RESUMO
Alzheimer's disease (AD) is a progressive neurodegenerative brain disease. Thus, drugs including donepezil, rivastigmine, and galantamine are not entirely effective in the treatment of this multifactorial disease. The present study evaluates eight derivatives (3a-3h) as candidates with stronger anti-AD potential but with less side effects. Reactive oxygen species (ROS) assays were used to assess oxidative stress which involve in the neurodegeneration. The neuroprotective properties of 3e against oxidative stress were done in three experiments using MTT test. The anti-AD potential was determined based on their anticholinesterase inhibition ability, determined using Ellman's method, Aß aggregation potential according to thioflavin (Th) fluorescence assay, and their antioxidative and anti-inflammatory activities. Compound 3e exhibited moderate cholinesterase inhibition activity (AChE, IC50 = 0.131 µM; BuChE, IC50 = 0.116 µM; SI = 1.13), significant inhibition of Aß(1-42) aggregation (55.7%, at 5 µM) and acceptable neuroprotective activity. Extensive analysis of in vitro and in vivo assays indicates that new cyclopentaquinoline derivatives offer promise as candidates for new anti-AD drugs.
Assuntos
Doença de Alzheimer , Fármacos Neuroprotetores , Humanos , Doença de Alzheimer/tratamento farmacológico , Neuroproteção , Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Estresse Oxidativo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêuticoRESUMO
One of the main goals of recent bioinorganic chemistry studies has been to design and synthesize novel substances to treat human diseases. The promising compounds are metal-based and metal ion binding components such as vanadium-based compounds. The potential anticancer action of vanadium-based compounds is one of area of investigation in this field. In this study, we present five oxovanadium(IV) and dioxovanadium(V) complexes as potential PTP1B inhibitors with anticancer activity against the MCF-7 breast cancer cell line, the triple negative MDA-MB-231 breast cancer cell line, and the human keratinocyte HaCaT cell line. We observed that all tested compounds were effective inhibitors of PTP1B, which correlates with anticancer activity. [VO(dipic)(dmbipy)]·2 H2O (Compound 4) and [VOO(dipic)](2-phepyH)·H2O (Compound 5) possessed the greatest inhibitory effect, with IC50 185.4 ± 9.8 and 167.2 ± 8.0 nM, respectively. To obtain a better understanding of the relationship between the structure of the examined compounds and their activity, we performed a computer simulation of their binding inside the active site of PTP1B. We observed a stronger binding of complexes containing dipicolinic acid with PTP1B. Based on our simulations, we suggested that the studied complexes exert their activity by stabilizing the WPD-loop in an open position and limiting access to the P-loop.
Assuntos
Neoplasias da Mama , Compostos Organometálicos , Simulação por Computador , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Feminino , Humanos , Compostos Organometálicos/química , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Vanádio/química , Vanádio/farmacologiaRESUMO
The pyridinium-2-carbaldoximes with quinolinium carboxamide moiety were designed and synthesised as cholinesterase reactivators. The prepared compounds showed intermediate-to-high inhibition of both cholinesterases when compared to standard oximes. Their reactivation ability was evaluated in vitro on human recombinant acetylcholinesterase (hrAChE) and human recombinant butyrylcholinesterase (hrBChE) inhibited by nerve agent surrogates (NIMP, NEMP, and NEDPA) or paraoxon. In the reactivation screening, one compound was able to reactivate hrAChE inhibited by all used organophosphates and two novel compounds were able to reactivate NIMP/NEMP-hrBChE. The reactivation kinetics revealed compound 11 that proved to be excellent reactivator of paraoxon-hrAChE better to obidoxime and showed increased reactivation of NIMP/NEMP-hrBChE, although worse to obidoxime. The molecular interactions of studied reactivators were further identified by in silico calculations. Molecular modelling results revealed the importance of creation of the pre-reactivation complex that could lead to better reactivation of both cholinesterases together with reducing particular interactions for lower intrinsic inhibition by the oxime.
