Insect pheromones as reversible competitive inhibitors of acetylcholinesterase

Summary

Structural aspects of insect pheromones, especially their hydrophobicity, prompted the examination of them by in vitro and in vivo experiments as inhibitors of acetylcholinesterase. All 17 pheromones assayed in sufficient detail were reversible, competitive inhibitors of acetylcholinesterase: K_i values ranged from 0.27 mM for frontalin to 9.3 mM for ipsenol, both aggregation pheromones. All seven pheromones assayed with Tribolium castaneum immobilised this species with an effect that was weakly dose-responsive over the range of concentrations tested. Concentrations eliciting 25% immobility (IC₂₅) ranged from 2.0x10³ ppm for 3-methy 1–2-cyclohexenone to 2.0x10⁴ ppm for cis-7, cis-11-hexadecadien-1-yl acetate, both sex attractants. Such efficacies suggest that the pheromones tested would be effective as defence agents only in species living in a confined area, as under bark, or in aggregations.     

Synthesis,biological evaluation and molecular modeling of aloe-emodin derivatives as new acetylcholinesterase inhibitors

A series of aloe-emodin derivatives were designed, synthesized and evaluated as acetylcholinesterase inhibitors. Most of the new prepared compounds showed remarkable acetylcholinesterase inhibitory activities. Among them, the compound 1-((4,5-dihydroxy-9,10-dioxo-9,10-dihydroanthracen-2-yl) methyl) pyridin-1-ium chloride (C3) which has a pyridinium substituent possessed the best inhibitory activity of acetylcholinesterase (IC₅₀ = 0.09 μM). The docking study performed with AUTODOCK demonstrated that C3 could interact with the catalytic active site (CAS) and the peripheral anionic site (PAS) of acetylcholinesterase.     

Synthesis,biological evaluation,and molecular modeling of berberine derivatives as potent acetylcholinesterase inhibitors

By targeting the dual active sites of acetylcholinesterase (AChE), a new series of berberine derivatives was designed, synthesized, and evaluated as AChE inhibitors. Most of the derivatives inhibited AChE in the sub-micromolar range. Compound 8c, berberine linked with phenol by a 4-carbon spacer, showed the most potent inhibition of AChE. A kinetic study of AChE and BuChE indicated that a mix-competitive binding mode existed for these berberine derivatives. Molecular modeling studies confirmed that these hybrids target both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. This is the first report where AChE inhibitory activity has been associated with berberine as a lead molecule.     

Synthesis and in vitro anticancer evaluation of some fused indazoles,quinazolines and quinolines as potential EGFR inhibitors

derivatives of benzo[g]indazole 5a, b, benzo[h]quinazoline 7, 12a-c, 13a-c and 15a-c and benzo[h]quinoline 17a-c and 19a-c were synthesized from 6-methoxy-3,4-dihydronaphthalen-1(2H)-one (1). Anticancer activity of all the synthesized compounds was evaluated against four cancerous cell lines; HepG2, MCF-7, HCT116 and Caco-2. MCF-7 cells emerged as the most sensitive cell line against the target compounds. All the examined compounds, except 5a and 5b, displayed potent to moderate anticancer activity against MCF-7 cells with an IC₅₀ values ranging from 7.21 to 21.55 µM. In particular, compounds 15c and 19b emerged as the most potent derivatives against EGFR-expressing MCF-7 cells with IC₅₀ values = 7.70 ± 0.39 and 7.21 ± 0.43 μM, respectively. Additionally, both compounds did not display any significant cytotoxicity towards normal BHK-21 fibroblast cells (IC₅₀ value > 200 µM), thereby providing a good safety profile as anticancer agents. Furthermore, compounds 15c and 19b displayed potent inhibitory activity towards EGFR in the sub-micromolar range (IC₅₀ = 0.13 ± 0.01 and 0.14 ± 0.01 μM, respectively), compared to that of Erlotinib (IC₅₀ = 0.11 ± 0.01 μM). Docking studies for 15c and 19b into EGFR active site was carried out to explore their potential binding modes. Therefore, compounds 15c and 19b can be considered as interesting candidates for further development of more potent anticancer agents.     

Synthesis of tricyclic analogs of stephaoxocanidine and their evaluation as acetylcholinesterase inhibitors

The synthesis of simplified analogs of the novel isoquinoline alkaloid stephaoxocanidine, carrying the oxazaphenalene ABC-ring system of the natural product, and their activity as inhibitors of the enzyme acetylcholinesterase, are reported. 5,6-Dimethoxy-7H -8-oxa-1-aza-phenalen-9-one (5) was as active as a Narcissus extract enriched in galantamine.     

