RESUMO
The increasing threat of nuclear incidents and the widespread use of ionizing radiation (IR) in medical treatments underscore the urgent need for effective radiation countermeasures. Despite the availability of compounds such as amifostine, their clinical utility is significantly limited by adverse side effects and logistical challenges in administration. This study focuses on the synthesis and evaluation of novel piperazine derivatives as potential radioprotective agents, with the aim of overcoming the limitations associated with current countermeasures. We designed, synthesized, and evaluated a series of 1-(2-hydroxyethyl)piperazine derivatives. The compounds were assessed for cytotoxicity across a panel of human cell lines, and for their radioprotective effects in the MOLT-4 lymphoblastic leukemia cell line and in peripheral blood mononuclear cells (PBMCs) exposed to gamma radiation. The radioprotective efficacy was further quantified using the dicentric chromosome assay (DCA) to measure DNA damage mitigation. Among the synthesized derivatives, compound 6 demonstrated the most significant radioprotective effects in vitro, with minimal cytotoxicity across the tested cell lines. Compound 3 also showed notable efficacy, particularly in reducing dicentric chromosomes, thus indicating its potential to mitigate DNA damage from IR. Both compounds exhibited superior safety profiles and effectiveness compared to amifostine, suggesting their potential as more viable radioprotective agents. This study highlights the development of novel piperazine derivatives with promising radioprotective properties. Compound 6 emerged as the leading candidate, offering an optimal balance between efficacy and safety, with compound 3 also displaying significant potential. These findings support the further development and clinical evaluation of these compounds as safer, and more effective radiation countermeasures.
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Since the discovery of antimicrobial agents, the misuse of antibiotics has led to the emergence of bacterial strains resistant to both antibiotics and common disinfectants like quaternary ammonium compounds (QACs). A new class, 'gemini' QACs, which contain two polar heads, has shown promise. Octenidine (OCT), a representative of this group, is effective against resistant microorganisms but has limitations such as low solubility and high cytotoxicity. In this study, we developed 16 novel OCT derivatives. These compounds were subjected to in silico screening to predict their membrane permeation. Testing against nosocomial bacterial strains (G+ and G-) and their biofilms revealed that most compounds were highly effective against G+ bacteria, while compounds 7, 8, and 10-12 were effective against G- bacteria. Notably, compounds 6-8 were significantly more effective than OCT and BAC standards across the bacterial panel. Compound 12 stood out due to its low cytotoxicity and broad-spectrum antimicrobial activity, comparable to OCT. It also demonstrated impressive antifungal activity. Compound 1 was highly selective to fungi and four times more effective than OCT without its cytotoxicity. Several compounds, including 4, 6, 8, 9, 10, and 12, showed strong virucidal activity against murine cytomegalovirus and herpes simplex virus 1. In conclusion, these gemini QACs, especially compound 12, offer a promising alternative to current disinfectants, addressing emerging resistances with their enhanced antimicrobial, antifungal, and virucidal properties.
