RESUMO
Therapeutic options for Alzheimer's disease are limited. Dual compounds targeting two pathways concurrently may enable enhanced effect. The study focuses on tacrine derivatives inhibiting acetylcholinesterase (AChE) and simultaneously N-methyl-D-aspartate (NMDA) receptors. Compounds with balanced inhibitory potencies for the target proteins (K1578 and K1599) or increased potency for AChE (K1592 and K1594) were studied to identify the most promising pro-cognitive compound. Their effects were studied in cholinergic (scopolamine-induced) and glutamatergic (MK-801-induced) rat models of cognitive deficits in the Morris water maze. Moreover, the impacts on locomotion in the open field and AChE activity in relevant brain structures were investigated. The effect of the most promising compound on NMDA receptors was explored by in vitro electrophysiology. The cholinergic antagonist scopolamine induced a deficit in memory acquisition, however, it was unaffected by the compounds, and a deficit in reversal learning that was alleviated by K1578 and K1599. K1578 and K1599 significantly inhibited AChE in the striatum, potentially explaining the behavioral observations. The glutamatergic antagonist dizocilpine (MK-801) induced a deficit in memory acquisition, which was alleviated by K1599. K1599 also mitigated the MK-801-induced hyperlocomotion in the open field. In vitro patch-clamp corroborated the K1599-associated NMDA receptor inhibitory effect. K1599 emerged as the most promising compound, demonstrating pro-cognitive efficacy in both models, consistent with intended dual effect. We conclude that tacrine has the potential for development of derivatives with dual in vivo effects. Our findings contributed to the elucidation of the structural and functional properties of tacrine derivatives associated with optimal in vivo pro-cognitive efficacy.
Assuntos
Inibidores da Colinesterase , Cognição , Maleato de Dizocilpina , Aprendizagem em Labirinto , Ratos Wistar , Receptores de N-Metil-D-Aspartato , Tacrina , Animais , Tacrina/farmacologia , Inibidores da Colinesterase/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Masculino , Ratos , Maleato de Dizocilpina/farmacologia , Aprendizagem em Labirinto/efeitos dos fármacos , Cognição/efeitos dos fármacos , Acetilcolinesterase/metabolismo , Escopolamina , Antagonistas de Aminoácidos Excitatórios/farmacologia , Memória/efeitos dos fármacosRESUMO
The current study imposes a new class of organophosphorus (OP)-inhibited cholinesterase reactivators by conceptualizing a family of asymmetric bisoximes with various reactivating scaffolds. Several novel nucleophilic warheads were investigated, putting forward 29 novel reactivating options, by evaluating their nucleophilicity and ability to directly decompose OP compounds. Adopting the so-called zwitterionic strategy, 17 mono-oxime and nine bisoxime reactivators were discovered with major emphasis on the bifunctional-moiety approach. Compounds were compared with clinically used standards and other known experimentally highlighted reactivators. Our results clearly favor the concept of asymmetric bisoximes as leading reactivators in terms of efficacy and versatility. These top-ranked compounds were characterized in detail by reactivation kinetics parameters and evaluated for potential CNS availability. The highlighted molecules 55, 57, and 58 with various reactivating warheads, surpassed the reactivating potency of pralidoxime and several notable uncharged reactivators. The versatility of lead drug candidate 55 was also inspected on OP-inhibited butyrylcholinesterase, revealing a much higher rate compared to existing clinical antidotes.