Assuntos
Inibidores da Colinesterase/farmacologia , Compostos de Piridínio/farmacologia , Compostos de Quinolínio/farmacologia , Acetilcolinesterase/metabolismo , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Compostos de Piridínio/síntese química , Compostos de Piridínio/química , Compostos de Quinolínio/síntese química , Compostos de Quinolínio/química , Proteínas Recombinantes/metabolismo , Relação Estrutura-AtividadeRESUMO
Effective therapy of Alzheimer's disease (AD) requires treatment with a combination of drugs that modulate various pathomechanisms contributing to the disease. In our research, we have focused on the development of multi-target-directed ligands - 5-HT6 receptor antagonists and cholinesterase inhibitors - with disease-modifying properties. We have performed extended in vitro (FRET assay) and in cellulo (Escherichia coli model of protein aggregation) studies on their ß-secretase, tau, and amyloid ß aggregation inhibitory activity. Within these multifunctional ligands, we have identified compound 17 with inhibitory potency against tau and amyloid ß aggregation in in cellulo assay of 59% and 56% at 10 µM, respectively, hBACE IC50=4 µM, h5TH6 K i=94 nM, hAChE IC50=26 nM, and eqBuChE IC50=5 nM. This study led to the development of multifunctional ligands with a broad range of biological activities crucial not only for the symptomatic but also for the disease-modifying treatment of AD.
Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Inibidores da Colinesterase/química , Colinesterases/metabolismo , Receptores de Serotonina/metabolismo , Proteínas tau/metabolismo , Doença de Alzheimer/prevenção & controle , Inibidores da Colinesterase/metabolismo , Desenho de Fármacos , Escherichia coli , Transferência Ressonante de Energia de Fluorescência , Humanos , Ligantes , Modelos Moleculares , Agregados Proteicos , Relação Estrutura-AtividadeRESUMO
A series of new tetrahydroacridine and 3,5-dichlorobenzoic acid hybrids with different spacers were designed, synthesized, and evaluated for their ability to inhibit both cholinesterase enzymes. Compounds 3a, 3b, 3f, and 3g exhibited selective butyrylcholinesterase (EqBuChE) inhibition with IC50 values ranging from 24 to 607 nM. Among them, compound 3b was the most active (IC50 = 24 nM). Additionally, 3c (IC50 for EeAChE = 25 nM and IC50 for EqBuChE = 123 nM) displayed dual cholinesterase inhibitory activity and was the most active compound against acetylcholinesterase (AChE). Active compound 3c was also tested for the ability to inhibit Aß aggregation. Theoretical physicochemical properties of the compounds were calculated using ACD Labs Percepta and Chemaxon. A Lineweaver-Burk plot and docking study showed that 3c targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Moreover, 3c appears to possess neuroprotective activity and could be considered a free-radical scavenger. In addition, 3c did not cause DNA damage and was found to be less toxic than tacrine after oral administration; it also demonstrated little inhibitory activity towards hyaluronidase (HYAL), which may indicate that it possesses anti-inflammatory properties. The screening for new in vivo interactions between 3c and known receptors was realized by yeast three-hybrid technology (Y3H).
Assuntos
Doença de Alzheimer/tratamento farmacológico , Clorobenzoatos/química , Inibidores da Colinesterase/síntese química , Fármacos Neuroprotetores/síntese química , Tacrina/análogos & derivados , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Domínio Catalítico , Linhagem Celular Tumoral , Células Cultivadas , Inibidores da Colinesterase/efeitos adversos , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Colinesterases/química , Colinesterases/metabolismo , Sequestradores de Radicais Livres/efeitos adversos , Sequestradores de Radicais Livres/síntese química , Sequestradores de Radicais Livres/farmacologia , Sequestradores de Radicais Livres/uso terapêutico , Humanos , Hialuronoglucosaminidase/antagonistas & inibidores , Camundongos , Simulação de Acoplamento Molecular , Fármacos Neuroprotetores/efeitos adversos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Ligação Proteica , Multimerização Proteica/efeitos dos fármacosRESUMO
The inverse correlation observed between Alzheimer's disease (AD) and cancer has prompted us to look for cholinesterase-inhibiting activity in phenothiazine derivatives that possess anticancer properties. With the use of in silico and in vitro screening methods, our study found a new biological activity in anticancer polycyclic, tricyclic, and tetracyclic compounds. The virtual screening of a library of 120 ligands, which are the derivatives of azaphenothiazine, led to the identification of 25 compounds that can act as potential inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Biological assays revealed the presence of selective inhibitors of eeAChE (electric eel AChE) or eqBuChE (equine serum BuChE) and nonselective inhibitors of both enzymes among the tested compounds. Their potencies against eeAChE were in a submicromolar-to-micromolar range with IC50 values from 0.78 to 19.32 µM, while their IC50 values against eqBuChE ranged from 0.46 to 10.38 µM. The most potent among the compounds tested was the tetracyclic derivative, 6-(4-diethylaminobut-2-ynyl)-9-methylthioquinobenzothiazine 24, which was capable of inhibiting both enzymes. 9-Fluoro-6-(1-piperidylethyl)quinobenzothiazine 23 was found to act as a selective inhibitor of eqBuChE with an IC50 value of 0.46 µM. Compounds with such a dual antitumor and cholinesterase-inhibitory activity can be considered as a valuable combination for the treatment of both cancer and AD prevention. The results presented in this study might open new directions of research on the group of tricyclic phenothiazine derivatives.