Syntheses and spectroscopic characterization of some phosphoramidates as reversible inhibitors of human acetylcholinesterase and determination of their potency

The ability of phosphoramidates Me2NP(O)(Cl)(p-NHC6H4NO2) 1, Me2NP(O)(p-NHC6H4NO2)2 2, (CH3C6H4O-p)P(O)(p-NHC6H4NO2)2 3 and (CH3C6H40-p)2P(O)(p-NHC6H4NO2) 4 to inhibit human acetylcholinesterase (hAChE) has been evaluated by a modified Ellman's method and spectrophotometric measurements. Results showed that compounds 1 and 2 do not have any inhibitory potency, whereas compounds 3 and 4 were reversible mixed inhibitors. The IC50 values for inhibitors 3 and 4 were 0.143 and 0.581 mM, respectively. The previously unknown compounds 3 and 4 were synthesized and characterized by 1H, 13C, 31P NMR and IR spectroscopy and elemental analysis.     

Synthesis and biological evaluation of novel flavonoid derivatives as dual binding acetylcholinesterase inhibitors

A new series of flavonoid derivatives have been designed, synthesised and evaluated as acetylcholinesterase inhibitors that could bind simultaneously to the peripheral and catalytic sites of the enzyme. Among them, fifteen derivatives were found to inhibit the enzyme in the micromolar range and isoflavone derivatives possessed more potent inhibitory activity than other flavonoid derivatives. The best compound 9a had its inhibitory activity (IC₅₀ = 0.093μM) in the same range as the reference compound, donepezil (IC₅₀ = 0.025μM). Preliminary structure-activity relationships and a molecular modeling study for 9a have revealed that the isoflavone moiety plays a key role in the interaction of this series of derivatives with AChE by acting as an anchor in its peripheral anionic site.     

Synthesis and biological evaluation of novel flavonoid derivatives as dual binding acetylcholinesterase inhibitors

A new series of flavonoid derivatives have been designed, synthesised and evaluated as acetylcholinesterase inhibitors that could bind simultaneously to the peripheral and catalytic sites of the enzyme. Among them, fifteen derivatives were found to inhibit the enzyme in the micromolar range and isoflavone derivatives possessed more potent inhibitory activity than other flavonoid derivatives. The best compound 9a had its inhibitory activity (IC(50) = 0.093 microM) in the same range as the reference compound, donepezil (IC(50) = 0.025 microM). Preliminary structure-activity relationships and a molecular modeling study for 9a have revealed that the isoflavone moiety plays a key role in the interaction of this series of derivatives with AChE by acting as an anchor in its peripheral anionic site.     

Design,synthesis and evaluation of new thiazole-piperazines as acetylcholinesterase inhibitors

In this study, some new 2-(4-substituted piperazine-1-yl)-N-[4-(2-methylthiazol-4-yl)phenyl]acetamide derivatives were synthesized. The synthesized compounds were screened for their anticholinesterase activity on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes by in vitro Ellman’s method. The structural elucidation of the compounds was performed by using IR, ¹H-NMR, ¹³C-NMR and FAB⁺-MS spectral data and elemental analyses results. Biological assays revealed that at 0.1 µM concentration, the most active compounds against AChE were 5n, 5o and 5p that indicated 96.44, 99.83 and 89.70% inhibition rates, respectively. Besides, IC₅₀ value of the compound 5o was determined as 0.011 µM, whereas IC₅₀ value of standard drug donepezil was 0.054 µM. The synthesized compounds did not show any notable inhibitory activity against BChE.     

Synthesis and molecular docking studies of some 4-phthalimidobenzenesulfonamide derivatives as acetylcholinesterase and butyrylcholinesterase inhibitors

A series of 4-phthalimidobenzenesulfonamide derivatives were designed, synthesized and evaluated for the inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Structures of the title compounds were confirmed by spectral and elemental analyses. The cholinesterase (ChE) inhibitory activity studies were carried out using Ellman’s colorimetric method. The biological activity results revealed that all of the title compounds (except for compound 8) displayed high selectivity against AChE. Among the tested compounds, compound 7 was found to be the most potent against AChE (IC₅₀=?1.35?±?0.08?μM), while compound 3 exhibited the highest inhibition against BuChE (IC₅₀=?13.41?±?0.62?μM). Molecular docking studies of the most active compound 7 in AChE showed that this compound can interact with both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE.     

