Design and synthesis of donepezil analogues as dual AChE and BACE-1 inhibitors.

Abstract:

:Multi-target-directed ligands (MTDLs) centered on β-secretase 1 (BACE-1) inhibition are emerging as innovative therapeutics in addressing the complexity of neurodegenerative diseases. A new series of donepezil analogues was designed, synthesized and evaluated as MTDLs against neurodegenerative diseases. Profiling of donepezil, a potent acetylcholinesterase (hAChE) inhibitor, into BACE-1 inhibition was achieved through introduction of backbone amide linkers to the designed compounds which are capable of hydrogen-bonding with BACE-1 catalytic site. In vitro assays and molecular modeling studies revealed the dual mode of action of compounds 4-6 against hAChE and BACE-1. Notably, compound 4 displayed potent hAChE inhibition (IC50 value of 4.11 nM) and BACE-1 inhibition (IC50 value of 18.3 nM) in comparison to donepezil (IC50 values of 6.21 and 194 nM against hAChE and BACE-1, respectively). Moreover, 4 revealed potential metal chelating property, low toxicity on SH-SY5Y neuroblastoma cells and ability to cross the blood-brain barrier (BBB) in PAMPA-BBB assay which renders 4 a potential lead for further optimization of novel small ligands for the treatment of Alzheimer's disease.

journal_name

Bioorg Chem

journal_title

Bioorganic chemistry

authors

Gabr MT,Abdel-Raziq MS

doi

10.1016/j.bioorg.2018.06.031

subject

Has Abstract

pub_date

2018-10-01 00:00:00

pages

245-252

eissn

0045-2068

issn

1090-2120

pii

S0045-2068(18)30412-7

journal_volume

80

pub_type

杂志文章
  • Synthesis, molecular docking and cytotoxicity evaluation of novel 2-(4-amino-benzosulfonyl)-5H-benzo[b]carbazole-6,11-dione derivatives as histone deacetylase (HDAC8) inhibitors.

    abstract::A new series of 2-(4-aminobenzosulfonyl)-5H-benzo[b]carbazole-6,11-dione derivatives, which has not been reported yet, has been synthesized from 1,4-naphthoquinone and 4-aminophenylsulfone involving an Michael addition, benzoylation and Pd catalyzed coupling. This set of compounds has been evaluated for in vitro cytot...

    journal_title:Bioorganic chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bioorg.2014.01.002

    authors: Ravichandiran P,Jegan A,Premnath D,Periasamy VS,Muthusubramanian S,Vasanthkumar S

    更新日期:2014-04-01 00:00:00

  • Synthesis, biological evaluation and molecular docking studies of bis-chalcone derivatives as xanthine oxidase inhibitors and anticancer agents.

    abstract::In this study, a series of B-ring fluoro substituted bis-chalcone derivatives were synthesized by Claisen-Schmidt condensation reactions and evaluated for their ability to inhibit xanthine oxidase (XO) and growth inhibitory activity against MCF-7 and Caco-2 human cancer cell lines, in vitro. According to the results o...

    journal_title:Bioorganic chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bioorg.2019.103149

    authors: Burmaoglu S,Ozcan S,Balcioglu S,Gencel M,Noma SAA,Essiz S,Ates B,Algul O

    更新日期:2019-10-01 00:00:00

  • Synthesis and characterization of new inhibitors of cholinesterases based on N-phenylcarbamates: In vitro study of inhibitory effect, type of inhibition, lipophilicity and molecular docking.

    abstract::Based on current treatment of Alzheimer's disease, where the carbamate inhibitor Rivastigmine is used, two series of carbamate derivatives were prepared: (i) N-phenylcarbamates with additional carbamate group (1-12) and (ii) N-phenylcarbamates with monosaccharide moiety (13-24). All compounds were tested for the inhib...

    journal_title:Bioorganic chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bioorg.2018.03.012

    authors: Vorčáková K,Májeková M,Horáková E,Drabina P,Sedlák M,Štěpánková Š

    更新日期:2018-08-01 00:00:00

  • Novel carbazole-stilbene hybrids as multifunctional anti-Alzheimer agents.

    abstract::Molecules capable of engaging with multiple targets associated with pathological condition of Alzheimer's disease have proved to be potential anti-Alzheimer's agents. In our goal to develop multitarget-directed ligands for the treatment of Alzheimer's disease, a novel series of carbazole-based stilbene derivatives wer...