Assuntos
Antibacterianos , Testes de Sensibilidade Microbiana , Compostos de Amônio Quaternário , Compostos de Amônio Quaternário/farmacologia , Compostos de Amônio Quaternário/síntese química , Compostos de Amônio Quaternário/química , Relação Estrutura-Atividade , Antibacterianos/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Animais , Estrutura Molecular , Biofilmes/efeitos dos fármacos , Antifúngicos/farmacologia , Antifúngicos/síntese química , Antifúngicos/química , Antivirais/farmacologia , Antivirais/síntese química , Antivirais/química , Relação Dose-Resposta a Droga , Humanos , Fungos/efeitos dos fármacos , Bactérias/efeitos dos fármacos , Piridinas/farmacologia , Piridinas/química , Piridinas/síntese química , Compostos de Piridínio/farmacologia , Compostos de Piridínio/síntese química , Compostos de Piridínio/química , Camundongos , IminasRESUMO
N-methyl-D-aspartate receptors (NMDARs) play a significant role in developing several central nervous system (CNS) disorders. Currently, memantine, used for treating Alzheimer's disease, and ketamine, known for its anesthetic and antidepressant properties, are two clinically used NMDAR open-channel blockers. However, despite extensive research into NMDAR modulators, many have shown either harmful side effects or inadequate effectiveness. For instance, dizocilpine (MK-801) is recognized for its powerful psychomimetic effects due to its high-affinity and nearly irreversible inhibition of the GluN1/GluN2 NMDAR subtypes. Unlike ketamine, memantine and MK-801 also act through a unique, low-affinity "membrane-to-channel inhibition" (MCI). We aimed to develop an open-channel blocker based on MK-801 with distinct inhibitory characteristics from memantine and MK-801. Our novel compound, K2060, demonstrated effective voltage-dependent inhibition in the micromolar range at key NMDAR subtypes, GluN1/GluN2A and GluN1/GluN2B, even in the presence of Mg2+. K2060 showed reversible inhibitory dynamics and a partially trapping open-channel blocking mechanism with a significantly stronger MCI than memantine. Using hippocampal slices, 30⯵M K2060 inhibited excitatory postsynaptic currents in CA1 hippocampal neurons by â¼51â¯%, outperforming 30⯵M memantine (â¼21â¯% inhibition). K2060 exhibited No Observed Adverse Effect Level (NOAEL) of 15â¯mg/kg upon intraperitoneal administration in mice. Administering K2060 at a 10â¯mg/kg dosage resulted in brain concentrations of approximately 2⯵M, with peak concentrations (Tmax) achieved within 15â¯minutes. Finally, applying K2060 with trimedoxime and atropine in mice exposed to tabun improved treatment outcomes. These results underscore K2060's potential as a therapeutic agent for CNS disorders linked to NMDAR dysfunction.
Assuntos
Maleato de Dizocilpina , Receptores de N-Metil-D-Aspartato , Animais , Maleato de Dizocilpina/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Camundongos , Masculino , Antagonistas de Aminoácidos Excitatórios/farmacologia , Humanos , Memantina/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Camundongos Endogâmicos C57BL , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismoRESUMO
Six novel brominated bis-pyridinium oximes were designed and synthesized to increase their nucleophilicity and reactivation ability of phosphorylated acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Their pKa was valuably found lower to parent non-halogenated oximes. Stability tests showed that novel brominated oximes were stable in water, but the stability of di-brominated oximes was decreased in buffer solution and their degradation products were prepared and characterized. The reactivation screening of brominated oximes was tested on AChE and BChE inhibited by organophosphorus surrogates. Two mono-brominated oximes reactivated AChE comparably to non-halogenated analogues, which was further confirmed by reactivation kinetics. The acute toxicity of two selected brominated oximes was similar to commercially available oxime reactivators and the most promising brominated oxime was tested in vivo on sarin- and VX-poisoned rats. This brominated oxime showed interesting CNS distribution and significant reactivation effectiveness in blood. The same oxime resulted with the best protective index for VX-poisoned rats.
Assuntos
Acetilcolinesterase , Butirilcolinesterase , Inibidores da Colinesterase , Reativadores da Colinesterase , Agentes Neurotóxicos , Compostos Organotiofosforados , Oximas , Sarina , Animais , Oximas/farmacologia , Oximas/química , Reativadores da Colinesterase/farmacologia , Reativadores da Colinesterase/química , Inibidores da Colinesterase/toxicidade , Inibidores da Colinesterase/farmacologia , Acetilcolinesterase/metabolismo , Acetilcolinesterase/efeitos dos fármacos , Butirilcolinesterase/metabolismo , Ratos , Masculino , Compostos Organotiofosforados/toxicidade , Sarina/toxicidade , Agentes Neurotóxicos/toxicidade , Ratos Wistar , Halogenação , Substâncias para a Guerra Química/toxicidade , Compostos de Piridínio/farmacologia , Estabilidade de MedicamentosRESUMO
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
The search for novel drugs to address the medical needs of Alzheimer's disease (AD) is an ongoing process relying on the discovery of disease-modifying agents. Given the complexity of the disease, such an aim can be pursued by developing so-called multi-target directed ligands (MTDLs) that will impact the disease pathophysiology more comprehensively. Herewith, we contemplated the therapeutic efficacy of an amiridine drug acting as a cholinesterase inhibitor by converting it into a novel class of novel MTDLs. Applying the linking approach, we have paired amiridine as a core building block with memantine/adamantylamine, trolox, and substituted benzothiazole moieties to generate novel MTDLs endowed with additional properties like N-methyl-d-aspartate (NMDA) receptor affinity, antioxidant capacity, and anti-amyloid properties, respectively. The top-ranked amiridine-based compound 5d was also inspected by in silico to reveal the butyrylcholinesterase binding differences with its close structural analogue 5b. Our study provides insight into the discovery of novel amiridine-based drugs by broadening their target-engaged profile from cholinesterase inhibitors towards MTDLs with potential implications in AD therapy.