Assuntos
Butirilcolinesterase , Reativadores da Colinesterase , Intoxicação por Organofosfatos , Oximas , Oximas/química , Oximas/farmacologia , Reativadores da Colinesterase/química , Reativadores da Colinesterase/farmacologia , Butirilcolinesterase/metabolismo , Butirilcolinesterase/química , Humanos , Intoxicação por Organofosfatos/tratamento farmacológico , Acetilcolinesterase/metabolismo , Antídotos/química , Antídotos/farmacologia , Cinética , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Animais , Compostos Organofosforados/químicaRESUMO
Insecticides represent the most crucial element in the integrated management approach to malaria and other vector-borne diseases. The evolution of insect resistance to long-used substances and the toxicity of organophosphates (OPs) and carbamates are the main factors contributing to the development of new, environmentally safe pesticides. In our work, fourteen compounds of 7-methoxytacrine-tacrine heterodimers were tested for their insecticidal effect. Compounds were evaluated in vitro on insect acetylcholinesterase from Anopheles gambiae (AgAChE) and Musca domestica (MdAChE). The evaluation was executed in parallel with testing on human erythrocyte acetylcholinesterase (HssAChE) and human butyrylcholinesterase (HssBChE) using a modified Ellman's method. Compound efficacy was determined as IC50 values for the respective enzymes and selectivity indexes were expressed to compare the interspecies selectivity. Docking studies were performed to predict the binding modes of selected compounds. K1328 and K1329 provided high HssAChE/AgAChE selectivity outperforming standard pesticides (carbofuran and bendiocarb), and thus can be considered as suitable lead structure for novel anticholinesterase insecticides.
Assuntos
Anopheles , Carbofurano , Inseticidas , Animais , Humanos , Inibidores da Colinesterase/toxicidade , Acetilcolinesterase/metabolismo , Butirilcolinesterase , Tacrina , Mosquitos Vetores , Anopheles/metabolismo , Carbamatos , OrganofosfatosRESUMO
Alzheimer's disease (AD) is a devastating neurological disorder characterized by the pathological accumulation of macromolecular Aß and tau leading to neuronal death. Drugs approved to treat AD may ameliorate disease symptoms, however, no curative treatment exists. Aß peptides were discovered to be substrates of adenosine triphosphate-(ATP)-binding cassette (ABC) transporters. Activators of these membrane-bound efflux proteins that promote binding and/or translocation of Aß could revolutionize AD medicine. The knowledge about ABC transporter activators is very scarce, however, the few molecules that were reported contain substructural features of multitarget (pan-)ABC transporter inhibitors. A cutting-edge strategy to obtain new drug candidates is to explore and potentially exploit the recently proposed multitarget binding site of pan-ABC transporter inhibitors as anchor point for the development of innovative activators to promote Aß clearance from the brain. Molecular associations between functional bioactivities and physicochemical properties of small-molecules are key to understand these processes. This study provides an analysis of a recently reported unique multitarget dataset for the correlation between multitarget bioactivity and physicochemistry. Six novel pan-ABC transporter inhibitors were validated containing substructural features of ABC transporter activators, which underpins the relevance of the multitarget binding site for the targeted development of novel AD diagnostics and therapeutics.
Assuntos
Doença de Alzheimer , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Transportadores de Cassetes de Ligação de ATP/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Transporte Biológico , Encéfalo/metabolismo , Fenômenos Químicos , HumanosRESUMO
Chemoresistance of cancer cells is a hallmark of treatment failure and the poor patient prognosis. The mechanism of resistance is often connected to the overexpression of specific kinases involved in DNA damage response cascade. Contrary, selected kinase inhibition can augment cancer cell sensitization to conventional therapy, enabling more efficient treatment. Among those kinases, ataxia-telangiectasia and Rad3-related kinase (ATR), the major responder to replication stress, stands out as one of the most attractive targets. Inspired by clinical candidates targeting ATR, we designed and prepared a small, focused library of 40 novel compounds building on 7-azaindoles, 2,7-diazaindoles, and 1H-pyrazoles as core structures. All the compounds alone or combined with cisplatin (CDDP) were screened against a panel of nine cancer cell lines and one healthy cell line. Three highlighted compounds (3, 22, and 29) were selected for broad oncology panel screening containing 104 kinases. Only compound 29, the 2,7-diazaindole representative, showed ATR inhibitory efficacy with the IC50 around 10 µM. In contrast, the compound 22, 7-azaindole congener with the most pronounced cytotoxicity profile exceeding CDDP alone or in combination with CDDP, expressed the multi-kinase activity. Highlighted representatives, including compound 29, were also effective alone against primary glioblastoma. Overall, we showed that 7-azaindole, and 2,7-diazaindole scaffolds could be considered novel pharmacophores delivering anticancer activity.
Assuntos
Antineoplásicos , Antineoplásicos/farmacologia , Proteínas Mutadas de Ataxia Telangiectasia , Linhagem Celular Tumoral , Cisplatino/farmacologia , Humanos , Indóis , Pirazóis/farmacologiaRESUMO
High lethality, fast action, and simple synthesis make nerve agents (NAs) the most dreaded chemical weapons (CWs) of mass destruction in the world. Disturbances of the autonomic nervous system and neuromuscular junction (NMJ) by NAs and organophosphorus (OP) insecticides lead to cholinergic crisis and skeletal muscle paralysis. Current medical intervention has remained mostly unchanged since their first discovery in the 1950s. Within this overview, we have followed their development, clinical successes, and failures and discuss the major demerits of available antidotes. In current times, with precision medicine becoming increasingly relevant in various fields of medicine, the antidotal approach should be broadened to better cope with individual cases of NA intoxication. When possible, countermeasures could be targeted directly to achieve a better patient prognosis. As the threat of NA misuse and accidental cases of OP insecticide intoxication are still omnipresent, advancement of intervention expertise and further research in this field should be supported.
Assuntos
Reativadores da Colinesterase , Intoxicação por Organofosfatos , Antídotos/uso terapêutico , Humanos , Intoxicação por Organofosfatos/tratamento farmacológico , OximasRESUMO
The search for novel and effective therapeutics for Alzheimer's disease (AD) is the main quest that remains to be resolved. The goal is to find a disease-modifying agent able to confront the multifactorial nature of the disease positively. Herewith, a family of huprineY-tryptophan heterodimers was prepared, resulting in inhibition of cholinesterase and neuronal nitric oxide synthase enzymes, with effect against amyloid-beta (Aß) and potential ability to cross the blood-brain barrier. Their cholinesterase pattern of behavior was inspected using kinetic analysis in tandem with docking studies. These heterodimers exhibited a promising pharmacological profile with strong implication in AD.
Assuntos
Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Aminoquinolinas/farmacologia , Inibidores da Colinesterase/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Fármacos Neuroprotetores/farmacologia , Triptofano/farmacologia , Doença de Alzheimer/metabolismo , Aminoquinolinas/química , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Compostos Heterocíclicos de 4 ou mais Anéis/química , Humanos , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Relação Estrutura-Atividade , Triptofano/químicaRESUMO
Tacrine is a classic drug whose efficacy against neurodegenerative diseases is still shrouded in mystery. It seems that besides its inhibitory effect on cholinesterases, the clinical benefit is co-determined by NMDAR-antagonizing activity. Our previous data showed that the direct inhibitory effect of tacrine, as well as its 7-methoxy derivative (7-MEOTA), is ensured via a "foot-in-the-door" open-channel blockage, and that interestingly both tacrine and 7-MEOTA are slightly more potent at the GluN1/GluN2A receptors when compared with the GluN1/GluN2B receptors. Here, we report that in a series of 30 novel tacrine derivatives, designed for assessment of structure-activity relationship, blocking efficacy differs among different compounds and receptors using electrophysiology with HEK293 cells expressing the defined types of NMDARs. Selected compounds (4 and 5) potently inhibited both GluN1/GluN2A and GluN1/GluN2B receptors; other compounds (7 and 23) more effectively inhibited the GluN1/GluN2B receptors; or the GluN1/GluN2A receptors (21 and 28). QSAR study revealed statistically significant model for the data obtained for inhibition of GluN1/Glu2B at -60 mV expressed as IC50 values, and for relative inhibition of GluN1/Glu2A at +40 mV caused by a concentration of 100 µM. The models can be utilized for a ligand-based virtual screening to detect potential candidates for inhibition of GluN1/Glu2A and/or GluN1/Glu2B subtypes. Using in vivo experiments in rats we observed that unlike MK-801, the tested novel compounds did not induce hyperlocomotion in open field, and also did not impair prepulse inhibition of startle response, suggesting minimal induction of psychotomimetic side effects. We conclude that tacrine derivatives are promising compounds since they are centrally available subtype-specific inhibitors of the NMDARs without detrimental behavioral side-effects.
Assuntos
Inibidores da Colinesterase/química , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Tacrina/química , Acetilcolinesterase/química , Acetilcolinesterase/genética , Acetilcolinesterase/metabolismo , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Cães , Desenho de Fármacos , Meia-Vida , Humanos , Locomoção/efeitos dos fármacos , Masculino , Potenciais da Membrana/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , Relação Quantitativa Estrutura-Atividade , Ratos , Ratos Wistar , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Tacrina/metabolismo , Tacrina/farmacologiaRESUMO
Since 2002, no clinical candidate against Alzheimer's disease has reached the market; hence, an effective therapy is urgently needed. We followed the so-called "multitarget directed ligand" approach and designed 36 novel tacrine-phenothiazine heterodimers which were in vitro evaluated for their anticholinesterase properties. The assessment of the structure-activity relationships of such derivatives highlighted compound 1dC as a potent and selective acetylcholinesterase inhibitor with IC50 = 8 nM and 1aA as a potent butyrylcholinesterase inhibitor with IC50 = 15 nM. Selected hybrids, namely, 1aC, 1bC, 1cC, 1dC, and 2dC, showed a significant inhibitory activity toward τ(306-336) peptide aggregation with percent inhibition ranging from 50.5 to 62.1%. Likewise, 1dC and 2dC exerted a remarkable ability to inhibit self-induced Aß1-42 aggregation. Notwithstanding, in vitro studies displayed cytotoxicity toward HepG2 cells and cerebellar granule neurons; no pathophysiological abnormality was observed when 1dC was administered to mice at 14 mg/kg (i.p.). 1dC was also able to permeate to the CNS as shown by in vitro and in vivo models. The maximum brain concentration was close to the IC50 value for acetylcholinesterase inhibition with a relatively slow elimination half-time. 1dC showed an acceptable safety and good pharmacokinetic properties and a multifunctional biological profile.
Assuntos
Doença de Alzheimer , Tacrina , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides , Animais , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Desenho de Fármacos , Camundongos , Fenotiazinas/farmacologia , Relação Estrutura-Atividade , Tacrina/farmacologiaRESUMO
Selective killing of cancer cells while sparing healthy ones is the principle of the perfect cancer treatment and the primary aim of many oncologists, molecular biologists, and medicinal chemists. To achieve this goal, it is crucial to understand the molecular mechanisms that distinguish cancer cells from healthy ones. Accordingly, several clinical candidates that use particular mutations in cell-cycle progressions have been developed to kill cancer cells. As the majority of cancer cells have defects in G1 control, targeting the subsequent intraS or G2/M checkpoints has also been extensively pursued. This review focuses on clinical candidates that target the kinases involved in intraS and G2/M checkpoints, namely, ATR, CHK1, and WEE1 inhibitors. It provides insight into their current status and future perspectives for anticancer treatment. Overall, even though CHK1 inhibitors are still far from clinical establishment, promising accomplishments with ATR and WEE1 inhibitors in phase II trials present a positive outlook for patient survival.
RESUMO
To date, the only treatments developed for poisoning by organophosphorus compounds, the most toxic chemical weapons of mass destruction, have exhibited limited efficacy and versatility. The available causal antidotes are based on reactivation of the enzyme acetylcholinesterase (AChE), which is rapidly and pseudo-irreversibly inhibited by these agents. In this study, we developed a novel series of monoquaternary reactivators combining permanently charged moieties tethered to position 6- of 3-hydroxypyridine-2-aldoxime reactivating subunit. Highlighted representatives (21, 24, and 27; also coded as K1371, K1374, and K1375, respectively) that contained 1-phenylisoquinolinium, 7-amino-1-phenylisoquinolinium and 4-carbamoylpyridinium moieties as peripheral anionic site ligands, respectively, showed efficacy superior or comparable to that of the clinically used standards. More importantly, these reactivators exhibited wide-spectrum efficacy and were minutely investigated via determination of their reactivation kinetics in parallel with molecular dynamics simulations to study their mechanisms of reactivation of the tabun-inhibited AChE conjugate. To further confirm the potential applicability of these candidates, a mouse in vivo assay was conducted. While K1375 had the lowest acute toxicity and the most suitable pharmacokinetic profile, the oxime K1374 with delayed elimination half-life was the most effective in ameliorating the signs of tabun toxicity. Moreover, both in vitro and in vivo, the versatility of the agents was substantially superior to that of clinically used standards. Their high efficacy and broad-spectrum capability make K1374 and K1375 promising candidates that should be further investigated for their potential as nerve agents and insecticide antidotes.
Assuntos
Acetilcolinesterase/efeitos dos fármacos , Antídotos/farmacologia , Reativadores da Colinesterase/farmacologia , Acetilcolinesterase/metabolismo , Animais , Antídotos/síntese química , Antídotos/química , Reativadores da Colinesterase/síntese química , Reativadores da Colinesterase/química , Feminino , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Simulação de Dinâmica Molecular , Oximas/síntese química , Oximas/química , Oximas/farmacologia , Relação Estrutura-AtividadeRESUMO
The trends of novel AD therapeutics are focused on multitarget-directed ligands (MTDLs), which combine cholinesterase inhibition with additional biological properties such as antioxidant properties to positively affect neuronal energy metabolism as well as mitochondrial function. We examined the in vitro effects of 10 novel MTDLs on the activities of mitochondrial enzymes (electron transport chain complexes and citrate synthase), mitochondrial respiration, and monoamine oxidase isoform (MAO-A and MAO-B) activity. The drug-induced effects of 7-MEOTA-adamantylamine heterodimers (K1011, K1013, K1018, K1020, and K1022) and tacrine/7-MEOTA/6-chlorotacrine-trolox heterodimers (K1046, K1053, K1056, K1060, and K1065) were measured in pig brain mitochondria. Most of the substances inhibited complex I- and complex II-linked respiration at high concentrations; K1046, K1053, K1056, and K1060 resulted in the least inhibition of mitochondrial respiration. Citrate synthase activity was not significantly inhibited by the tested substances; the least inhibition of complex I was observed for compounds K1060 and K1053, while both complex II/III and complex IV activity were markedly inhibited by K1011 and K1018. MAO-A was fully inhibited by K1018 and K1065, and MAO-B was fully inhibited by K1053 and K1065; the other tested drugs were partial inhibitors of both MAO-A and MAO-B. The tacrine/7-MEOTA/6-chlorotacrine-trolox heterodimers K1046, K1053, and K1060 seem to be the most suitable molecules for subsequent in vivo studies. These compounds had balanced inhibitory effects on mitochondrial respiration, with low complex I and complex II/III inhibition and full or partial inhibition of MAO-B activity.
Assuntos
Metabolismo Energético , Mitocôndrias/metabolismo , Monoaminoxidase/metabolismo , Tacrina/farmacologia , Doença de Alzheimer/tratamento farmacológico , Animais , Respiração Celular/efeitos dos fármacos , Complexo II de Transporte de Elétrons/metabolismo , Metabolismo Energético/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/enzimologia , Inibidores da Monoaminoxidase/farmacologia , Suínos , Tacrina/químicaRESUMO
Organophosphate (OP) intoxications from nerve agent and OP pesticide exposures are managed with pyridinium aldoxime-based therapies whose success rates are currently limited. The pyridinium cation hampers uptake of OPs into the central nervous system (CNS). Furthermore, it frequently binds to aromatic residues of OP-inhibited acetylcholinesterase (AChE) in orientations that are nonproductive for AChE reactivation, and the structural diversity of OPs impedes efficient reactivation. Improvements of OP antidotes need to include much better access of AChE reactivators to the CNS and optimized orientation of the antidotes' nucleophile within the AChE active-center gorge. On the basis of X-ray structures of a CNS-penetrating reactivator, monoxime RS194B, reversibly bound to native and venomous agent X (VX)-inhibited human AChE, here we created seven uncharged acetamido bis-oximes as candidate antidotes. Both oxime groups in these bis-oximes were attached to the same central, saturated heterocyclic core. Diverse protonation of the heterocyclic amines and oxime groups of the bis-oximes resulted in equilibration among up to 16 distinct ionization forms, including uncharged forms capable of diffusing into the CNS and multiple zwitterionic forms optimal for reactivation reactions. Conformationally diverse zwitterions that could act as structural antidote variants significantly improved in vitro reactivation of diverse OP-human AChE conjugates. Oxime group reorientation of one of the bis-oximes, forcing it to point into the active center for reactivation, was confirmed by X-ray structural analysis. Our findings provide detailed structure-activity properties of several CNS-directed, uncharged aliphatic bis-oximes holding promise for use as protonation-dependent, conformationally adaptive, "smart" accelerated antidotes against OP toxicity.
Assuntos
Acetilcolinesterase/química , Antídotos/química , Sistema Nervoso Central/efeitos dos fármacos , Inibidores da Colinesterase/química , Reativadores da Colinesterase/química , Acetamidas/química , Acetamidas/uso terapêutico , Antídotos/síntese química , Antídotos/uso terapêutico , Sistema Nervoso Central/enzimologia , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/uso terapêutico , Reativadores da Colinesterase/síntese química , Reativadores da Colinesterase/uso terapêutico , Cristalografia por Raios X , Humanos , Cinética , Organofosfatos/química , Organofosfatos/toxicidade , Compostos Organofosforados/química , Compostos Organofosforados/toxicidade , Oximas/síntese química , Oximas/química , Oximas/farmacologia , Oximas/uso terapêutico , Conformação Proteica/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Chemoresistance, radioresistance, and the challenge of achieving complete resection are major driving forces in the search for more robust and targeted anticancer therapies. Targeting the DNA damage response has recently attracted research interest, as these processes are enhanced in tumour cells. The major replication stress responder is ATM and Rad3-related (ATR) kinase, which is attracting attention worldwide with four drug candidates currently in phase I/II clinical trials. This review addresses a potent and selective small-molecule ATR inhibitor, which is known as VX-970 (also known as berzosertib or M6620), and summarizes the existing preclinical data to provide deep insight regarding its real potential. We also outline the transition from preclinical to clinical studies, as well as its relationships with other clinical candidates (AZD6738, VX-803 [M4344], and BAY1895344). The results suggest that VX-970 is indeed a promising anticancer drug that can be used both as monotherapy and in combination with either chemotherapy or radiotherapy strategies. Based on patient anamnesis and biomarker identification, VX-970 could become a valuable tool for oncologists in the fight against cancer.
Assuntos
Antineoplásicos/uso terapêutico , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Descoberta de Drogas , Isoxazóis/uso terapêutico , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirazinas/uso terapêutico , Animais , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Sinergismo Farmacológico , Humanos , Isoxazóis/efeitos adversos , Terapia de Alvo Molecular , Neoplasias/enzimologia , Neoplasias/patologia , Inibidores de Proteínas Quinases/efeitos adversos , Pirazinas/efeitos adversos , Transdução de Sinais , Sulfonas/uso terapêutico , Resultado do TratamentoRESUMO
The series of symmetrical and unsymmetrical isoquinolinium-5-carbaldoximes was designed and prepared for cholinesterase reactivation purposes. The novel compounds were evaluated for intrinsic acetylcholinesterase (AChE) or butyrylcholinesterase (BChE) inhibition, when the majority of novel compounds resulted with high inhibition of both enzymes and only weak inhibitors were selected for reactivation experiments on human AChE or BChE inhibited by sarin, VX, or paraoxon. The AChE reactivation for all used organophosphates was found negligible if compared to the reactivation ability of obidoxime. Importantly, two compounds were found to reactivate BChE inhibited by sarin or VX better to obidoxime at human attainable concentration. One compound resulted as better reactivator of NEMP (VX surrogate)-inhibited BChE than obidoxime. The in vitro results were further rationalized by molecular docking studies showing future directions on designing potent BChE reactivators.
Assuntos
Acetilcolinesterase/efeitos dos fármacos , Butirilcolinesterase/efeitos dos fármacos , Reativadores da Colinesterase/farmacologia , Isoquinolinas/síntese química , Isoquinolinas/farmacologia , Inibidores da Colinesterase/farmacologia , Humanos , Isoquinolinas/química , Simulação de Acoplamento MolecularRESUMO
Acetylcholinesterase cysteine-targeted insecticides against malaria vector Anopheles gambia and other mosquitos have already been introduced. We have applied the olefin metathesis for the preparation of cysteine-targeted insecticides in high yields. The prepared compounds with either a succinimide or maleimide moiety were evaluated on Anopheles gambiae and human acetylcholinesterase with relatively high irreversible inhibition of both enzymes but poor selectivity. The concept of cysteine binding was not proved by several methods, and poor stability was observed of the chosen most potent/selective compounds in a water/buffer environment. Thus, our findings do not support the proposed concept of cysteine-targeted selective insecticides for the prepared series of succinimide or maleimide compounds.
RESUMO
Aim: Organophosphorus compounds are irreversible inhibitors of AChE. Without immediate countermeasure, intoxication leads quickly to death. None of the clinically-used causal antidotes can ensure a good prognosis for any poisoned patient. When fallen into the wrong hands, organophosphates represent a serious threat to mankind. Results & methodology: Herein, we describe two novel compounds as unique merged molecules built on a tacrine scaffold against organophosphorus intoxication. These reactivators of AChE have balanced physicochemical properties, and should be able to cross the blood-brain barrier with a slightly lowered cytotoxicity profile compared to reference tacrine. Conclusion: Their efficiency compared with pralidoxime and obidoxime was proved against dichlorvos.
Assuntos
Inibidores da Colinesterase/farmacologia , Compostos Organofosforados/toxicidade , Oximas/farmacologia , Inibidores da Colinesterase/química , Compostos Organofosforados/química , Oximas/química , Relação Estrutura-AtividadeRESUMO
Alzheimer's Disease (AD) is a neurodegenerative disorder with an increasing impact on society. Because currently available therapy has only a short-term effect, a huge number of novel compounds are developed every year exploiting knowledge of the various aspects of AD pathophysiology. To better address the pathological complexity of AD, one of the most extensively pursued strategies by medicinal chemists is based on Multi-target-directed Ligands (MTDLs). Donepezil is one of the currently approved drugs for AD therapy acting as an acetylcholinesterase inhibitor. In this review, we have made an extensive literature survey focusing on donepezil-derived MTDL hybrids primarily targeting on different levels cholinesterases and amyloid beta (Aß) peptide. The targeting includes direct interaction of the compounds with Aß, AChE-induced Aß aggregation, inhibition of BACE-1 enzyme, and modulation of biometal balance thus impeding Aß assembly.