5d exhibited an excellent inhibitory effect on the generation of NO (IC50 = 52.23 ± 0.97 μM), and low cytotoxicity (IC50 > 80 μM) against the RAW-264.7 cell lines. To further elucidate the possible anti-inflammatory mechanisms of compound 5d, the hallmark protein expressions of the NF-κB and MAPK pathways were studied in LPS-stimulated RAW264.7 cells. The results indicate that compound 5d not only significantly inhibits the phosphorylation levels of IKKα/IKKβ, IKβα, P65, ERK, JNK and P38 in the classic MAPK/NF-κB signaling pathway in a dose-dependent manner, but also down-regulates the secretion of pro-inflammatory factors such as NO, COX-2, TNF-α and IL-6. Further, the in vivo anti-inflammatory activity of compound 5d indicated that it could regulate the involvement of neutrophils, leukocytes and lymphocytes in inflammation processes, and reduce the expression of IL-1β, TNF-α and IL-6 in serum and tissues. These results strongly suggest that the piperazine/benzofuran hybrid 5d has a good potential for developing an anti-inflammatory lead compound, and the anti-inflammatory mechanism might be related to the NF-κB and MAPK signaling pathways.

Novel N-methylsulfonyl-indole derivatives: biological activity and COX-2/5-LOX inhibitory effect with improved gastro protective profile and reduced cardio vascular risks

Three novel series of N-methylsulfonylindole derivatives 3a&b, 4a–e, and 5a–e were synthesised. Different biological activities of the synthesised compounds were studied. Antimicrobial activity showed that, compounds 4b, 4e and 5d had selective antibacterial activity against the Gram-negative bacteria, Salmonella enterica and/or E. coli. The anti-oxidant activity of the synthesised compounds was evaluated by DPPH radical scavenging activity. In vitro anti-inflammatory activity was estimated. Compounds 4d, 4e, 5b, and 5d showed the highest anti-inflammatory activity. The COX-1, COX-2 and 5-LOX inhibitory activities were measured using enzyme immune assay (EIA) kits. Due to the dual COX-2/5-LOX inhibitory activity of compound 5d, its cardiovascular profile was determined by measuring cardiac biomarkers (LDH, CK-MB, and Tn-I). Besides, the histopathological study of the heart muscle and stomach were examined for the most active COX-2 inhibitors 4e and 5d. Finally, a molecular modelling study and pharmacokinetic properties were obtained using different computational methods.

Synthesis, Catalysis and Antimicrobial activity of 5d- metal chelate complex of Schiff base ligands

The metal chelates of Iridium, platinum and gold with schiff base were synthesized using metal perchlorates of the respective metal ions, and schiff base formation was done by reaction of anthranilic acid and ortho hydroxybenzaldehyde in ethanolic environment. Various analytical techniques, like, UV–Visible, FT-IR, elemental analysis, molar conductance and magnetic susceptibility have been used for crystal structural analysis. A general formula of the type [M (HL) OH] of the metal complexes have been proposed by elemental and spectral analysis. The ligand to metal ratio was found to be 1:1 in all the metal chelate complexes. As per the Infrared spectral data study the interaction of oxygen (phenolic OH and acidic COOH) and an azomethine nitrogen of ligand have been found to coordinate tridentately with central metal ion. For the synthesis of metal chelate complexes the utilized activation energy was evaluated by the broido method. The synthesized metal chelate complexes and the parent ligands were analyzed also for the antibacterial activity determination against gram positive (B. subtilis, Bacillus anthracis) and gram negative (Yersinia pestis, Escherichia coli) bacterial species.

