Synthesis and biological evaluation of thiophene derivatives as acetylcholinesterase inhibitors

A series of new thiophene derivatives has been synthesized using the Gewald protocol. The acetylcholinesterase inhibition activity was assayed according to Ellman's method using donepezil as reference. Some of the compounds were found to be more potent inhibitors than the reference. 2-(2-(4-(4-Methoxyphenyl)piperazin-1-yl)acetamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (IIId) showed 60% inhibition, compared to only 40% inhibition by donepezil.     

Synthesis and biological evaluation of novel dabigatran derivatives as thrombin inhibitors

Research on Chemical Intermediates - A novel series of 3-[{2-[(4-carbamimidoylphenylamino)methyl]-1-substituted-1H-benzoimidazole-5-carbonyl}(3-chloro-4-fluorophenyl)amino]propionic derivatives of...     

Synthesis and biological evaluation of lycorine derivatives as dual inhibitors of human acetylcholinesterase and butyrylcholinesterase

ABSTRACT: BACKGROUND: Alzheimer's disease (AD) is a neurologically degenerative disorder that affects more than 20 million people worldwide. The selective butyrylcholinesterase (BChE) inhibitors and bivalent cholinesterase (ChE) inhibitors represent new treatments for AD. FINDINGS: A series of lycorine derivatives (1--10) were synthesized and evaluated for anti-cholinesterase activity. Result showed that the novel compound 2-O-tert-butyldimethylsilyl-1-O-(methylthio)methyllycorine (7) was a dual inhibitor of human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBChE) with IC50 values of 11.40 [PLUS-MINUS SIGN] 0.66 muM and 4.17 [PLUS-MINUS SIGN] 0.29 muM, respectively. The structure-activity relationships indicated that (i) the 1-O-(methylthio)methyl substituent in lycorine was better than the 1-O-acetyl group for the inhibition of cholinesterase; (ii) the acylated or etherified derivatives of lycorine and lycorin-2-one were more potent against hBChE than hAChE; and (iii) the oxidation of lycorine at C-2 decreases the activity. CONCLUSION: Acylated or etherified derivatives of lycorine are potential dual inhibitors of hBChE and hAChE. Hence, further study on the modification of lycorine for ChE inhibition is necessary.     

Synthesis of new indole derivatives structurally related to donepezil and their biological evaluation as acetylcholinesterase inhibitors

New series of indole derivatives analogous to donepezil, a well known anti-Alzheimer and acetylcholinesterase inhibitor drug, was synthesized. A full chemical characterization of the new compounds is provided. Biological evaluation of the new compounds as acetylcholinesterase inhibitors was performed. Most of the compounds were found to have potent acetylcholinesterase inhibitor activity compared to donepezil as standard. The compound 1-(2-(4-(2-fluorobenzyl) piperazin-1-yl)acetyl)indoline-2,3-dione (IIId) was found to be the most potent.     

Synthesis and biological evaluation of novel isopropanolamine derivatives as non-peptide human immunodeficiency virus protease inhibitors

Novel potential human immunodeficiency virus (HIV) protease inhibitors were designed by a combination of nelfinavir and amprenavir motifs. The designed compounds were prepared by a facile synthetic route and their stereochemistry was further confirmed by a stereospecific synthesis from commercially available (S)-2-oxiranylmethyl m-nitrobenzenesulfonate. All compounds were tested for their ability in inhibiting HIV type 1 protease activity with the published method of reference 19. Derivatives 1a--u exhibited moderate to significant inhibitory activities in preliminary bioassay. The best compound 1a has IC50 value of 0.02 microM, comparable to that of amprenavir. A docking study on compounds 1a--u was performed using the published X-ray crystal structure of HIV type 1 protease, all compounds bound to the HIV type 1 protease in an extended conformation and the scaffoldings of the binding conformations could be aligned quite well. Comparative molecular field analysis (CoMFA) study was performed to explore the specific contributions of electrostatic and steric effects in the binding of these new compounds to HIV type 1 protease and a predictive CoMFA model was built with thirteen compounds as training set. Test analysis of other five compounds as test set demonstrated that the CoMFA model has strong predictive ability to this series of compounds. It will be very useful to further optimize the designed inhibitors.     