Assuntos
Doença de Alzheimer , Inibidores da Colinesterase , Humanos , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Inibidores da Colinesterase/química , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Butirilcolinesterase/metabolismo , Aminoquinolinas/uso terapêutico , Acetilcolinesterase/metabolismo , LigantesRESUMO
Tacrine (THA), a long withdrawn drug, is still a popular scaffold used in medicinal chemistry, mainly for its good reactivity and multi-targeted effect. However, THA-associated hepatotoxicity is still an issue and must be considered in drug discovery based on the THA scaffold. Following our previously identified hit compound 7-phenoxytacrine (7-PhO-THA), we systematically explored the chemical space with 30 novel derivatives, with a focus on low hepatotoxicity, anticholinesterase action, and antagonism at the GluN1/GluN2B subtype of the NMDA receptor. Applying the down-selection process based on in vitro and in vivo pharmacokinetic data, two candidates, I-52 and II-52, selective GluN1/GluN2B inhibitors thanks to the interaction with the ifenprodil-binding site, have entered in vivo pharmacodynamic studies. Finally, compound I-52, showing only minor affinity to AChE, was identified as a lead candidate with favorable behavioral and neuroprotective effects using open-field and prepulse inhibition tests, along with scopolamine-based behavioral and NMDA-induced hippocampal lesion models. Our data show that compound I-52 exhibits low toxicity often associated with NMDA receptor ligands, and low hepatotoxicity, often related to THA-based compounds.
Assuntos
Doença de Alzheimer , Doença Hepática Induzida por Substâncias e Drogas , Fármacos Neuroprotetores , Piperidinas , Humanos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Receptores de N-Metil-D-Aspartato , Tacrina/química , Inibidores da Colinesterase/química , Sítios de Ligação , Colinesterases , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológicoRESUMO
The BODIPY-labelled oxime reactivator was prepared and used to study its biodistribution into central nervous system. The newly synthesized oxime was found to be weak inhibitor of acetylcholinesterase and strong inhibitor of butyrylcholinesterase. Its reactivation ability for organophosphate inhibited acetylcholinesterase was found similar to a parent oxime. The BODIPY-labelled oxime was further encapsulated into recombinant human H-ferritin and evaluated in vitro and in vivo. The oxime or encapsulated oxime were found to be bioaccumulated primarily in liver and kidneys of mice, but some amount was distributed also to the brain, where it was detectable even after 24 h. The BODIPY-labelled oxime encapsulated to human H-ferritin showed better CNS bioaccumulation and tissue retention at 8 and 24 h time points compared to free oxime, although the fluorescence results might be biased due to BODIPY metabolites identified in tissue homogenates. Taken together, the study demonstrates the first utilization of recombinant ferritins for changing the unfavourable pharmacokinetics of oxime reactivators and brings promising results for follow-up studies.