Synthesis and biological evaluation of aminomethyl and alkoxymethyl derivatives as carbonic anhydrase,acetylcholinesterase and butyrylcholinesterase inhibitors

Compounds containing nitrogen and sulfur atoms can be widely used in various fields such as industry, medicine, biotechnology and chemical technology. Therefore, the reactions of aminomethylation and alkoxymethylation of mercaptobenzothiazole, mercaptobenzoxazole and 2-aminothiazole were developed. Additionally, the alkoxymethyl derivatives of mercaptobenzoxazole and 2-aminothiazole were synthesized by a reaction with hemiformals, which are prepared by the reaction of alcohols and formaldehyde. In this study, the inhibitory effects of these molecules were investigated against acetylcholinesterase (AChE), butyrylcholinesterase (BChE) enzymes and carbonic anhydrase I, and II isoenzymes (hCA I and II). Both hCA isoenzymes were significantly inhibited by the recently synthesized molecules, with K_i values in the range of 58–157?nM for hCA I, and 81–215?nM for hCA II. Additionally, the K_i parameters of these molecules for BChE and AChE were calculated in the ranges 23–88 and 18–78?nM, respectively.     

Synthesis and kinetic analysis of some phosphonate analogs of cyclophostin as inhibitors of human acetylcholinesterase

Two new monocyclic analogs of the natural AChE inhibitor cyclophostin and two exocyclic enol phosphates were synthesized. The potencies and mechanisms of inhibition of the bicyclic and monocyclic enol phosphonates and the exocyclic enol phosphates toward human AChE are examined. One diastereoisomer of the bicyclic phosphonate exhibits an IC₅₀ of 3 μM. Potency is only preserved when the cyclic enol phosphonate is intact and conjugated to an ester. Kinetic analysis indicates both a binding and a slow inactivation step for all active compounds. Mass spectrometric analysis indicates that the active site Ser is indeed phosphorylated by the bicyclic phosphonate.     

Studies on new,centrally active and reversible acetylcholinesterase inhibitors

We have synthesized the tertiary amines of pyridostigmine and neostigmine, 3-pyridinol dimethylcarbamate (norpyridostigmine) and 3-dimethylaminophenol dimethylcarbamate (norneostigmine) respectively, and we have tested their abilities to cross the blood-brain barrier and inhibit mouse brainAChE activity. The in vivo inhibition of AChE activity by norpyridostigmine reaches 72% at 10 minutes which is comparable to that seen with physostigmine (73% at 10 minutes). Inhibition by norneostigmine is less effective (50% at 10 minutes) and approaches that obtained with tetrahydroaminoacridine (57% at 10 minutes). These data show that both norpyridostigmine and norneostigmine cross the blood-brain barrier and that they are effective inhibitors of mouse brain AChE activity. These drugs could be useful in the treatment of memory, impairment associated with Alzheimer's disease, and other memory disorders.     

Synthesis of aminoalkyl-substituted coumarin derivatives as acetylcholinesterase inhibitors

Alzheimer’s disease, one of the most common forms of dementia, is a progressive neurodegenerative disorder symptomatically characterized by declines in memory and cognitive abilities. To date, the successful therapeutic strategy to treat AD is maintaining levels of acetylcholine by inhibiting acetylcholinesterase (AChE). In the present study, coumarin derivatives were designed and synthesized as AChE inhibitors based on the lead structure of scopoletin. Of those synthesized, pyrrolidine-substituted coumarins 3b and 3f showed ca. 160-fold higher AChE inhibitory activities than scopoletin. These compounds also ameliorated scopolamine-induced memory deficit in mice when administered orally at the dose of 1 and 2 mg/kg.     

Design,synthesis and pharmacological evaluation of chalcone derivatives as acetylcholinesterase inhibitors

A novel series of chalcone derivatives (4a–8d) were designed, synthesized, and evaluated for the inhibition activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The log P values of the compounds were shown to range from 1.49 to 2.19, which suggested that they were possible to pass blood brain barriers in vivo. The most promising compound 4a (IC₅₀: 4.68 μmol/L) was 2-fold more potent than Rivastigmine against AChE (IC₅₀: 10.54 μmol/L) and showed a high selectivity for AChE over BuChE (ratio: 4.35). Enzyme kinetic study suggested that the inhibition mechanism of compound 4a was a mixed-type inhibition. Meanwhile, the result of molecular docking showed its potent inhibition of AChE and high selectivity for AChE over BuChE.     