    journal_title:Bioorganic chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bioorg.2020.103977

    authors: Patel DV,Patel NR,Kanhed AM,Teli DM,Patel KB,Joshi PD,Patel SP,Gandhi PM,Chaudhary BN,Prajapati NK,Patel KV,Yadav MR

    更新日期:2020-08-01 00:00:00

  • New bisphosphorothioates and bisphosphoroamidates: synthesis, molecular modeling and determination of insecticide and toxicological profile.

    abstract::A series of new compounds, N,N'-bis(dialkylphosphoryl)diamines and S,S'-bis(dialkylphosphoryl)-1,3-propanedithiols were prepared by a Todd-Atherton like reaction of dialkylphosphites with symmetrical diamines and 1,3-propanedithiols in a biphasic system [F.R. Athertoon, H.T. Howard, A.R. Todd, J. Chem. Soc. (1948) 110...

    journal_title:Bioorganic chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bioorg.2006.08.006

    authors: dos Santos VM,Sant'Anna CM,Moya Borja GE,Chaaban A,Côrtes WS,DaCosta JB

    更新日期:2007-02-01 00:00:00

  • Heterocyclic periphery in the design of carbonic anhydrase inhibitors: 1,2,4-Oxadiazol-5-yl benzenesulfonamides as potent and selective inhibitors of cytosolic hCA II and membrane-bound hCA IX isoforms.

    abstract::A series of novel aromatic primary sulfonamides decorated with diversely substituted 1,2,4-oxadiazole periphery groups has been prepared using a parallel chemistry approach. The compounds displayed a potent inhibition of cytosolic hCA II and membrane-bound hCA IX isoforms. Due to a different cellular localization of t...

    journal_title:Bioorganic chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bioorg.2017.10.005

    authors: Krasavin M,Shetnev A,Sharonova T,Baykov S,Tuccinardi T,Kalinin S,Angeli A,Supuran CT

    更新日期:2018-02-01 00:00:00

  • Novel pyrimidine-pyridine hybrids: Synthesis, cyclooxygenase inhibition, anti-inflammatory activity and ulcerogenic liability.

    abstract::Some derivatives containing pyrido[2,3-d:6,5d']dipyrimidine-4,5-diones (9a-f), tetrahydropyrido[2,3-d]pyrimidine-6-carbonitriles (11a-c) and 6-(4-acetylphenyl)-2-thioxo-2,3,5,6,7,8-hexahydro-1H-pyrimido[4,5-d]pyrimidin-4-one (12) were synthesized from 6-amino-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (8). The anti-infla...

    journal_title:Bioorganic chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bioorg.2018.01.028

    authors: Abdelgawad MA,Bakr RB,Azouz AA

    更新日期:2018-04-01 00:00:00

  • Probing the antibacterial and anticancer potential of tryptamine based mixed ligand Schiff base Ruthenium(III) complexes.

    abstract::Development of new chemotherapeutic agents to treat microbial infections and recurrent cancers is of pivotal importance. Metal based drugs particularly ruthenium complexes have the uniqueness and desired properties that make them suitable candidates for the search of potential chemotherapeutic agents. In this study, t...

    journal_title:Bioorganic chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bioorg.2019.03.080

    authors: Malik MA,Raza MK,Dar OA,Amadudin,Abid M,Wani MY,Al-Bogami AS,Hashmi AA

    更新日期:2019-06-01 00:00:00

  • Discovery of a series of selective and cell permeable beta-secretase (BACE1) inhibitors by fragment linking with the assistance of STD-NMR.

    abstract::Two β-secreatase (BACE1) inhibitors from natural products (cinnamic acid and flavone) were linked to furnish potent, cell permeable BACE1 inhibitors with noncompetitive mode of inhibition, with the assistance of saturated transfer difference (STD)-NMR technique. Some of these conjugates also exhibited selective BACE1 ...

    journal_title:Bioorganic chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bioorg.2019.103253

    authors: Fang WS,Sun DY,Yang S,Cheng C,Moschke K,Li T,Sun S,Lichtenthaler SF,Huang J,Wang Y

    更新日期:2019-11-01 00:00:00

  • Novel cytisine derivatives exert anti-liver fibrosis effect via PI3K/Akt/Smad pathway.

    abstract::A series of new cytisine derivatives with a unique endocyclic scaffold were synthesized and evaluated for their inhibitory effect on collagen α1 (I) (COL1A1) promotor in human LX2 cells, taking cytisine as the lead. Structure-activity relationship (SAR) revealed that introducing a 12N-benzyl substitution might signifi...