Assuntos
Antineoplásicos/farmacologia , Derivados de Benzeno/química , Inibidores da Colinesterase/farmacologia , Neoplasias/tratamento farmacológico , Piridinas/química , Tiazinas/química , Acetilcolinesterase/química , Animais , Butirilcolinesterase/química , Proliferação de Células , Electrophorus , Cavalos , Humanos , Neoplasias/patologia , Células Tumorais CultivadasRESUMO
In the search for new treatments for complex disorders such as Alzheimer's disease the Multi-Target-Directed Ligands represent a very promising approach. The aim of the present study was to identify multifunctional compounds among several series of non-imidazole histamine H3 receptor ligands, derivatives of 1-[2-thiazol-5-yl-(2-aminoethyl)]-4-n-propylpiperazine, 1-[2-thiazol-4-yl-(2-aminoethyl)]-4-n-propylpiperazine and 1-phenoxyalkyl-4-(amino)alkylopiperazine using in vitro and in vivo pharmacological evaluation and computational studies. Performed in vitro assays showed moderate potency of tested compounds against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Molecular modeling studies have revealed possible interactions between the active compounds and both AChE and BuChE as well as the human H3 histamine receptor. Computational studies showed the high drug-likeness of selected compounds with very good physicochemical profiles. The parallel artificial membrane permeation assay proved outstanding blood-brain barrier penetration in test conditions. The most promising compound, A12, chemically methyl(4-phenylbutyl){2-[2-(4-propylpiperazin-1-yl)-1,3-thiazol-5-yl]ethyl}amine, possesses good balanced multifunctional profile with potency toward studied targets - H3 antagonist activity (pA2â¯=â¯8.27), inhibitory activity against both AChE (IC50â¯=â¯13.96⯵M), and BuChE (IC50â¯=â¯14.62⯵M). The in vivo pharmacological studies revealed the anti-amnestic properties of compound A12 in the passive avoidance test on mice.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Amnésia/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Modelos Animais de Doenças , Piperazinas/química , Receptores Histamínicos H3/metabolismo , Acetilcolinesterase/química , Adjuvantes Anestésicos/toxicidade , Amnésia/induzido quimicamente , Animais , Butirilcolinesterase/química , Inibidores da Colinesterase/química , Biologia Computacional , Técnicas In Vitro , Ligantes , Masculino , Camundongos , Modelos Moleculares , Estrutura Molecular , Receptores Histamínicos H3/química , Escopolamina/toxicidade , Relação Estrutura-AtividadeRESUMO
Here we report the two-step synthesis of 8 new cyclopentaquinoline derivatives as modifications of the tetrahydroacridine structure. Next, the biological assessment of each of them was performed. Based on the obtained results we identified 6-chloro-N-[2-(2,3-dihydro-1H-cyclopenta[b]quinolin-9-ylamino)-hexyl]]-nicotinamide hydrochloride (3e) as the most promising compound with inhibitory potencies against EeAChE and EqBuChE in the low nanomolar level 67 and 153 nM, respectively. Moreover, 3e compound is non-hepatotoxic, able to inhibit amyloid beta aggregation, and shows a mix-type of cholinesterase's inhibition. The mixed type of inhibition of the compound was confirmed by molecular modeling. Then, yeast three-hybrid (Y3H) technology was used to confirm the known ligand-receptor interactions. New derivatives do not show antioxidant activity (confirmed by the use of two different tests). A pKa assay method was developed to identify the basic physicochemical properties of 3e compound. A LogP assay confirmed that 3e compound fulfills Lipinsky's rule of five.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/síntese química , Fármacos Neuroprotetores/síntese química , Quinolinas/química , Peptídeos beta-Amiloides/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Inibidores da Colinesterase/farmacologia , Humanos , Simulação de Acoplamento Molecular , Fármacos Neuroprotetores/farmacologia , Ligação ProteicaRESUMO