Synthesis,biological evaluation and molecular modeling of substituted 2-aminobenzimidazoles as novel inhibitors of acetylcholinesterase and butyrylcholinesterase

A series of novel 2-aminobenzimidazole derivatives were synthesized under microwave irradiation. Their biological activities were evaluated on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). A number of the 2-aminobenzimidazole derivatives showed good inhibitory activities to AChE and BuChE. Among them, compounds 9, 12 and 13 were found to be >25-fold more selective for BuChE than AChE. No evidence of cytotoxicity was observed by MTT assay in PC12 cells or HepG2 cells exposed to 100 μM of the compounds. Molecular modeling studies indicate that the benzimidazole moiety of compounds 9, 12 and 13 forms a face-to-face π–π stacking interaction in a ‘sandwich’ form with the indole ring of Trp82 (4.09 Å) in the active gorge, and compounds 12 and 13 form a hydrogen bond with His438 at the catalytic site of BuChE. In addition, compounds 12 and 13 fit well into the hydrophobic pocket formed by Ala328, Trp430 and Tyr332 of BuChE. Our data suggest the 2-aminobenzimidazole drugs as promising new selective inhibitors for AChE and BuChE, potentially useful to treat neurodegenerative diseases.     

Synthesis and in vitro evaluation of pseudosaccharinamine derivatives as potential elastase inhibitors

Pseudosaccharinamine derivatives were evaluated for elastase inhibitory activity. Ester derivatives of pseudosaccharinamine displayed reversible and high inhibition of human leukocyte elastase (HLE) as compared to porcine pancreatic elastase (PPE). Cyanomethyl (2S,3S)-2-(1,1-dioxobenzo[d]isothiazol-3-ylamino)-3-methylpentanoate was found to inhibit HLE at Ki=0.8 microM.     

Synthesis,biological evaluation and molecular docking of novel pyrazole derivatives as potent carbonic anhydrase and acetylcholinesterase inhibitors

A series of substituted pyrazole compounds (1–8 and 9a, b) were synthesized and their structure was characterized by IR, NMR, and Mass analysis. These obtained novel pyrazole derivatives (1–8 and 9a, b) were emerged as effective inhibitors of the cytosolic carbonic anhydrase I and II isoforms (hCA I and II) and acetylcholinesterase (AChE) enzymes with K_i values in the range of 1.03 ± 0.23–22.65 ± 5.36 µM for hCA I, 1.82 ± 0.30–27.94 ± 4.74 µM for hCA II, and 48.94 ± 9.63–116.05 ± 14.95 µM for AChE, respectively. Docking studies were performed for the most active compounds, 2 and 5, and binding mode between the compounds and the receptors were determined.     

Design,synthesis, and evaluation of carboxyl-modified oseltamivir derivatives with improved lipophilicity as neuraminidase inhibitors

In this study, a series of carboxyl-modified oseltamivir analogs with improved lipophilicity were designed and synthesized, and their inhibitory activities against neuraminidase from influenza A virus H5N1 subtype were evaluated. The results demonstrated that compound 5m exhibited potent inhibitory activity (IC₅₀?=?1.30?±?0.23?μM), and it targeted the recently discovered 430-cavity. Compound 5m (Log D?=??0.12) is more lipophilic than oseltamivir carboxylate (Log D?=??1.69) at pH 7.4, which is potentially propitious to improved membrane permeability and oral drug absorption. Meanwhile, 5m showed high stability in human liver microsomes. The findings of this study can be valuable in identifying neuraminidase inhibitors with optimal lipophilicity and in the exploration of 430-cavity.     

Synthesis and biological evaluation of some thiazole derivatives as new cholinesterase inhibitors

In the present study, some thiazole derivatives were synthesized via the ring closure reaction of 1-[2-(2-oxobenzo[d]thiazol-3(2H)-yl)acetyl]thiosemicarbazide with various phenacyl bromides. The chemical structures of the compounds were elucidated by ¹H NMR, ¹³C NMR and mass spectral data and elemental analyses. Each derivative was evaluated for its ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) using a modification of Ellman’s spectrophotometric method. The compounds were also investigated for their cytotoxic properties using MTT assay. The most potent AChE inhibitor was found as compound 4e (IC₅₀?=?25.5?±?2.12 µg/mL) followed by compounds 4i (IC₅₀?=?38.50?±?2.12 µg/mL), 4c (IC₅₀?=?58.42?±?3.14 µg/mL) and 4g (IC₅₀?=?68?±?2.12 µg/mL) when compared with eserine (IC₅₀?=?0.025?±?0.01 µg/mL). Effective compounds on AChE exhibited weak inhibition on BuChE (IC₅₀ > 80 µg/mL). MTT assay indicated that the cytotoxic dose (IC₅₀?=?71.67?±?7.63 µg/mL) of compound 4e was higher than its effective dose.