Synthesis and biological evaluation of triazepane derivatives as DPP-IV inhibitors

A series of triazepane derivatives such as (R)-3-amino-1-(1,2,5-triazepan-1-yl)-4-(2,4,5-trifluorophenyl)butan-1-ones (7, 13a-p) and (R)-3-amino-1-(1,2,5-triazepan-5-yl)-4-(2,4,5-trifluorophenyl)butan-1-ones (17a-e) was synthesized and evaluated for their ability to inhibit dipeptidyl peptidase IV (DPP-IV) enzyme. Compounds with the acid moiety were found to be potent inhibitors of DPP-IV without inhibiting CYP 3A4. Among them, compound 13p ((R)-4-[1-acetyl-2-{3-amino-4-(2,4,5-trifluorophenyl)butanoyl-1,2,5-triazepan-5-carbonyl}benzoic acid]) showed a good in vitro activity without inhibiting CYP.     

Synthesis,biological evaluation,and computational studies of novel fused six-membered O-containing heterocycles as potential acetylcholinesterase inhibitors

An efficient, borax-catalyzed protocol for the synthesis of novel 4-aryl-substituted-4H-pyran derivatives fused to α-pyrone ring in a one-pot is described. By this achievement, some novel 4-aryl substituted 4H-pyrans fused to the α-pyrone ring as potential acetylcholinesterase inhibitors (AChEIs) with good to excellent yields are obtained from a one-pot three-component reaction between various aryl aldehydes, 4-hydroxy-6-methyl-2H-pyran-2-one and malononitrile. The method is a facile, inexpensive, practical and highly efficient one to obtain target compounds. The chemical structures of all compounds were characterized by FT-IR, FT-¹³CNMR and FT-¹HNMR, MS spectroscopy and also elemental analyses data. Furthermore, the purity of all novel compounds was checked by HPLC. In addition, both molecular modelling studies and Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMETox) prediction nominated all compounds as good acetylcholinesterase inhibitors to the potential treatment of Alzheimer, Parkinson and Autism diseases that among them compound 4f showed the best activity against acetylcholinesterase enzyme.     

Synthesis of stemofoline analogues as acetylcholinesterase inhibitors

Thirty-two new stemofoline analogues were prepared from didehydrostemofoline for studies as AChE inhibitors. C-3 Side-chain modified amino, carbamate, triazole and oxazole stemofoline derivatives were prepared. In general the amine derivatives were found to be stronger inhibitors of AChE than their alcohol analogues that we previously reported. Compounds 5 and 26, with small C-3 side-chain substituents, were two of the most active inhibitors. Preliminary molecular docking studies suggested that these compounds may inhibit AChE by binding horizontally along the passage of the active-site gorge and block access to acetylcholine.     

新型萘酰亚胺衍生物的合成及抗肿瘤活性评价

本文合成了三种新的萘酰亚胺衍生物,并对其体外抗肿瘤活性进行了评价.初步实验结果表明,以芳基修饰氨萘菲特芳环上氨基所得化合物体外活性不如阳性对照氨萘菲特.而利用1,4-丁二醇修饰4-溴-1,8-萘酐芳环上溴原子得到的化合物3与阳性对照及其它两种衍生物相比对肝癌细胞HepG2具有较低的IC_(50)值.     

Synthesis and biological evaluation of echinocystic acid derivatives as HCV entry inhibitors

A series of echinocystic acid (EA) 28-COOH derivatives was synthesized, and their anti-HCV entry activity was evaluated by HCVpp and VSVpp entry assay. It was found that some of them showed moderate anti-HCV entry activity, especially compound 12, and these modifications also removed the undesired hemolytic effect.     