Selective butyrylcholinesterase inhibitors could be the promising drug candidates, used in treatment of Alzheimer's disease. The study describes the synthesis and biological activity of novel carbamate derivatives with N-phenylpiperazine, N-benzylpiperazine and 4-benzylpiperidine moieties. Biological studies revealed that most of these compounds displayed significant activity against BuChE. Compound 16 (3-(4-phenyl-piperazin-1-ylmethyl)-phenyl phenylcarbamate) turned out to be the most active (IC50â¯=â¯2.00⯵M for BuChE). For all synthesized compounds lipophilicity and other physicochemical properties were calculated using computer programs. Relationship between these properties and activity was also checked. Binding mode with enzyme and the ensuing differences in activity were explained by the molecular modeling studies.
Assuntos
Acetilcolinesterase/metabolismo , Butirilcolinesterase/metabolismo , Carbamatos/farmacologia , Inibidores da Colinesterase/farmacologia , Animais , Carbamatos/síntese química , Carbamatos/química , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Electrophorus , Cavalos , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
The complex nature of Alzheimer's disease calls for multidirectional treatment. Consequently, the search for multi-target-directed ligands may lead to potential drug candidates. The aim of the present study is to seek multifunctional compounds with expected activity against disease-modifying and symptomatic targets. A series of 15 drug-like various substituted derivatives of 2-(benzylamino-2-hydroxyalkyl)isoindoline-1,3-diones was designed by modification of cholinesterase inhibitors toward ß-secretase inhibition. All target compounds have been synthesized and tested against eel acetylcholinesterase (eeAChE), equine serum butyrylcholinesterase (eqBuChE), human ß-secretase (hBACE-1), and ß-amyloid (Aß-aggregation). The most promising compound, 12 (2-(5-(benzylamino)-4-hydroxypentyl)isoindoline-1,3-dione), displayed inhibitory potency against eeAChE (IC50 = 3.33 µM), hBACE-1 (43.7% at 50 µM), and Aß-aggregation (24.9% at 10 µM). Molecular modeling studies have revealed possible interaction of compound 12 with the active sites of both enzymes-acetylcholinesterase and ß-secretase. IN CONCLUSION: modifications of acetylcholinesterase inhibitors led to the discovery of a multipotent anti-Alzheimer's agent, with moderate and balanced potency, capable of inhibiting acetylcholinesterase, a symptomatic target, and disease-modifying targets: ß-secretase and Aß-aggregation.
Assuntos
Desenho de Fármacos , Isoindóis/química , Isoindóis/farmacologia , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/química , Butirilcolinesterase/química , Técnicas de Química Sintética , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Relação Dose-Resposta a Droga , Ligação de Hidrogênio , Concentração Inibidora 50 , Isoindóis/síntese química , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
A novel series of 9-amino-1,2,3,4-tetrahydroacridine derivatives with 2-fluorobenzoic acid or 3-fluorobenzoic acid moiety were designed, synthesized and evaluated as inhibitors of cholinesterases and aggregation of ß-amyloid. In the study target compounds were very potent inhibitors of AChE and BChE. The most promising agents had higher inhibitory potency than the reference drugs which was tacrine. Ultimately, the kinetic assay shows the most active target compound 3c against AChE. Almost all of them were more potent against BChE than AChE. Compound 3c in various concentrations was tested by aggregation experiment. Inhibition of ß-amyloid aggregation was 77.32% and 80.43% at 50µM and 100µM, respectively. Therefore, compound 3c is a promising agent for the treatment of AD.