RESUMO
Tacrine was withdrawn from clinical use as a drug against Alzheimer's disease in 2013, mainly due to drug-induced liver injury. The culprit of tacrine-associated hepatotoxicity is believed to be the 7-OH-tacrine metabolite, a possible precursor of quinone methide (Qmeth), which binds to intracellular -SH proteins. In our study, several different animal and human models (liver microsomes, primary hepatocytes, and liver slices) were used to investigate the biotransformation and hepatotoxicity of tacrine and its 7-substituted analogues (7-methoxy-, 7-phenoxy-, and 7-OH-tacrine). Our goal was to find the most appropriate in vitro model for studying tacrine hepatotoxicity and, through rational structure modifications, to develop derivatives of tacrine that are less prone to Qmeth formation. Our results show that none of animal models tested accurately mimic human tacrine biotransformation; however, the murine model seems to be more suitable than the rat model. Tacrine metabolism was overall most accurately mimicked in three-dimensional (3D) spheroid cultures of primary human hepatocytes (PHHs). In this system, tacrine and 7-methoxytacrine were hydroxylated to 7-OH-tacrine, whereas 7-phenoxytacrine formed, as expected, only trace amounts. Surprisingly, however, our study showed that 7-OH-tacrine was the least hepatotoxic (7-OH-tacrine < tacrine < 7-methoxytacrine < 7-phenoxytacrine) even after doses had been adjusted to achieve the same intracellular concentrations. The formation of Qmeth-cysteine and Qmeth-glutathione adducts after human liver microsome incubation was confirmed by all of the studied tacrine derivatives, but these findings were not confirmed after incubation with 3D PHH spheroids. Therefore, the presented data call into question the suggested previously hypothesized mechanism of toxicity, and the results open new avenues for chemical modifications to improve the safety of novel tacrine derivatives.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Indolquinonas , Metanfetamina , Humanos , Animais , Camundongos , Ratos , Tacrina/toxicidade , BiotransformaçãoRESUMO
Phenotypic screening of an in-house library of small molecule purine derivatives against Mycobacterium tuberculosis (Mtb) led to the identification of 2-morpholino-7-(naphthalen-2-ylmethyl)-1,7-dihydro-6H-purin-6-one 10 as a potent antimycobacterial agent with MIC99 of 4 µM. Thorough structure-activity relationship studies revealed the importance of 7-(naphthalen-2-ylmethyl) substitution for antimycobacterial activity, yet opened the possibility of structural modifications at positions 2 and 6 of the purine core. As the result, optimized analogues with 6-amino or ethylamino substitution 56 and 64, respectively, were developed. These compounds showed strong in vitro antimycobacterial activity with MIC of 1 µM against Mtb H37Rv and against several clinically isolated drug-resistant strains, had limited toxicity to mammalian cell lines, medium clearance with respect to phase I metabolic deactivation (27 and 16.8 µL/min/mg), sufficient aqueous solubility (>90 µM) and high plasma stability. Interestingly, investigated purines, including compounds 56 and 64, lacked activity against a panel of Gram-negative and Gram-positive bacterial strains, indicating a specific mycobacterial molecular target. To investigate the mechanism of action, Mtb mutants resistant to hit compound 10 were isolated and their genomes were sequenced. Mutations were found in dprE1 (Rv3790), which encodes decaprenylphosphoryl-ß-d-ribose oxidase DprE1, enzyme essential for the biosynthesis of arabinose, a vital component of the mycobacterial cell wall. Inhibition of DprE1 by 2,6-disubstituted 7-(naphthalen-2-ylmethyl)-7H-purines was proved using radiolabelling experiments in Mtb H37Rv in vitro. Finally, structure-binding relationships between selected purines and DprE1 using molecular modeling studies in tandem with molecular dynamic simulations revealed the key structural features for effective drug-target interaction.