Synthesis and biological evaluation of novel triazole derivatives as antifungal agents

A series of 1-(benzylamino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-l-yl)propan-2-ols compounds were synthesized and evaluated for their antifungal activities in vitro.The results showed that compounds 6A and 6B exhibited good antifungal activity.Compound 6A8 showed the strongest antifungal activity,which was significantly higher than that of the lead compounds and positive-control drugs Fluconazole and Itraconazole.In particular,the antifungal activity of compound 6A8 against Candida albicans and Candida krusei(MIC80 both at 0.00097μg/mL) was 515 and 64 times that of Fluconazole,respectively.The structure-activity relationships of the synthesized compounds were discussed,and the docking model of the target compounds with fungal lanosterol 14α-demethylase (CYP51) was analyzed.     

Design and activity of cationic fullerene derivatives as inhibitors of acetylcholinesterase

Four different regioisomers of cationic bis-N,N-dimethylfulleropyrrolidinium salts have been prepared and evaluated as inhibitors of the enzymatic activity of acetylcholinesterase. These fullerene-based derivatives were found to be noncompetitive inhibitors of acetylthiocholine hydrolysis. Molecular modelling was used to describe the possible interactions between the fullerene cage and the amino acids surrounding the cavity of the enzyme. The cationic C(60) derivatives used in this study represent a new class of molecules potentially able to modulate the enzymatic activity of acetylcholinesterase.     

Synthesis and biological evaluation of novel N-(alkoxyphenyl)-aminocarbonylbenzoic acid derivatives as PTP1B inhibitors

<正>Based on the fact that petroselinic acid showed good inhibitory activity(IC_(50) = 6.99μmol/L) against protein tyrosine phophatase 1B(PTP1B) in vitro,a series of novel N-(alkoxyphenyl)-aminocarbonylbenzoic acid derivatives were designed and synthesized.The results indicated that most of the derivatives showed more potent activities against PTP1B.Especially,compound 13 had obvious activity with an IC_(50) of 106 nmol/L in vitro.     

Synthesis and pharmacological effects of novel benzenesulfonamides carrying benzamide moiety as carbonic anhydrase and acetylcholinesterase inhibitors

N -(1-(4-Methoxyphenyl)-3-oxo-3-((4-( N -(substituted)sulfamoyl)phenyl)amino)prop-1-en-1-yl)benzamides 3a – g were designed since sulfonamide and benzamide pharmacophores draw great attention in novel drug design due to their wide range of bioactivities including acetylcholinesterase (AChE) and human carbonic anhydrase I and II (hCA I and hCA II) inhibitory potencies. Structure elucidation of the compounds was carried out by 1H NMR, 13C NMR, and HRMS spectra. In vitro enzyme assays showed that the compounds had significant inhibitory potential against hCA I, hCA II, and AChE enzymes at nanomolar levels. Ki values were in the range of 4.07 ± 0.38 – 29.70 ± 3.18 nM for hCA I and 10.68 ± 0.98 – 37.16 ± 7.55 nM for hCA II while Ki values for AChE were in the range of 8.91 ± 1.65 – 34.02 ± 5.90 nM. The most potent inhibitors 3g (Ki = 4.07 ± 0.38 nM, hCA I), 3c (Ki = 10.68 ± 0.98 nM, hCA II ) , and 3f (Ki = 8.91 ± 1.65 nM, AChE) can be considered as lead compounds of this study with their promising bioactivity results. Secondary sulfonamides showed promising enzyme inhibitory effects on AChE while primary sulfonamide derivative was generally effective on hCA I and hCA II isoenzymes.     

Synthesis of novel flavonoid derivatives as potential HIV‐ Integrase inhibitors

Eighteen novel flavonoid derivatives ‐ substituted chalcones and flavones were synthesized and characterized by using NMR, IR, UV/Vis spectroscopy and elemental analysis. The target compounds were achieved by using a sequence of simple and effective reactions starting from phloroglucinol. The initial hydroxyl groups were protected by methylation and in the final flavones the 5‐OH group was selectively demethylated by means of AlBr₃. 5‐methoxy flavones exhibit a strong fluorescence, which was quenched after the removal of the methyl group.     

Synthesis and biological activity of 3,6-diaryl-7H-thiazolo[3,2-b][1,2,4]triazin-7-one derivatives as novel acetylcholinesterase inhibitors

Acetylcholinesterase inhibitors played significant roles in treatment of Alzheimer’s disease. Based on the research foundation of our previous work and molecular modeling, twelve 3,6-diaryl-7H-thiazolo[3,2-b][1,2,4]triazin-7-one derivatives were synthesized and characterized by mass spectra, infrared spectra, NMR and elemental analyses. The study of AChE inhibitory activity was carried out using the Ellman colorimetric assay with huperzine-A as the positive control. All target compounds exhibited more than 40% inhibition at 10 μM. Some target compounds showed good inhibition against AChE. The preliminary structure-activity relationships were the halogen atoms at the phenyl ring at the C6 position, the hydroxy groups and the long side chains at the phenyl ring at the C3 position of the parent nucleus played significant roles in the AChE inhibitory activity of the target compounds.     

Synthesis and in vitro study of new coumarin derivatives linked to nicotinonitrile moieties as potential acetylcholinesterase inhibitors

The appropriate pyridine-2(1H)-thiones were reacted with an equivalent amount of 5-(chloromethyl)-2-hydroxybenzaldehyde in ethanol in the presence of potassium hydroxide to give the corresponding 2-hydroxybenzaldehyde derivatives in excellent yields. The latter derivatives were taken as key synthons for the preparation of the target hybrids. Therefore, 2-hydroxybenzaldehydes were reacted with benzoylglycine in acetic anhydride in the presence of fused sodium acetate at 100°C for 6 hours to afford a new series of nicotinonitrile-coumarin hybrids. The in vitro acetylcholinesterase inhibitory activities were estimated for the new coumarins. The results were expressed as the inhibition percentage of the tested hybrids at concentration of 25 nM, compared to donepezil as a reference (inhibition percentage of 70.5). Coumarin hybrids linked to 6-(4-nitrophenyl) or 6-(4-chlorophenyl)-4-phenylnicotinonitrile exhibited more effective inhibitory activities than donepezil with inhibition percentages of 94.1 and 72.3, respectively. The new coumarins were tested for their free radical-scavenging capabilities against DPPH. Furthermore, some new coumarins were tested for in vitro cytotoxic activity against each MCF-10A, MCF-7, Caco2, and HEPG2. The new hybrids showed cytotoxicity in micromolar range (IC₅₀ of 3.5-13.9 μM) against all tested cell lines. These results clearly demonstrated that the hybrids being tested are not cytotoxic at the concentration required to inhibit acetylcholinesterase effectively.     

Synthesis and biological evaluation of novel N-(alkyoxyphenyl)- aminocarbonylbenzoic acid derivatives as PTP1B inhibitors

Based on the fact that petroselinic acid showed good inhibitory activity (IC50=6.99 µmol/L) against protein tyrosine phophatase 1B(PTP1B) in vitro,a series of novel N-(alkoxyphenyl)-aminocarbonyl benzoic acid derivatives were designed and synthesised. The results indicated that most of the derivatives showed more potent activities against PTP1B. Especially, compound 13 had obvious activity with an IC50 of 106 nmol/L in vitro.     

Synthesis and biological evaluation of substituted indazolyl amide derivatives as S-adenosyl-L-homocysteine hydrolase inhibitors

A series of novel amide derivatives bearing an indazole moiety were synthesized and evaluated for their in vitro S-adenosyl-L-homocysteine hydrolase (SAHase) inhibitory activity. Among these compounds, 8b, 8m, 8r and 8w showed better or similar inhibitory effects compared to the positive control aristeromycin. These results provide a novel lead for the discovery of more potent non-adenosine analogs as SAHase inhibitors.     

Synthesis and biological evaluation of novel acenaphthene derivatives as potential antitumor agents

Twelve novel acenaphthene derivatives have been synthesized. The structures of all compounds were confirmed by 1H-NMR, MS and elemental analysis. Their antitumor activities were evaluated in six human solid tumor cell lines, namely non-small cell lung cancer (H460), human colon adenocarcinoma (SW480), human breast cancer cell (MDA-MB-468 and SKRB-3), human melanoma cell (A375) and human pancreatic cancer (BxPC-3). Among them, compound 3c shows the best antitumor activity against SKRB-3 cell line, as high as the positive control adriamycin.