Assuntos
Acridinas/farmacologia , Doença de Alzheimer/tratamento farmacológico , Benzoatos/farmacologia , Inibidores da Colinesterase/farmacologia , Acridinas/síntese química , Acridinas/química , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Benzoatos/química , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Colinesterases/metabolismo , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Alzheimer's disease (AD) is the most common progressive form of brain neurodegeneration and the most prevailing cause of dementia. Unfortunately, the aetiology of AD is not completely studied but different factors are associated with the development of AD such as among others low level of acetylcholine, aggregation of ß-amyloid (Aß), hyperphosphorylated tau protein, oxidative stress, and inflammation. The study encompass organic syntheses of 2,3-dihydro-1H-cyclopenta[b]quinoline with 5,6-dichloronicotinic acid and suitable linkers derivatives as multifunctional agents for AD treatment. Afterwards self-induced amyloid beta aggregation, inhibition studies of acetylcholinesterase and butyrylcholinesterase and molecular docking studies were performed. The results showed that 3b compound exhibited the best acetylcholinesterase inhibitory activity, with IC50 value of 0.052 µM which is lower compared to references. Besides, all synthesised compounds showed good butyrylcholinesterase inhibitory activity with IC50 values from 0.071 to 0.797 µM. Compound 3b exhibited strong Aß1-42 aggregation inhibitory effect with 25.7% at 5 µM to 92.8% at 100 µM as well as good anti-inflammatory effect. Thus, new compounds could create new perspectives for further development as a multi-target-directed agent for AD treatment.
Assuntos
Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Aminoquinolinas/farmacologia , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Inibidores de Glicosídeo Hidrolases/farmacologia , Hialuronoglucosaminidase/antagonistas & inibidores , Niacinamida/análogos & derivados , Doença de Alzheimer/metabolismo , Aminoquinolinas/síntese química , Aminoquinolinas/química , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Proliferação de Células/efeitos dos fármacos , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Enguias , Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/química , Cavalos , Humanos , Hialuronoglucosaminidase/metabolismo , Modelos Moleculares , Estrutura Molecular , Niacinamida/síntese química , Niacinamida/química , Niacinamida/farmacologia , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/metabolismo , Agregados Proteicos/efeitos dos fármacos , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
In recent years, multitarget-directed ligands have become an interesting strategy in a search for a new treatment of Alzheimer's disease. Combination of both: a histamine H3 receptor antagonist/inverse agonist and a cholinesterases inhibitor in one molecule could provide a new therapeutic opportunity. Here, we present biological evaluation of histamine H3 receptor ligands-chlorophenoxyalkylamine derivatives against cholinesterases: acetyl- and butyrylcholinesterase. The target compounds showed cholinesterase inhibitory activity in a low micromolar range. The most potent in this group was 1-(7-(4-chlorophenoxy)heptyl)homopiperidine (18) inhibiting the both enzymes (EeAChE IC50=1.93µM and EqBuChE IC50=1.64µM). Molecular modeling studies were performed to explain the binding mode of 18 with histamine H3 receptor as well as with cholinesterases.
Assuntos
Acetilcolinesterase/metabolismo , Aminas/química , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/química , Piperidinas/química , Receptores Histamínicos H3/metabolismo , Acetilcolinesterase/química , Sítios de Ligação , Butirilcolinesterase/química , Domínio Catalítico , Humanos , Cinética , Ligantes , Simulação de Acoplamento Molecular , Piperidinas/síntese química , Receptores Histamínicos H3/química , Relação Estrutura-AtividadeRESUMO
A series of new biphenyl bis-sulfonamide derivatives 2a-3p were synthesized in good to excellent yield (76-98%). The inhibitory potential of the synthesized compounds on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) was investigated. Most of the screened compounds showed modest in vitro inhibition for both AChE and BChE. Compared to the reference compound eserine (IC50 0.04 ± 0.0001 µM for AChE) and (IC50 0.85 ± 0.0001 µM for BChE), the IC50 values of these compounds were ranged from 2.27 ± 0.01 to 123.11 ± 0.04 µM for AChE and 7.74 ± 0.07 to <400 µM for BuChE. Among the tested compounds, 3p was found to be the most potent against AChE (IC50 2.27 ± 0.01 µM), whereas 3g exhibited the highest inhibition for BChE (IC50 7.74 ± 0.07 µM). Structure-activity relationship (SAR) of these compounds was developed and elaborated with the help of molecular docking studies.
Assuntos
Acetilcolinesterase/metabolismo , Compostos de Bifenilo/farmacologia , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Sulfonamidas/farmacologia , Animais , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/química , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Humanos , Simulação de Acoplamento Molecular , Fisostigmina/farmacologia , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , TorpedoRESUMO
In this study 36 new compounds were synthesized by condensing barbituric acid or thiobarbituric acid and respective anilines (bearing different substituents) in the presence of triethyl orthoformate in good yields. In vitro urease inhibition studies against jack bean urease revealed that barbituric acid derived compounds (1-9 and 19-27) were found to exhibit low to moderate activity however thiobarbituric acid derived compounds (10-18 and 28-36) showed significant inhibition activity at low micro-molar concentrations. Among the synthesized compounds, compounds (15), (12), (10), (36), (16) and (35) showed excellent urease inhibition with IC50 values 8.53 ± 0.027, 8.93 ± 0.027, 12.96 ± 0.13, 15 ± 0.098, 18.9 ± 0.027 and 19.7 ± 0.63 µM, respectively, even better than the reference compound thiourea (IC50 = 21 ± 0.011). The compound (11) exhibited comparable activity to the standard with IC50 value 21.83 ± 0.19 µM. In silico molecular docking studies for most active compounds (10), (12), (15), (16), (35) and (36) and two inactive compounds (3) and (6) were performed to predict the binding patterns.
Assuntos
Inibidores Enzimáticos/química , Tiobarbitúricos/química , Tiobarbitúricos/síntese química , Urease/antagonistas & inibidores , Simulação por Computador , Modelos Moleculares , Relação Estrutura-AtividadeRESUMO
A novel series of 9-amino-1,2,3,4-tetrahydroacridine derivatives with 4-dimethylaminobenzoic acid moiety was synthesized and tested towards inhibition of cholinesterases and amyloid ß aggregation. Target compounds were designed as dual binding site cholinesterase inhibitors able to bind to both the catalytic and the peripheral site of the enzyme and therefore potentially endowed with other properties. The obtained derivatives were very potent inhibitors of both cholinesterases (EeAChE, EqBChE) with IC50 values ranging from sub-nanomolar to nanomolar range, and the inhibitory potency of the most promising agents was higher than that of the reference drugs (rivastigmine and tacrine). The kinetic studies of the most active compound 3a revealed competitive type of AChE inhibition. Moreover, all target compounds were more potent inhibitors of human AChE than tacrine with the most active compound 3b (IC50 = 19 nM). Compound 3a was also tested and displayed inhibitory potency against AChE-induced Aß 1-42 aggregation (80.6% and 91.3% at 50 µM and 100 µM screening concentration, respectively). Moreover, cytotoxicity assay performed on A549 cells did not indicate toxicity of this agent. Compound 3a is a promising candidate for further development of novel multi-functional agents in the therapy of AD.
Assuntos
Acridinas/síntese química , Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/uso terapêutico , Acridinas/química , Inibidores da Colinesterase/química , Desenho de Fármacos , Humanos , Modelos Moleculares , Relação Estrutura-AtividadeRESUMO
The study presents the discovery of novel butyrylcholinesterase (BuChE) inhibitors among derivatives of azaphenothiazines by application of in silico and in vitro screening methods. From an in-house library of compounds, 143 heterocyclic molecules derived from the azaphenothiazine scaffold were chosen for virtual screening. Based on results of the docking procedure, 15 compounds were identified as exhibiting the best fit for the two screening complexes (ligand - AChE and ligand - BuChE). Five compounds displayed moderate AChE and good BuChE inhibitory activity at screening concentrations of 10 µM. The IC50 values for active BuChE inhibitors were in the 11.8-122.2 nM range. Three of the most active inhibitors are tetra- or pentacyclic derivatives of azaphenothiazines with the same N-methyl-2-piperidinethyl substituent.
Assuntos
Acetilcolinesterase/química , Compostos Aza/química , Butirilcolinesterase/química , Inibidores da Colinesterase/química , Fenotiazinas/química , Acetilcolinesterase/isolamento & purificação , Animais , Compostos Aza/síntese química , Butirilcolinesterase/isolamento & purificação , Inibidores da Colinesterase/síntese química , Descoberta de Drogas , Electrophorus , Ensaios Enzimáticos , Ensaios de Triagem em Larga Escala , Cavalos , Cinética , Simulação de Acoplamento Molecular , Fenotiazinas/síntese química , Piperidinas/química , Bibliotecas de Moléculas Pequenas , Relação Estrutura-Atividade , Interface Usuário-ComputadorRESUMO
ß-Secretase (BACE-1) constitutes an important target for search of anti-Alzheimer's drugs. The first inhibitors of this enzyme were peptidic compounds with high molecular weight and low bioavailability. Therefore, the search for new efficient non-peptidic inhibitors has been undertaken by many scientific groups. We started our work from the development of in silico methodology for the design of novel BACE-1 ligands. It was validated on the basis of crystal structures of complexes with inhibitors, redocking, cross-docking and training/test sets of reference ligands. The presented procedure of assessment of the novel compounds as ß-secretase inhibitors could be widely used in the design process.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Biologia Computacional/métodos , Desenho Assistido por Computador , Desenho de Fármacos , Inibidores de Proteases/farmacologia , Secretases da Proteína Precursora do Amiloide/química , Secretases da Proteína Precursora do Amiloide/metabolismo , Sítios de Ligação , Domínio Catalítico , Simulação por Computador , Cristalografia por Raios X , Modelos Moleculares , Inibidores de Proteases/química , Inibidores de Proteases/metabolismo , Ligação Proteica , Estrutura Terciária de Proteína , Reprodutibilidade dos TestesRESUMO
The main protease (Mpro) of SARS-CoV-2 is an essential enzyme that plays a critical part in the virus's life cycle, making it a significant target for developing antiviral drugs. The inhibition of SARS-CoV-2 Mpro has emerged as a promising approach for developing therapeutic agents to treat COVID-19. This review explores the structure of the Mpro protein and analyzes the progress made in understanding protein-ligand interactions of Mpro inhibitors. It focuses on binding kinetics, origin, and the chemical structure of these inhibitors. The review provides an in-depth analysis of recent clinical trials involving covalent and non-covalent inhibitors and emerging dual inhibitors targeting SARS-CoV-2 Mpro. By integrating findings from the literature and ongoing clinical trials, this review captures the current state of research into Mpro inhibitors, offering a comprehensive understanding of challenges and directions in their future development as anti-coronavirus agents. This information provides new insights and inspiration for medicinal chemists, paving the way for developing more effective Mpro inhibitors as novel COVID-19 therapies.
Assuntos
Antivirais , Tratamento Farmacológico da COVID-19 , Proteases 3C de Coronavírus , Inibidores de Proteases , SARS-CoV-2 , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/enzimologia , Humanos , Antivirais/farmacologia , Antivirais/química , Antivirais/uso terapêutico , Proteases 3C de Coronavírus/antagonistas & inibidores , Proteases 3C de Coronavírus/metabolismo , Proteases 3C de Coronavírus/química , Inibidores de Proteases/farmacologia , Inibidores de Proteases/química , Inibidores de Proteases/uso terapêutico , COVID-19/virologiaRESUMO
Computer simulations constitute the basis of the design and discovery of new drugs. This approach is not only significant with regards to finding new structures, but also for selecting the molecules with the highest probability of being useful in the diagnostic process and treatment of numerous diseases. In our work, we used computational software to analyze 32 new acetylcholinesterase (AChE) inhibitors and formulate ADMET predictions. To understand the influence of the structure of our derivatives on binding mode, we docked all structures to the active site of AChE and assigned some pharmacophoric features. Finally, we undertook a chemometric analysis of all the compounds on the basis of FT-IR, which gave us the possibility of performing a fast categorization of the analyzed compounds and design compounds with similar structures.