Assuntos
Antituberculosos , Mycobacterium tuberculosis , Animais , Antituberculosos/química , Oxirredutases do Álcool/química , Purinas/farmacologia , Relação Estrutura-Atividade , Simulação de Dinâmica Molecular , Proteínas de Bactérias/metabolismo , Mamíferos/metabolismoRESUMO
Alzheimer's disease (AD) is a complex disease with an unknown etiology. Available treatments, limited to cholinesterase inhibitors and N-methyl-d-aspartate receptor (NMDAR) antagonists, provide symptomatic relief only. As single-target therapies have not proven effective, rational specific-targeted combination into a single molecule represents a more promising approach for treating AD, and is expected to yield greater benefits in alleviating symptoms and slowing disease progression. In the present study, we designed, synthesized, and biologically evaluated 24 novel N-methylpropargylamino-quinazoline derivatives. Initially, compounds were thoroughly inspected by in silico techniques determining their oral and CNS availabilities. We tested, in vitro, the compounds' effects on cholinesterases and monoamine oxidase A/B (MAO-A/B), as well as their impacts on NMDAR antagonism, dehydrogenase activity, and glutathione levels. In addition, we inspected selected compounds for their cytotoxicity on undifferentiated and differentiated neuroblastoma SH-SY5Y cells. We collectively highlighted II-6h as the best candidate endowed with a selective MAO-B inhibition profile, NMDAR antagonism, an acceptable cytotoxicity profile, and the potential to permeate through BBB. The structure-guided drug design strategy applied in this study imposed a novel concept for rational drug discovery and enhances our understanding on the development of novel therapeutic agents for treating AD.
Assuntos
Doença de Alzheimer , Neuroblastoma , Humanos , Doença de Alzheimer/tratamento farmacológico , Inibidores da Monoaminoxidase/uso terapêutico , Neuroblastoma/tratamento farmacológico , Inibidores da Colinesterase/uso terapêutico , Monoaminoxidase/metabolismo , Desenho de Fármacos , Acetilcolinesterase/metabolismo , Relação Estrutura-AtividadeRESUMO
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
The fluorinated bis-pyridinium oximes were designed and synthesized with the aim of increasing their nucleophilicity and potential to reactivate phosphorylated human recombinant acetylcholinesterase (AChE) and human purified plasmatic butyrylcholinesterase (BChE) in relation to chlorinated and non-halogenated oxime analogues. Compared to non-halogenated oximes, halogenated oximes showed lower pKa of the oxime group (fluorinated < chlorinated < non-halogenated) along with higher level of oximate anion formation at the physiological pH, and had a higher binding affinity of both AChE and BChE. The stability tests showed that the fluorinated oximes were stable in water, while in buffered environment di-fluorinated oximes were prone to rapid degradation, which was reflected in their lower reactivation ability. Mono-fluorinated oximes showed comparable reactivation to non-halogenated (except asoxime) and mono-chlorinated oximes in case of AChE inhibited by sarin, cyclosarin, VX, and tabun, but were less efficient than di-chlorinated ones. The same trend was observed in the reactivation of inhibited BChE. The advantage of halogen substituents in the stabilization of oxime in a position optimal for in-line nucleophilic attack were confirmed by extensive molecular modelling of pre-reactivation complexes between the analogue oximes and phosphorylated AChE and BChE. Halogen substitution was shown to provide oximes with additional beneficial properties, e.g., fluorinated oximes gained antioxidative capacity, and moreover, halogens themselves did not increase cytotoxicity of oximes. Finally, the in vivo administration of highly efficient reactivator and the most promising analogue, 3,5-di-chloro-bispyridinium oxime with trimethylene linker, provided significant protection of mice exposed to sarin and cyclosarin.
Assuntos
Reativadores da Colinesterase , Agentes Neurotóxicos , Acetilcolinesterase/metabolismo , Animais , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/química , Reativadores da Colinesterase/química , Halogênios , Camundongos , Agentes Neurotóxicos/farmacologia , Compostos Organofosforados , Oximas/química , Sarina/químicaRESUMO
As a widely distributed parasitic nematode of ruminants, Haemonchus contortus has become resistant to most anthelmintic classes, there has been a major demand for new compounds against H. contortus and related nematodes. Recent phenotypic screening has revealed two compounds, designated as BLK127 and HBK4, that are active against H. contortus larvae. The present study was designed to assess the activity of these compounds against H. contortus eggs and adults, hepatotoxicity in rats and sheep, as well as biotransformation in H. contortus adults and the ovine liver. Both compounds exhibited no inhibitory effect on the hatching of eggs. The benzyloxy amide BLK127 significantly decreased the viability of adults in sensitive and resistant strains of H. contortus and showed no hepatotoxic effect, even at the highest concentration tested (100 µM). In contrast, HBK4 had no impact on the viability of H. contortus adults and exhibited significant hepatotoxicity. Based on these findings, HBK4 was excluded from further studies, while BLK127 seems to be a potential candidate for a new anthelmintic. Consequently, biotransformation of BLK127 was tested in H. contortus adults and the ovine liver. In H. contortus, several metabolites formed via hydroxylation, hydrolysis and glycosidation were identified, but the extent of biotransformation was low, and the total quantity of the metabolites formed did not differ significantly between the sensitive and resistant strains. In contrast, ovine liver cells metabolized BLK127 more extensively with a glycine conjugate of 4-(pentyloxy)benzoic acid as the main BLK127 metabolite.
RESUMO
The organophosphorus antidotes, so-called oximes, are able to restore the enzymatic function of acetylcholinesterase (AChE) or butyrylcholinesterase (BChE) via cleavage of organophosphate from the active site of the phosphylated enzyme. In this work, the charged pyridinium oximes containing thiocarboxamide moiety were designed, prepared and tested. Their stability and pKa properties were found to be analogous to parent carboxamides (K027, K048 and K203). The inhibitory ability of thiocarboxamides was found in low µM levels for AChE and high µM levels for BChE. Their reactivation properties were screened on human recombinant AChE and BChE inhibited by nerve agent surrogates and paraoxon. One thiocarboxamide was able to effectively restore function of NEMP- and NEDPA-AChE, whereas two thiocarboxamides were able to reactivate BChE inhibited by all tested organophosphates. These results were confirmed by reactivation kinetics, where thiocarboxamides were proved to be effective, but less potent reactivators if compared to carboxamides.
Assuntos
Inibidores da Colinesterase/farmacologia , Organofosfatos/farmacologia , Oximas/farmacologia , Compostos de Piridínio/farmacologia , Compostos de Sulfidrila/farmacologia , Acetilcolinesterase/metabolismo , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Organofosfatos/síntese química , Organofosfatos/química , Oximas/síntese química , Oximas/química , Compostos de Piridínio/síntese química , Compostos de Piridínio/química , Relação Estrutura-Atividade , Compostos de Sulfidrila/síntese química , Compostos de Sulfidrila/químicaRESUMO
Schizophrenia is a serious mental disorder without a fully understood pathomechanism, but which involves dysregulation of neurotransmitters and their receptors. The best option for the management of schizophrenia comprises so-called multi-target ligands, similar to the third generation of neuroleptics. Dopamine type 2 receptors (D2Rs) are the main target in the treatment of schizophrenia, in particular for mitigation of the positive symptoms. Due to the high expression of 5-hydroxytryptamine type 3 receptors (5-HT3Rs) in human brain areas responsible for emotional behavior, motivation, and cognitive function, 5-HT3Rs represent a potential target for modulating the cognitive and negative symptoms of schizophrenia. Here we present the design, synthesis, and both in vitro and in vivo biological evaluation of 1,4-disubstituted aromatic piperazines. Screening of in vitro properties revealed the two most promising drug candidates (21 and 24) which were found to be potent D2Rs and moderate 5-HT3R antagonists, and which were forwarded to in vivo studies in Wistar rats. Considering toxicity, administration of the maximal feasible dose of 21 (2 mg/kg) did not produce any side effects. By contrast, the higher solubility of 24 led to revelation of mild and temporary side effects at the dose of 20 mg/kg. Importantly, both 21 and 24 showed facile crossing of the blood-brain barrier, even exerting higher levels in the brain in comparison to plasma. In a behavioral study using the acute amphetamine model of psychosis, we showed that compound 24 ameliorated both positive and negative effects of amphetamine including hyperlocomotion, social impairments, and disruption of prepulse inhibition. The effect of the highest dose (10 mg/kg) was comparable to the effect of the reference dose of aripiprazole (1 mg/kg).
Assuntos
Antipsicóticos , Esquizofrenia , Animais , Antipsicóticos/efeitos adversos , Piperazinas/farmacologia , