Synthesis and Biological Evaluation of Some 1,2‐Disubstituted Benzimidazole Derivatives as New Potential Anticancer Agents

The synthesis of some new 1‐(2‐aryl‐2‐oxoethyl)‐2‐[(morpholine‐4‐yl)thioxomethyl]benzimidazole derivatives and investigation of their anticancer activities were the aims of this work. 2‐(Chloromethyl)benzimidazole compound was reacted with sulfur and morpholine via Willgerodt–Kindler reaction to give 2‐[(morpholine‐4‐yl)thioxomethyl]benzimidazole. Then, the obtained compound was reacted with appropriate α‐bromoacetophenone derivatives in the presence of potassium carbonate to give the final products. Structure elucidation of the final compounds was achieved by FT‐IR, ¹H NMR spectroscopy and MS spectrometry. The anticancer activities of the final compounds were evaluated by MTT assay, BrdU method, and flow cytometric analysis on C6, MCF‐7, and A549 tumor cells. Most of the synthesized compounds exhibited considerable selectivity against the MCF‐7 and C6 cell lines.     

New morpholine‐liganded palladium(II) N‐heterocyclic carbene complexes: Synthesis,characterization, crystal structure,and DNA‐binding studies

A series of the morpholine‐liganded palladium(II) complexes ( 1a–e ) bearing N‐heterocyclic carbene (NHC) functionalized by benzonitrile were synthesized. These complexes were synthesized from (NHC)Pd(II)(pyridine) complexes (PEPPSI) and morpholine. The new complexes were fully characterized by using ¹H NMR, ¹³C NMR, Fourier‐transform infrared spectroscopy, and elemental analysis techniques. Single‐crystal X‐ray diffraction was used to determine the structure of a derivative. The DNA‐binding studies of the new (NHC)Pd(II)morpholine complexes were examined using the pBR322 plasmid. The 2,4,6‐trimethylbenzyl derivative compound has the most DNA binding activity. In addition, for the 3‐methylbenzyl derivative compound, oxidation effects were observed at concentrations higher than 100 µg/ml. Also, the molecular and crystal structures of the complex 3‐methylbenzyl derivative compound were recorded by using a single‐crystal X‐ray diffraction method.     

Graph theoretical analysis,insilico modeling,design, and synthesis of compounds containing benzimidazole skeleton as antidepressant agents

In this study, drug target was identified using KEGG database and network analysis through Cytoscape software. Designed series of novel benzimidazoles were taken along with reference standard Flibanserin for insilico modeling. The novel 4‐(1H‐benzo[d]imidazol‐2‐yl)‐N‐(substituted phenyl)‐4‐oxobutanamide ( 3a–j ) analogs were synthesized and evaluated for their antidepressant activity. Reaction of 4‐(1H‐benzo[d]imidazol‐2‐yl)‐4‐oxobutanoic acid ( 1 ) with 4‐(1H‐benzo [d] imidazol‐2‐yl)‐4‐oxobutanoyl chloride ( 2 ) furnished novel 4‐(1H‐benzo [d] imidazol‐2‐yl)‐N‐(substituted phenyl)‐4‐oxobutanamide ( 3a–j ). All the newly synthesized compounds were characterized by IR, ¹H‐NMR, and mass spectral analysis. The antidepressant activities of synthesized derivatives were compared with standard drug clomipramine at a dose level of 20 mg/kg. Among the derivatives tested, most of the compounds were found to have potent activity against depression. The high level of activity was shown by the compounds 3d , 3e , 3i, and it significantly reduced the duration of immobility time at the dose level of 50 mg/kg.     

Syntheses and Configurations of Some Thiomorpholide S-Oxides,Trithiozine Metabolites

Two metabolites of trithiozine, namely 4-(3,5-dimethoxy-4-hydroxythiobenzoyl)morpholine S-oxide (2a) and 4-(3,4,5-trimethoxythiobenzoyl)morpholine S-oxide (2b) , were synthesized by oxidation of the thioamides 1a, b or, in the case of 2b , by reaction of E- and Z-(3,4,5-trimethoxyphenyl)(methylthio)sulfine (4) with morpholine. Both procedures afford the compounds 2a, b as single isomers having the same configuration at the sulfine group. The NMR behaviour of the aromatic ortho protons of 2b , when compared to that of other aromatic sulfines with known structures in the presence of lanthanide shift reagents, supports the Z-configuration.     

Synthesis,Characterization and In Vitro Antimicrobial Evaluation of Novel Pyrazolothiazol-4(5H)-one Derivatives

Antimicrobial screening of several novel pyrazolothiazol-4(5H)-one derivatives (3a-3j) has been performed. Reaction of aromatic aldehydes with aromatic ketones yielded starting chalcones (1a-1j) which have been subsequently reacted with thiosemicarbazide for obtaining N-thiocarbamoylpyrazole derivatives (2a-2j). These were further cyclized to pyrazolothiazol-4(5H)-one derivatives (3a-3j) in the presence of ethylbromoacetate. The structures of newly synthesized compounds were confirmed by FTIR and ¹H NMR and/or MS. The in vitro antimicrobial activity of these compounds was evaluated against Gram positive bacteria, Gram negative bacteria and fungi. Their minimum inhibitory concentration was determined by tube dilution method. The results showed that most of the compounds have promising antimicrobial activity as compared to standard drugs. Among the test compounds, 2-[5(4-chlorophenyl)-3-phenyl-4,5-dihydropyrazol-1-yl]-thiazol-4(5H)-one (3e) was found to show the most potent antimicrobial activity.     

molidustat的合成工艺研究

目的对molidustat的合成工艺进行研究。方法以4,6-二氯嘧啶为原料,先后引入吗啉、肼取代基,制备获得中间体4-(6-肼基嘧啶-4-基)吗啉(2);1H-1,2,3-三氮唑和溴乙酸乙酯为原料,经烃基化、缩合反应,制备获得中间体(Z/E)-3-(二甲基氨基)-2-(1H-1,2,3-三氮唑-1-基)丙烯酸乙酯(4)。中间体2和4在三氟乙酸的催化下,经环合反应制备得到molidustat(5),然后经成盐反应得到其钠盐(6)。结果合成了目标化合物molidustat及其钠盐,并利用1H-NMR、MS确证了结构。此路线的总收率为31.5%。结论该合成工艺步骤短,操作简单,可适应未来工业化放大生产,具有良好的应用前景。     

Synthesis of deuterium,tritium, and carbon‐14 labeled BIRB 796, a p38 MAP kinase inhibitor

1‐(5‐tert‐Butyl‐2‐p‐tolyl‐2H‐pyrazol‐3‐yl)‐3‐[4‐(2‐morpholin‐4‐yl‐ethoxy)naphthalen‐1‐yl]urea (BIRB 796), currently in clinical trials for the treatment of inflammatory diseases, is a potent inhibitor of p38 MAP kinase. Labeled BIRB 796 with stable and radioactive isotopes was required for metabolism, distribution, and absorption studies. We first report the synthesis of carbon‐14 labeled BIRB 796 with a specific activity of 2 GBq/mmol (54.2 mCi/mmol), using [¹⁴C]‐phosgene under modified Schotten–Baumann conditions; second the preparation of tritium‐labeled BIRB 796 with a specific activity of 659 GBq/mmol (17.81 Ci/mmol) by reductive dehalogenation of iodo‐BIRB 796 with tritium gas; and finally, the synthesis of ²H₈‐BIRB 796 using morpholine‐2,2,3,3,5,5,6,6‐²H₈ with isotopic enrichment of 98.9 at% ²H. Copyright © 2004 John Wiley & Sons, Ltd.     

Search for New Anticonvulsant Compounds,Part 2. Structure-Activity Relationship Studies of New N-Substituted Amides of α-Piperazine-γ-Hydroxybutyric Acid as Active Anticonvulsants

In a search for new anticonvulsants, two series of compounds, viz. derivatives of N-benzylamides of α-(4-phenylpiperazine)-γ-hydroxybutyric acid ( A and derivatives of N-benzylamides of α-(4-benzylpiperazine)-γ-hydroxybutyric acid ( B ), were investigated. These amides were obtained by aminolysis of 3-(4-phenyl-, or 4-benzylpiperazine)-tetrahydrofuran-2-one with primary arylalkylamines (i.e. 2-phenylethylamine and 2,3,4-substituted derivatives of benzylamine). Preliminary pharmacological tests, a maximal electroshock (MES) and a subcutaneous metrazole (scMet), and a rotorod toxicity assay were employed. All compounds displayed anticonvulsant activity at range of doses 100–300 mg/kg in the MES screens. In order to point to some structural features correlating with the MES anticonvulsant activity crystal structure analysis followed by conformational analysis was carried out on two representative compounds of series A and B .     

Synthesis,anti-inflammatory,analgesic, and antibacterial activities of some triazole,triazolothiadiazole, and triazolothiadiazine derivatives

This study is concerned with the synthesis of new 1,2,4-triazoles, 1,3,4-thiadiazoles, and 1,3,4-thiadiazines derivatives. Derivatives 3a–i were obtained by condensation of 4-amino-3-(4-pyridine)-5-mercapto-1,2,4-triazole 1 with the appropriate aldehyde. Compounds 4a–i were synthesized in a one pot reaction involving compounds 3a–i, formaldehyde, and morpholine. Condensation of compound 1 with the appropriate acids or 4-substituted phenacyl bromide gave compounds 6a–d and 8a–f respectively. The chemical structures of the newly synthesized derivatives were elucidated using different spectral and elemental methods of analysis. All compounds were evaluated for their anti-inflammatory activity and the most potent derivatives were tested for their analgesic activity using indomethacin as a reference drug. In addition, ulcerogenicity and LD₅₀ for the most active compounds were evaluated. Moreover, the antibacterial activities of the newly synthesized derivatives were investigated.     

Binding Orientations,QSAR, and Molecular Design of Thiophene Derivative Inhibitors

A theoretical study on binding orientations and quantitative structure–activity relationship of thiophene derivatives as inhibitors towards tubulin has been carried out by using the docking analysis and the comparative molecular field analysis. The appropriate binding orientations and conformations of these compounds interacting with tubulin were revealed by docking study; and a 3D‐quantitative structure–activity relationship model showing significant statistical quality and satisfying predictive ability was established, in which the correlation coefficient (R²) and cross‐validation coefficient (q²) are 0.949 and 0.743, respectively. The same model was further applied to predict the pIC₅₀ values for nine congeneric compounds as external test set, and the predictive correlation coefficient reaches 0.929, thus the predictive ability of this 3D‐quantitative structure–activity relationship model can be further confirmed. Some key structural factors of the compounds responsible for cytotoxicity were discussed in detail. Based on these structural factors, three new compounds with higher activity have been designed, and their cytotoxicities were also predicted by the established 3D‐quantitative structure–activity relationship model from comparative molecular field analysis as well as the docking analysis. We hope these theoretical results can be confirmed by experimental work.     

Potential adrenal gland imaging agents. II: Radioiodination of p-hydroxyphenyl derivatives of digitoxigenin, dihydrodigitoxigenin and scillarenin

Potential Adrenal Gland Imaging Agents. II: Radioiodination of p-Hydroxyphenyl Derivatives of Digitoxigenin, Dihydrodigitoxigenin and Scillarenin As potential adrenal gland imaging agents the p-hydroxyphenyl derivatives of the aglycones digitoxigenin (1) , dihydrodigitoxigenin (2) and scillarenin (3) are synthetized and radioiodinated. The aglycones are dehydrogenated to the corresponding ketones and reacted regioselectively with 2-(4-lithiophenoxy)tetrahydropyran (18) to yield 7-9 . The protecting group is removed under mild conditions and 3-(p-hydroxyphenyl)-3-hydroxydigitoxigenin (10), 3-(p-hydroxyphenyl)-3-hydroxydihydrodigitoxigenin (11) and 3-(p-hydroxyphenyl)-3-hydroxyscillarenin (12) are obtained. The insertion of the p-hydroxyphenyl group allows the aglycone derivatives to be radioiodinated rapidly. An activity of 10 to 41 mCi per mg starting material is obtained with carrier-free ¹³¹I.     

Synthesis and anti-HIV activity of 4-[(1,2-dihydro-2-oxo-3H-indol-3-ylidene) amino]-N(4,6-dimethyl-2-pyrimidinyl)-benzene sulfonamide and its derivatives

4-[(1,2-Dihydro-2-oxo-3H-indol-3-ylidene) amino]-N(4,6-dimethyl-2-pyrimidinyl)-benzene sulphonamide and its derivatives were synthesized by reaction of isatin and its derivatives with sulphadimidine. Their chemical structures have been confirmed by IR, ¹H NMR data and elemental analysis. Investigation of anti-HIV activity of compounds were tested against replication of HIV-1 (IIIB) and HIV-2 (ROD) strains in acutely infected MT-4 cells and the activity compared with standard azidothymidine. Among the compounds tested, 4-[(1,2-dihydro-2 oxo-3H-indol-3-ylidene)amino]-N(4,6-dimethyl-2-pyrimidinyl)-benzene sulphonamide and its N-acetyl derivative were the most active compounds.     

Synthesis, antiplatelet aggregation activity, and molecular modeling study of novel substituted-piperazine analogues

Abstract  

New carbamoylpyridine and carbamoylpiperidine analogues containing nipecotic acid scaffold were designed, synthesized, and evaluated for their platelet aggregation inhibitory activity. Molecular modeling investigation was performed and the impact of lipophilicity on activity was also discussed. Structure activity relationship among this series was obtained. N ¹-[1-(4-bromobenzyl)-3-piperidino-carbonyl]-N ⁴-(2-chlorophenyl)-piperazine hydrobromide (20), and 1,4-bis-[3-[N ⁴-(2-chlorophenyl)-N ¹-(piperazino-carbonyl)]-piperidin-1-yl-methyl]-benzene dibromide (30) are the most active antiplatelet aggregating compounds in this study, both at concentration of 0.06 μM.     

Synthesis,cytotoxicity, and antibacterial studies of 2,4,5,6-substituted hexahydro-1H-isoindole-1,3(2H)-dione

In this study, synthesis of novel isoindole-1,3-dione analogues bearig halo, hydroxy, and acetoxy groups at the position 4,5,6 of the bicyclic imide ring was performed to examine their potential anticancer effects against some cell lines. A multistep chemical pathway was used to synthesize the derivatives. The cytotoxic effect of trisubstituted isoindole derivatives were evaluated by determining cellular viability using the MTT assay against A549, PC-3, HeLa, Caco-2, and MCF-7 cell lines. The C-2 selective ring-opening products were obtained from the ring-opening reaction of 5-alkyl/aryl-2-hydroxyhexahydro-4H-oxireno[2,3-e]isoindole-4,6(5H)-diones with nucleophiles such as chloride (Cl⁻) and bromide (Br⁻) ions. In addition, the ring-opening products halodiols were converted to their related acetates. The anticancer activity of synthesized isoindole-1,3-dione derivatives was investigated against HeLa, A549, MCF-7, PC3, and Caco-2 cells in vitro and resulted in varies cytotoxic effect depend on the group attached to the isoindole molecule. Furthermore, the evaluation of the antimicrobial action of trisubstituted isoindole derivatives against Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli) bacteria was assessed and found out selective inhibition of the both bacterial growth via different trisubstituted isoindole derivatives. The results of this work encourage further research on the potential utilization of trisubstituted isoindole derivatives as cytotoxic and antimicrobial agents.     

Binding site analysis of CCR2 through in silico methodologies: docking, CoMFA, and CoMSIA

Chemokine receptor (CCR2) is a G protein‐coupled receptor that contains seven transmembrane domains. CCR2 is targeted for diseases like arthritis, multiple sclerosis, vascular disease, obesity and type 2 diabetes. Herein, we report on a binding site analysis of CCR2 through docking and three‐dimensional quantitative structure–activity relationship (3D‐QSAR). The docking study was performed with modeled receptor (CCR2) using β2‐andrenergic receptor structure as a template. Comparative molecular field analysis (CoMFA)‐ and comparative molecular similarity indices analysis (CoMSIA)‐based 3D‐QSAR models were developed using two different schemes: ligand‐based (CoMFA; q² = 0.820, r² = 0.966, = 0.854 and CoMSIA; q² = 0.762, r² = 0.846, = 0.684) and receptor‐guided (CoMFA; q² = 0.753, r² = 0.962, = 0.786, CoMSIA; q² = 0.750, r² = 0.800, = 0.797) methods. 3D‐QSAR analysis revealed the contribution of electrostatic and hydrogen bond donor parameters to the inhibitory activity. Contour maps suggested that bulky substitutions on the para position of R¹ substituted phenyl ring, electronegative and donor substitutions on meta (5′) and ortho (2′) position of R² substituted phenyl ring were favorable for activity. The results correlate well with previous results and newly report additional residues that may be crucial in CCR2 antagonism.     

Synthesis and elastase inhibition activities of novel aryl,substituted aryl,and heteroaryl oxime ester derivatives

Fifteen novel aryl, substituted aryl and heteroaryl γ‐hydroxy‐ ( 2a–e ), γ‐methoxyimin o‐ (3a–e ), and γ‐benzyloxyimino‐ ( 4a–e ) butyric acid methyl esters were investigated for their enzyme inhibition, and the synthesis of 10 compounds ( 3a–e , 4a–e ) is given in this study. The other five compounds ( 2a–e ) were synthesized before in another study. Compounds 3a–e and 4a–e were synthesized in this work as original compounds and characterized by ¹H and ¹³C NMR, IR, mass, and elemental analyses. Their (E/Z)‐isomerisation ratios were analyzed by ¹H and ¹³C NMR. All of them are of pure (E)‐configuration. Due to the literature survey, the elastase inhibition activity was not studied for these compounds. Elastase inhibition ability was investigated in this work for five γ‐hydroxy‐ ( 2a–e ), five γ‐methoxy‐ ( 3a–e ), and five γ‐benzyloxyimino‐ ( 4a–e ) butyric acid methyl esters. All these 15 compounds showed elastase inhibition activity. Compound 2b was the best one and exhibited a better activity than the standard ursolic acid whereas compound 2a worked like the standard. All these compounds can be novel elastase inhibitor agents in the pharmaceutical and cosmetic industries.

     

Synthesis of N3-fumaramoyl-L-2,3-diaminopropanoic acid analogues,the irreversible inhibitors of glucosamine synthetase

Several analogues of N³-fumaramoyl-L-2,3-diaminopropanoic acid were synthesized and evaluated for inhibition of glucosamine-6-phosphate synthetase activity. The syntheses were accomplished by acylation reaction of N²-tert.-butoxycarbonyl-L-2,3-diaminopropanoic acid (Boc-A₂pr) or N²-tert.-butoxy-carbonyl-L-2,4-diaminobutanoic acid (Boc-A₂-bu) with the N-succinimidoyl esters of several derivatives of α, β-unsaturated acids 2a-d followed by deprotection of the Boc groups. The obtained compounds were tested for inhibition of glucosamine synthetase isolated from Salmonella typhimurium and Saccharomyces cerevisiae. The results indicated that among the synthesized compounds, N³-4-methoxyfumaroyl-L-2,3-diaminopropanoic acid (FMDP) was the most powerful inhibitor of glucosamine synthetase.     

Motor inhibition induced by aporphine derivatives in the mouse

The ability of some aporphine and benzylisoquinoline derivatives to inhibit mouse spontaneous locomotor activity at low doses, and at higher doses to have a reduced motor inhibitory effect, was used to determine whether motor inhibitory and facilitatory potentials could be dissociated, and the optimal structure required to cause these behavioural changes. Ability to displace [³H]2-amino-6,7-dihydroxy-1,2,3,4-tetrahydro-naphthalene [³H]ADTN from its binding sites in rat striatal tissue was used as a broad measure of the abilities of the test compounds to bind to the ‘dopamine receptor’. The order of potency for ‘low dose’ inhibition of mouse spontaneous locomotion was (1) (-)N-n-propylnorapomorphine>(2) apomorphine > (3) (-)2,10,11-trihydroxy-N-n-propylnoraporphine > (4) (-)2,10,11-trihydroxyaporphine > (5) f-10,11-dihydroxy-N-(hydroxy-ethyl)noraporphine > (6) norapomorphine > (7) (±)10-hydroxy-N-n-propylnoraporphine > (8) 1-(3,4-dihydroxybenzyl)-2-n-propyl-1,2,3,4-tetrahydroiso- quinoline. The latter two compounds were only weakly active and (±)8-hydroxy-N-n-propylnoraporphine and 1-(4-hydroxybenzyl)-2-n-propyl-1,2,3,4-tetrahydroisoquinoline were inactive. The reduction in motor inhibitory effect as dose of agonist was increased (indicative of facilitation of locomotion) was only observed with compounds 1 and 2, other compounds (3 and 4) caused non-specific changes which interfered with motor performance or the doses required were so large as to render testing impractical (5,6,7 and 8). The potent motor inhibitory actions of compounds 1–4 were antagonized by pretreatment with spiperone but not with prazosin or yohimbine. Specific binding of 2·0nM [³H]ADTN was displaced by nanomolar concentrations of (±)-ADTN and aporphine derivatives. Isoapomorphine and the two benzylisoquinoline derivatives were ineffective at 10^?6M. The optimal structure for those derivatives examined was shown in all tests to be (-)N-n-propylnorapomorphine.     

Disposition and metabolism of indeloxazine hydrochloride,a cerebral activator,in rats

1. The disposition and metabolism of indeloxazine hydrochloride ((±) -2-[(inden-7-yloxy)methyl]morpholine hydrochloride) were studied in male Sprague-Dawley rats.

2. After oral administration of ¹⁴C-indeloxazine hydrochloride, the plasma concentration of total radioactivity reached a maximum at 15 min and declined with an apparent half-life of 2.2h in the first 6h period and declined more slowly thereafter. Unchanged drug in the plasma represented 13.5%, 5.9% and 0.4% of the total radioactivity at 15 min, 1 h and 6 h respectively after administration and levels decayed with a half-life of 0.9 h.

3. After oral and i.v. administration of the labelled compound, the urinary and faecal excretion of radioactivity in 72 h were 61–65% and 31–36% of the dose, respectively. Biliary excretion in bile duct-cannulated animals amounted to 49% of the dose in 72 h.

4. Seven metabolites have been isolated from the plasma or urine and characterized by i.r., n.m.r. and mass spectrometry. They were derived through dihydrodiol formation in the indene ring, hydroxylation of the indene ring and N-acetylation, oxidation and oxidative degradation of the morpholine ring. Some metabolites were excreted as their glucuronic acid or glucose conjugates. The major metabolite appcared to the trans-indandiol analogue of indeloxazine.

5. Possible metabolic pathways of degradation of the morpholine ring are discussed.