    journal_title:Bioorganic chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bioorg.2019.103032

    authors: Tang S,Li Y,Bao Y,Dai Z,Niu T,Wang K,He H,Song D

    更新日期:2019-09-01 00:00:00

  • Benzopyrone represents a privilege scaffold to identify novel adenosine A1/A2A receptor antagonists.

    abstract::Adenosine receptor antagonists are under investigation as potential drug candidates for the treatment of certain cancers, neurological disorders, depression and potentially improve tumour immunotherapy. The benzo-γ-pyrone scaffold is well-known in medicinal chemistry with diverse pharmacological activities attributed ...

    journal_title:Bioorganic chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bioorg.2018.01.004

    authors: van der Walt MM,Terre'Blanche G

    更新日期:2018-04-01 00:00:00

  • Correlation study on methoxylation pattern of flavonoids and their heme-targeted antiplasmodial activity.

    abstract::A library of 33 polymethoxylated flavones (PMF) was evaluated for heme-binding affinity by biomimetic MS assay and in vitro antiplasmodial activity on two strains of P. falciparum. Stability of heme adducts was discussed using the dissociation voltage at 50% (DV50). No correlation was observed between the methoxylatio...

    journal_title:Bioorganic chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bioorg.2020.104243

    authors: Ortiz S,Vásquez-Ocmín PG,Cojean S,Bouzidi C,Michel S,Figadère B,Grougnet R,Boutefnouchet S,Maciuk A

    更新日期:2020-11-01 00:00:00

  • Design, synthesis and molecular modeling studies of new series of s-triazine derivatives as antimicrobial agents against multi-drug resistant clinical isolates.

    abstract::Three novel series of s-triazine derivatives, including thirty-five new compounds 2a-d, 3a-3p, 4b-d, 5b-d, 6d-6d, and 7a-7f were synthesized comprising a diversity of substituents based on the structure of Astrazeneca arylaminotriazine DNA gyrase B inhibitor. The antimicrobial activity was determined for all compounds...

    journal_title:Bioorganic chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bioorg.2019.103013

    authors: Haiba NS,Khalil HH,Moniem MA,El-Wakil MH,Bekhit AA,Khattab SN

    更新日期:2019-08-01 00:00:00

  • Taxumarienes A-G, seven new α-glucosidase inhibitory taxane-diterpenoids from the leaves of Taxus mairei.

    abstract::Seven new taxane diterpenoids taxumarienes A-G (1-7) were isolated from the leaves of Taxus mairei, along with seven known analogous (8-14). The structures of the new compounds were elucidated based on the analysis of NMR and MS spectroscopy. All isolates were evaluated for their α-glucosidase inhibitory activities. A...

    journal_title:Bioorganic chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bioorg.2019.103400

    authors: Chen K,Liu XQ,Wang WL,Luo JG,Kong LY

    更新日期:2020-01-01 00:00:00

  • Auspicious role of the steroidal heterocyclic derivatives as a platform for anti-cancer drugs.

    abstract::Steroids are polycyclic compounds that have a wide range of biological activities. They are bio-synthesized from cholesterol through a series of enzyme-mediated transformations, so they are highly lipophilic and readily enter most cells to interact with intracellular receptors, making them ideal vehicles for targeting...

    journal_title:Bioorganic chemistry

    pub_type: 杂志文章,评审

    doi:10.1016/j.bioorg.2017.06.006

    authors: Tantawy MA,Nafie MS,Elmegeed GA,Ali IAI

    更新日期:2017-08-01 00:00:00

  • Ursolic and oleanolic acid derivatives with cholinesterase inhibiting potential.

    abstract::Triterpenoids are in the focus of scientific interest, and they were evaluated for many pharmacological applications among them their ability to act as inhibitors of cholinesterases. These inhibitors are still of interest as drugs that improve the life quality of patients suffering from age-related dementia illnesses ...

    journal_title:Bioorganic chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bioorg.2018.12.013

    authors: Loesche A,Köwitsch A,Lucas SD,Al-Halabi Z,Sippl W,Al-Harrasi A,Csuk R

    更新日期:2019-04-01 00:00:00

  • Radical formation and coupling of hydroxycinnamic acids containing 1,2-dihydroxy substituents.

    abstract::Hydroxycinnamic acids involved in the deposition and cross-linking of plant cell-wall polymers do not usually contain 1,2-dihydroxy substituents, despite the presence of both 3,4-dihydroxycinnamic acid and 4,5-dihydroxy-3-methoxycinnamic acid as intermediates in the biogenesis of lignin. Since the O-methyl transferase...

    journal_title:Bioorganic chemistry

    pub_type: 杂志文章

    doi:10.1016/s0045-2068(03)00042-7

    authors: Russell WR,Burkitt MJ,Scobbie L,Chesson A

    更新日期:2003-06-01 00:00:00

  • Antimalarial activity of HIV-1 protease inhibitor in chromone series.

    abstract::Increasing parasite resistance to nearly all available antimalarial drugs becomes a serious problem to human health and necessitates the need to continue the search for new effective drugs. Recent studies have shown that clinically utilized HIV-1 protease (HIV-1 PR) inhibitors can inhibit the in vitro and in vivo grow...

    journal_title:Bioorganic chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bioorg.2014.10.006

    authors: Lerdsirisuk P,Maicheen C,Ungwitayatorn J

    更新日期:2014-12-01 00:00:00

  • Novel artemisinin derivatives with potent anticancer activities and the anti-colorectal cancer effect by the mitochondria-mediated pathway.

    abstract::Many artemisinin derivatives have good inhibitory effects on malignant tumors. In this work, a novel series of artemisinin derivatives containing piperazine and fluorine groups were designed and synthesized and their structures were confirmed by 1H NMR, 13C NMR and HRMS technologies. The in vitro cytotoxicity against ...

    journal_title:Bioorganic chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bioorg.2020.104496

    authors: Lin L,Lu W,Dai T,Chen H,Wang T,Yang L,Yang X,Liu Y,Sun D

    更新日期:2021-01-01 00:00:00

  • Design, synthesis and biological evaluation of novel 1,2,3-triazole linked coumarinopyrazole conjugates as potent anticholinesterase, anti-5-lipoxygenase, anti-tyrosinase and anti-cancer agents.

    abstract::A series of new 1,2,3-triazole linked coumarinopyrazole conjugates 4a-e and 5a-e have been synthesized via the Copper(I)-catalysed Alkyne-Azide Cycloaddition (CuAAC). Going through the reaction of compound 2 with the 3-propargyl bromide gave a mixture of propargylated regioisomers 3 + 3' used as a dipolarophile to acc...

    journal_title:Bioorganic chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bioorg.2018.06.005

    authors: Chekir S,Debbabi M,Regazzetti A,Dargère D,Laprévote O,Ben Jannet H,Gharbi R

    更新日期:2018-10-01 00:00:00

  • Preparative scale application of Mucor circinelloides ene-reductase and alcohol dehydrogenase activity for the asymmetric bioreduction of α,β-unsaturated γ-ketophosphonates.

    abstract::The fungus Mucor circinelloides exhibits high potential for green chemistry and technological applications. Recently M. circinelloides, which so far was considered mainly as a platform for biodiesel production, was found to exhibit high ene-reductase activity. In our current research we applied this promising microorg...

    journal_title:Bioorganic chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bioorg.2019.103548

    authors: Janicki I,Kiełbasiński P,Szeląg J,Głębski A,Szczęsna-Antczak M

    更新日期:2020-03-01 00:00:00

  • Role of the PH domain in regulating in vitro autophosphorylation events required for reconstitution of PDK1 catalytic activity.

    abstract::In addition to its catalytic domain, phosphoinsositide-dependent protein kinase-1 (PDK1) contains a C-terminal pleckstrin homology (PH) domain, which binds the membrane-bound phosphatidylinositol (3,4,5)-triphosphate [PI(3,4,5)P3] second messenger. Here, we report in vitro kinetic, phosphopeptide mapping, and oligomer...

    journal_title:Bioorganic chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bioorg.2006.05.002

    authors: Gao X,Harris TK

    更新日期:2006-08-01 00:00:00

  • 1,2,3-Triazole-based kojic acid analogs as potent tyrosinase inhibitors: Design, synthesis and biological evaluation.

    abstract::A series of kojic acid-derived compounds 6a-p bearing aryloxymethyl-1H-1,2,3-triazol-1-yl moiety were designed by modifying primary alcoholic group of kojic acid as tyrosinase inhibitors. The target compounds 6a-p were synthesized via click reaction. All compounds showed very potent anti-tyrosinase activity (IC50s = 0...

    journal_title:Bioorganic chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bioorg.2018.10.069

    authors: Ashooriha M,Khoshneviszadeh M,Khoshneviszadeh M,Moradi SE,Rafiei A,Kardan M,Emami S

    更新日期:2019-02-01 00:00:00

  • Antitrypanosomal activity of epi-polygodial from Drimys brasiliensis and its effects in cellular membrane models at the air-water interface.

    abstract::Epi-polygodial, a drimane sesquiterpene was isolated from Drimys brasiliensis (Winteraceae). This compound demonstrated high parasite selectivity towards Trypanosoma cruzi trypomastigotes (IC50 = 5.01 μM) with a selectivity index higher than 40. These results were correlated with the effects observed when this compoun...

    journal_title:Bioorganic chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bioorg.2018.11.048

    authors: Gonçalves GEG,Morais TR,Gomes KS,Costa-Silva TA,Tempone AG,Lago JHG,Caseli L

    更新日期:2019-03-01 00:00:00

  • Pesimquinolones I-S, eleven new quinolone alkaloids produced by Penicillium simplicissimum and their inhibitory activity on NO production.

    abstract::Eleven undescribed quinolone alkaloids, pesimquinolones I-S (1-4 and 6-12), as well as eleven known congeners (5 and 13-22), were isolated from the solid culture broth of the fungus Penicillium simplicissimum. Their chemical structures with absolute configurations were established by a combination of NMR spectroscopy,...

    journal_title:Bioorganic chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bioorg.2021.104635

    authors: Dai C,Li X,Zhang K,Li XN,Wang W,Zang Y,Chen X,Li Q,Wei M,Chen C,Zhu H,Zhang Y

    更新日期:2021-01-08 00:00:00

  • Design and synthesis of new benzoxazole/benzothiazole-phthalimide hybrids as antitumor-apoptotic agents.

    abstract::Herein, we synthesized a series of twelve benzoxazole and benzothiazole derivatives incorporated with phthalimide core as anticancer agents. The most active compounds were 5a and 5g against HepG2 and MCF7 cell lines with IC50 = 0.011 and 0.006 μM, respectively. They evaluated against EGFR and HER2 enzymes. From cell c...

    journal_title:Bioorganic chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bioorg.2019.102978

    authors: Philoppes JN,Lamie PF

    更新日期:2019-08-01 00:00:00

  • Evaluation of angularly condensed diquinothiazines as potential anticancer agents.

    abstract::We present efficient synthesis of isomeric types of angularly fused diquinothiazines in the reactions of 2,2'-dichloro-3,3'-diquinolinyl disulfide and diquinodithiin with 3-, 5-, 6- and 8-aminoquinolines. The pentacyclic diquinothiazine ring systems were identified as diquino[3,2-b;3',4'-e][1,4]thiazine, diquino[3,2-b...

    journal_title:Bioorganic chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bioorg.2019.04.005

    authors: Jeleń M,Pluta K,Latocha M,Morak-Młodawska B,Suwińska K,Kuśmierz D

    更新日期:2019-06-01 00:00:00

  • Capsaicin: A "hot" KDM1A/LSD1 inhibitor from peppers.

    abstract::Capsaicinoids are plant secondary metabolites, and capsaicin is the main principal that responsible to the pungency of chili peppers, with widely application as food additive. In our study, capsaicin was characterized as lysine specific demethylase 1A (KDM1A/LSD1) inhibitor with IC50 of 0.6 ± 0.0421 μM in biochemical ...

    journal_title:Bioorganic chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bioorg.2020.104161

    authors: Jia G,Cang S,Ma P,Song Z

    更新日期:2020-10-01 00:00:00

  • Combinatorial synthesis and biological evaluation of peptide-binding GPCR-targeted library.

    abstract::As an effective strategy of the drug discovery for peptide-binding GPCRs based on the natural ligands, beta-turn peptidomimetic compound library with benzodiazepine skeleton was constructed using solid and solution phase parallel synthesis with four different scaffolds containing Phe, Lys, Ser and Glu, respectively. T...

    journal_title:Bioorganic chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bioorg.2009.04.001

    authors: Lee JY,Im I,Webb TR,McGrath D,Song MR,Kim YC

    更新日期:2009-06-01 00:00:00

  • Synthesis and antiproliferative activity of new 2-glyco-3-nitro-2H-chromenes.

    abstract::3-nitro-2H-chromenes and derivatives are compounds with diverse biological activity, among them, new 2-glyco-3-nitro-2H-chromenes have been prepared by one-pot oxa-Michael-Henry-dehydration reactions between carbohydrate-derived nitroalkenes and several salicylaldehydes, using a minimal amount of solvent and DBU as ca...

    journal_title:Bioorganic chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bioorg.2019.03.016

    authors: Luque-Agudo V,Albarrán-Velo J,Light ME,Padrón JM,Román E,Serrano JA,Gil MV

    更新日期:2019-06-01 00:00:00