Docking Simulations and Primary Assessment of Newly Synthesized Benzene Sulfonamide Pyrazole Oxadiazole Derivatives as Potential Antimicrobial and Antitubercular Agents

A novel series of benzene sulfonamide pyrazole oxadiazole derivatives have been synthesized by reaction of 4-(5-(3-fluoro-4-methoxyphenyl)-3-(hydrazinecarbonyl)-1H-pyrazol-1-yl) benzene sulfonamide with different substituted benzoic/pyridinyl/indolyl acids in phosphorous oxychloride, characterized by IR, 1H NMR, 13C NMR, MS analytical data and evaluated for their antimicrobial as well as antitubercular activity. Molecular docking studies against Mycobacterium tuberculosis β-ketoacyl-acyl carrier protein synthase A, (Kas-A) was carried out to understand the possible mode of its inhibition and potential of synthesized compounds as antitubercular agents. Antibacterial activity of compounds 5d (3-Cl) and 5f (2,4-diCl) were found good against E. coli, P. aeruginosa, S. aureus and S. pyogenes as compared to standard Ampicillin. Compound 5d was found active antitubercular agents against M. tuberculosis H37Rv.

Synthesis of Rottlerone Analogues and Evaluation of Their α-Glucosidase and DPP-4 Dual Inhibitory and Glucose Consumption-Promoting Activity.

Our previous study found that desmethylxanthohumol (1) inhibited α-glucosidase in vitro. Recently, further investigations revealed that dehydrocyclodesmethylxanthohumol (2) and its dimer analogue rottlerone (3) exhibited more potent α-glucosidase inhibitory activity than 1. The aim of this study was to synthesize a series of rottlerone analogues and evaluate their α-glucosidase and DPP-4 dual inhibitory activity. The results showed that compounds 4d and 5d irreversibly and potently inhibited α-glucosidase (IC50 = 0.22 and 0.12 μM) and moderately inhibited DPP-4 (IC50 = 23.59 and 26.19 μM), respectively. In addition, compounds 4d and 5d significantly promoted glucose consumption, with the activity of 5d at 0.2 μM being comparable to that of metformin at a concentration of 1 mM.

Synthesis, Characterization, Biological Screening, ADME and Molecular Docking Studies of 2-Phenyl Quinoline-4-Carboxamide Derivatives

In this work, some 2-phenyl quinoline-4-carboxamide derivatives (5a-j) were synthesized via base catalyzed Pfitzinger reaction of isatin and acetophenone followed by C-N coupling reaction using POCl3 and assessed them for their in vitro antimicrobial and anticancer activity. The structure of newly synthesized compound were established by FT-IR, 1H & 13C NMR and Mass spectrometric analysis. The synthesized carboxamides were subjected to preliminary in vitro antibacterial activity as well as for antifungal activity. Results of antibacterial activity were compared with standard antibacterial (ciprofloxocin) and antifungal (fluconozole). Among the tested compounds, 5d, 5f and 5h exhibited promising activity with zone of inhibition ranging from 10 to 25 mm. Further, the anticancer activity determined using MTT assay against two cancer cell lines. Compounds 5b, 5d, 5f and 5h showed good anticancer activity among all the other derivatives. In order to correlate the in vitro results, in silico ADME and Molecular docking studies were carried out for (5a-j). ADME properties results showed that all the compounds obey rule of Five rule except 5a, 5e and 5g compound. Molecular docking studies of the synthesized compounds showed good binding affinity through hydrogen bond interactions with key residues on active sites as well as neighboring residues within the active site of chosen target proteins viz. antibacterial, antifungal and anticancer. Comparison of both results of in silico as well as in vitro investigation suggests that the synthesized compounds may act as potential antimicrobial as well as anticancer agents.

Novel Triazole Derivatives Containing Different Ester Skeleton: Design, Synthesis, Biological Evaluation and Molecular Docking.

Invasive fungal disease constitutes a growing health problem and development of novel antifungal drugs with high potency and selectivity are in an urgent need. In this study, a novel series of triazole derivatives containing different ester skeleton were designed and synthesized. Microdilution broth method was used to investigate antifungal activity. Significant inhibitory activity of compounds 5c, 5d, 5e, 5f, 5m and 5n was evaluated against the Candida albicans (I), Candida albicans clinical isolate (II), Candida glabrata clinical isolate (I), and Candida glabrata (II) with minimum inhibitory concentrations (MIC80) values ranging from 2 to 16 µg/mL. Notably, compounds 5e and 5n showed the best inhibition against Candida albicans (II), Candida glabrata (I), and Candida glabrata (II) at the concentrations of 2 and 8 µg/mL, respectively. Molecular docking study revealed that the target compounds interacted with CYP51 mainly through hydrophobic and van der Waals interactions. The results indicated that these novel triazole derivatives could serve as promising leads for development of antifungal agents.

Synthesis, Anti-proliferative Evaluation, and Molecular Docking Studies of 3-(alkylthio)-5,6-diaryl-1,2,4-triazines as Tubulin Polymerization Inhibitors

Background: The role of microtubules in cell division and signaling, intercellular transport, and mitosis has been well known. Hence, they have been targeted for several anti-cancer drugs. Methods: A series of 3-(alkylthio)-5,6-diphenyl-1,2,4-triazines were prepared and evaluated for their cytotoxic activities in vitro against three human cancer cell lines; human colon carcinoma cells HT-29, human breast adenocarcinoma cell line MCF-7, human Caucasian gastric adenocarcinoma cell line AGS as well as fibroblast cell line NIH-3T3 by MTT assay. Docking simulation was performed to insert these compounds into the crystal structure of tubulin at the colchicine binding site to determine a probable binding model. Compound 5d as the most active compound was selected for studying of microtubule disruption. Results: Compound 5d showed potent cytotoxic activity against all cell lines. The molecular modeling study revealed that some derivatives of triazine strongly bind to colchicine binding site. The tubulin polymerization assay kit showed that the cytotoxic activity of 5d may be related to inhibition of tubulin polymerization. Conclusion: The cytotoxicity and molecular modeling study of the synthesized compounds with their inhibition activity in tubulin polymerization demonstrate the potential of triazine derivatives for development of new anti-cancer agents.

Design, Synthesis, and Cholinesterase Inhibition Assay of Coumarin-3-carboxamide-N-morpholine Hybrids as New Anti-Alzheimer Agents.

A new series of coumarin-3-carboxamide-N-morpholine hybrids 5a-5l was designed and synthesized as cholinesterases inhibitors. The synthetic approach for title compounds was started from the reaction between 2-hydroxybenzaldehyde derivatives and Meldrum's acid to afford corresponding coumarin-3-carboxylic acids. Then, amidation of the latter compounds with 2-morpholinoethylamine or N-(3-aminopropyl)morpholine led to the formation of the compounds 5a-5l. The in vitro inhibition screen against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) revealed that most of the synthesized compounds had potent AChE inhibitory while their BuChE inhibitions are moderate to weak. Among them, propylmorpholine derivative 5g (N-[3-(morpholin-4-yl)propyl]-2-oxo-2H-chromene-3-carboxamide) bearing an unsubstituted coumarin moiety and ethylmorpholine derivative 5d (6-bromo-N-[2-(morpholin-4-yl)ethyl]-2-oxo-2H-chromene-3-carboxamide) bearing a 6-bromocoumarin moiety showed the most activity against AChE and BuChE, respectively. The inhibitory activity of compound 5g against AChE was 1.78 times more than that of rivastigmine and anti-BuChE activity of compound 5d is approximately same as rivastigmine. Kinetic and docking studies confirmed the dual binding site ability of compound 5g to inhibit AChE.

Synthesis and Antioxidant Evaluation of a New Class of Thienopyrimidine-rhodanine Hybrids

Background: Antioxidants are proficient of stabilizing agents in the target cells and biological systems. The homeostatic equilibrium between the reactive oxygen species and endogenous antioxidants is important in maintaining healthy tissues. As some antioxidant agent’s show improved resistance, it is necessary to design the new heterocyclic molecules to form potent antioxidant agents with promising pharmacological applications. Moreover, thienopyrimidine derivatives has been the subject of much research due to their significance in different applications and their extensive potential pharmacological and medicinal activities like antibacterial, antifungal, anticancer, anticonvulsant, anti-inflammatory, analgesic, anti-viral, anti-oxidant, anti-diabetic and antimalarial properties. Although, recently rhodanine was reported as privileged hybrid in drug discovery and exhibited pharmacological activities such as anti-malarial, antibacterial, antiviral, antidiabetic agents. Hence, the development of new molecules within the scope of synthetic procedure of thienopyrimidine scaffold for heterocyclic synthesis would be worthy and well desired. Methods: All the target thienopyrimidine-rhodanine derivatives (5a-l) prepared from the Knoevenagel condensation with different substituted benzaldehydes in the presence of glacial acetic acid and 3-(thieno[2,3-d]pyrimidin-4-yl)-2-thioxothiazolidin-4-one (4). Although, all the synthesized compounds tested for their anti-oxidant activity investigated using DPPH radical scavenging, nitric oxide (NO) and ABTS activity. Results: All the thienopyrimidine-rhodanine derivatives (5a-l) were evaluated for their in vitro anti-oxidant activity. In fact, (Z)-5-(4-methylbenzylidene)-3-(thieno[2,3-d]pyrimidin-4-yl)-2- thioxothiazolidin-4-one (5c) with IC50 value 17.64 ± 0.06 µg/mL and (Z)-5-(2-nitrobenzylidene)-3- (thieno[2,3-d]pyrimidin-4-yl)-2-thioxothiazolidin-4-one (5j) with IC50 value 17.54 ± 0.23µg/mL showed excellent antioxidant activity nearly similar to the standard drug as an ascorbic acid (IC50 = 17.45 ± 0.03µg/mL). Conclusion: The objective of the present work was to design, synthesis and screened for their antioxidant activities of novel thienopyrimidine containing rhodanine derivatives with the hope of discovering new structure leads as the most potent antioxidant agents. Our aim has been achieved by the synthesis of thienopyrimidines with diver functionalities by exploiting 2-thioxothiazolidin-4-one chemistry and tested for antioxidant activity. The compounds 5c and 5j were found most potent activity compare to the standard ascorbic acid. Furthermore, the electron withdrawing groups at position-4 in benzene ring enhanced the activity, whereas the compounds 5d, 5f, 5i and 5l showed good activity all the three radical scavenging methods.

Synthesis of thiazolidine-2,4-dione derivatives: anticancer, antimicrobial and DNA cleavage studies.

In the search of efficient anticancer agents, here, new 5-(4-alkylbenzyledene)thiazolidine-2,4-dione derivatives (5a-g) have been successfully synthesized and characterized and are evaluated for anticancer and antimicrobial activities using DNA cleavage studies. In vitro studies on anticancer activity of compound 5d (NSC: 768619/1) was done against the full panel of 60 human tumor cell lines. The five-level dose activity results revealed that, the compound 5d was active against all the cell lines, it has shown potential activity against leukemia SR (GI50: 2.04μM), non-small cell lung cancer NCI-H522 (GI50: 1.36μM), colon cancer COLO 205 (GI50: 1.64μM), CNS cancer SF-539 (GI50: 1.87μM), melanoma SK-MEL-2 (GI50: 1.64μM), ovarian cancer OVCAR-3 (GI50: 1.87μM), renal cancer RXF 393 (GI50: 1.15μM), prostate cancer PC-3 (GI50: 1.90μM), and breast cancer MDA-MB-468(GI50: 1.11μM). DNA cleavage studies revealed that at 50μg/mL concentration, partial DNA digestion was observed and when the concentration is increasing to threefold (150μg/mL), complete linear DNA digestion and partial supercoiled DNA digestion was observed. Further antimicrobial studies indicate that all the synthesized compounds except compound 5a possess prominent activity against all the screened microbial species. This study throws a ray of light in the field of anticancer drugs.

One-pot, four-component synthesis of novel cytotoxic agents 1-(5-aryl-1,3,4-oxadiazol-2-yl)-1-(1H-pyrrol-2-yl)methanamines

A series of N-benzyl-1-(5-aryl-1,3,4-oxadiazol-2-yl)-1-(1H-pyrrol-2-yl)methanamines were synthesized via one-pot reaction of appropriate benzylamine, pyrrole-2-carbaldehyde, (N-isocyanimino)triphenylphosphorane, and a carboxylic acid. The anti-tumor potential of title compounds was tested against several cancer cell lines by using MTT assay. Some tested compounds including 5e, 5p and 5q exhibited comparable or better cytotoxic activity against A549, HT29 or HT1080 cells in comparison to the reference drug doxorubicin. Also, the cytotoxic activity of compounds 5d and 5n against MCF-7 was better than that of doxorubicin. Compound 5n with IC50 value of 4.3 μM was 4-fold more potent than doxorubicin. The structure–activity relationship study revealed that the introduction of halogen atoms on both 5-phenyl ring and N-benzyl part improved the cytotoxic activity against all tested cell lines.

Microwave-assisted synthesis of benzimidazole bearing 1,3,4-oxadiazole derivatives: screening for their in vitro antimicrobial activity

A rational approach was adopted for the synthesis of novel series of 1-(2-(1H-benzo[d]imidazol-2-yl)-2-methyl-5-aryl-1,3,4-oxadiazol-3(2H)-yl)-3-(4-chlorophenyl)prop-2-en-1-ones 5a–n under microwave irradiation technique. Synthesized compounds were tested for their in vitro antimicrobial activity against Gram-positive, Gram-negative strains of bacteria as well as fungal strains, and in vitro cytotoxicity study (HeLa cell lines) using MTT colorimetric assay. Among the screened compounds, 5b, 5c, 5d, 5g, and 5h showed most potent antibacterial activity, while compounds 5c, 5d, 5g, and 5h emerged as the most effective antifungal agents. The structure activity relationships revealed that presence of inductively electron withdrawing groups remarkably enhances the antimicrobial activity of newly synthesized compounds. Further, the results of preliminary MTT cytotoxicity studies on HeLa cells suggested that potent antimicrobial activity of 5b, 5c, 5d, 5g, and 5h is accompanied by low cytotoxicity.

A computational model of posterior parietal circuits during decision making and sequential planning

In the posterior parietal cortex (PPC), three anatomically separated but reciprocally interconnected subareas, the lateral intraparietal area (LIP), parietal reach region (PRR) and dorsal area 5 (area 5d), are involved in sensorimotor transformation during planning of eye/arm movements. We have previously designed the saccade/reach effector choice and sequential reach paradigms to dissociate cognitive and executive planning activity in PPC. During saccade/reach choice, LIP and PRR encodes potential saccade/reach plans in parallel before effector decision is formed, and the selected saccade/reach plans thereafter [1], whereas area 5d only reflects the decision outcome [2]. During sequential reach, PRR encodes both immediate and subsequent goals [3], whereas area 5d only represents the immediate upcoming reach [4]. Based on the experimental results above, we propose a network model to conceive the functional connectivity across these areas. The model is composed of an upstream layer representing the abstract motor intentions and a down-stream layer representing concrete motor commands. The up-stream layer consists of LIP and PRR neurons preferring different directions for saccade and reach, respectively, and two populations compete against each other. The down-stream layer is composed of area 5d neurons preferring arm movements to different directions. In each neuronal pool, each leaky integrate-andfire neuron excites others representing nearby targets but inhibits the remaining. The up-stream layer also feed-forwards to the down-stream layer to excite the neurons preferring the same effector and nearby target but to inhibit others. Furthermore, each LIP and PRR neuron receives self-excitation whose magnitudes are modulated by the rule-based behavioral context, reflecting the topdown feedback. Our simulation results show that, during the effector choice and instructed tasks, the effector information is ambiguous at first so that both LIP and PRR show strong responses and counterbalance the total input to area 5d. Once effector information is determined by either choice or instruction, LIP and PRR activities differentiate to trigger or suppress area 5d activity. During the classical memory saccade/reach tasks, effector information is given at the cue onset so that LIP and PRR activities began to differentiate and area 5d fires immediately. During the sequential reaching task, after two targets are simultaneously presented, the activity of the PRR encoding the 1st goal increases faster while the activity of the PRR encoding the 2nd goal increases slower but lasts longer due to the different recurrent connections modulated by the behavioral context. Consequentially, only the activity of the area 5d neuron encoding the 1st goal is elevated before the GO signal. Once the first reach is completed, the area 5d neuron preferring the 2nd goal begins to fire because top-down context information (efference copy in this case) reduces the strength of recurrent connection for the PRR neuron coding the 1st goal. Preliminary results indicate that our model captures all characteristics of neural activity we have observed so far. Our ongoing modeling work will help reveal the network mechanisms underlying the operation of the parietal sensorimotor circuits.

Dorsal parietal area 5 only encodes the immediate reach in sequential arm movement

To generate an action sequence, it is essential to integrate information regarding all temporally coordinating motor elements. Spatial information about both immediate and subsequent component reaches is encoded simultaneously in the parietal reach region (PRR) [1]. However, it is still unclear how a cognitive sequence conveying multiple goals in parallel is discomposed into series of discrete movement commands to be executed by the musculoskeletal system. In the present study, we recorded single-neuron activity from dorsal area 5 (area 5d) in the posterior parietal cortex while monkeys performed a memory-guided double-reach task. Briefly, the monkey was required to touch a fixation center at the trial beginning. Then, the first and second goals were simultaneously displayed for 400ms with a square and a triangle (shifted counter-clockwise from the square by 135°), respectively. After a 600ms delay, the center dot dimmed (GO signal) and the monkey was allowed to initiate the reaching sequence to touch the locations previously cued by the square and triangle in the correct order. Single-reach trials were pseudo-randomly interleaved with the double-reach trials for a control. Among all 98 task-related cells we recorded from two monkeys, 35 (36%), 75 (77%) and 75 (77%) exhibited significant directional tuning during the delay (0~400ms before GO), pre-movement (0~200ms before the onset of the 1st movement), and peri-movement (0~200ms after the onset of the 1st movement) periods, respectively. In all above groups, the tuning curves in double-reach were similar to those in the single-reach trials (p > 0.05). To quantitatively analyze tuning dynamics, we calculated the vector sum of the neuronal activity in a 200ms sliding window across all directions as the instantaneous preferred direction. Prior to the offset of the 1st movement, there was no significant difference in the preferred directions between single- and double-reach. Thereafter, the preferred direction in double-reach trials gradually rotated counter-clockwise toward the second reaching goal. Around 100ms before the onset of the 2nd movement, the shift saturated at 135° at the population level, co-varying with the switch of immediate reaching movements. We calculated the Fano Factor (FF, as the variance versus mean of the spike counts) across trials in each movement-direction/cell combination with a 100ms sliding window. In contrast to numerous other cortical sensorimotor regions [2], area 5d activity exhibited low variability (FF = ~1.0) and the FF changed modestly during the whole preparatory period. Although FF increased sharply after GO signal (up to ~1.3), this tendency could be weaken by aligning the spike trains to the movement onset (reduce to ~1.1) or by separating fast and slow reaction trials (reduce to ~1.1-1.2 only). This is generally the case regardless of aligning to the onset of the movement in the single reach trials, or 1st or 2nd movements in the double-reach trials. The results that area 5d activity only conveys information about the immediate reach with low variance stick to motor execution suggest that area 5d may play a key role in translating cognitive action sequences into executive motor commands to activate muscle synergies.

Synthesis, anticancer and cytostatic activity of some 6H-indolo[2,3-b]quinoxalines

Various 6-aralkyl-9-substituted-6H-indolo[2,3-b]quinoxalines were synthesized by reaction of 1,5-disubstituted 2,3-dioxo-2,3-dihydroindole and orthophenylene diamine. Appreciable anticancer activity of compounds 5b, 5d, 5g and 5l at various cell lines among 59 human tumor cell panels was observed. All the synthesized compounds were evaluated for cytostatic activity against human Molt 4/C8 and CEM T-lymphocytes as well as for murine L1210 leukemia cells. Compound 5h exhibited an I C50 of 23 micromol L(-1) against Molt 4/C8 and 38 micromol L(-1) against CEM compared to melphalan 3.2 micromol L(-1) and 2.5 micromol L(-1), respectively. The IC(50) for compound 7i against L1210 was 7.2 micromol L(-1) compared to melphalan 2.1 micromol L(-1).

Synthesis and characterization of phosphorous-bridged bisphenoxy titanium complexes and their application to ethylene polymerization

Phosphorous-bridged bisphenoxy titanium complexes were synthesized and their ethylene polymerization behavior was investigated. Bis[3- tert-butyl-5-methyl-2-phenoxy](phenyl)phosphine tetrahydrofuran titanium dichloride ( 4a) was obtained by treatment of 3 equiv of n-BuLi with bis[3- tert-butyl-2-hydroxy-5-methylphenyl](phenyl)phosphine hydrochloride salt ( 3a) followed by TiCl 4(THF) 2 in THF. THF-free complexes 5a– 5d were synthesized more conveniently by the direct reaction of MOM-protected ligands ( 2a– 2d) with TiCl 4 in toluene. X-ray analysis of 4a revealed that the ligand is bonded to the octahedral titanium (IV) center in a facial fashion and two chlorine atoms possess cis-geometry. Complexes 4a and 5a– 5d were utilized as catalyst precursors for ethylene polymerization. Complex 5c gave high molecular weight polyethylene ( M w = 1,170,000, M w/ M n = 2.0) upon activation with Al( i Bu) 3/[Ph 3C][B(C 6F 5) 4] (TB). Ethylene polymerization activity of 5d activated with Al( i Bu) 3/TB reached 49.0 × 10 6 g mol (cat) −1 h −1.

Coumarin, Chromone, and 4(3H)‐Pyrimidinone Novel Bicyclic and Tricyclic Derivatives as Antiplatelet Agents: Synthesis, Biological Evaluation, and Comparative Molecular Field Analysis.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Coumarin, chromone, and 4(3 H)-pyrimidinone novel bicyclic and tricyclic derivatives as antiplatelet agents: synthesis, biological evaluation, and comparative molecular field analysis

As a further part of our chemical and biological studies in this field, we describe the multistep preparations of the properly substituted 2-(1-piperazinyl)chromone 1b, 4-(1-piperazinyl)coumarins 5c– h, their linear benzo-fused analogues 4a, b and 8a, b, bicyclic ( 15e– g) and tricyclic ( 15h, i) fused derivatives of 6-(1-piperazinyl)pyrimidin-4(3 H)-one, and of the 4 H-pyrido[1,2- a]pyrimidine derivatives 9b, c. The in vitro evaluation of their inhibitory properties towards human platelet aggregation induced in platelet-rich plasma by ADP, collagen, or the Ca 2+ionophore A23187 showed the high activity of compounds 5d– g and 15f, g, i, among which the coumarins 5g and 5d proved to be, in that order, the most effective in vitro antiplatelet agents until now synthesized by us. Thus, in order to consider also the 4-aminocoumarin structural class, we developed a new statistically significant 3-D QSAR model, more general than the one previously obtained, through a further CoMFA study based on the antiplatelet activity data and molecular steric and electrostatic potentials of both the previously studied and herein described compounds.

Tissue-specific regulation of type III iodothyronine 5-deiodinase gene expression mediates the effects of prolactin and growth hormone in Xenopus metamorphosis.

Prolactin (PRL) and growth hormone (GH) are known to be able to act as antimetamorphic hormones. From investigations of how PRL inhibits Xenopus tail regression in vitro, it was found that the both hormones could, in addition to their known antimetamorphic actions, upregulate mRNA expression of type III iodothyronine 5-deiodinase (5D), an enzyme that inactivates thyroid hormones (TH). Conversely, both PRL and GH were found to downregulate 5D mRNA expression in the liver. Blockage by PRL of TH-induced tail regression in organ culture was released by treatment with iopanoic acid (IOP, an inhibitor of 5D activity). The IOP-released tail regression displayed a unique morphology of the larger fins retained on the regressing tails, consistent with the finding that mRNA for both PRL receptor and 5D were enriched in the fin. The results suggest that the metamorphosis-modulating actions of PRL and GH are mediated, at least partially, by tissue-specific regulation of 5D mRNA expression.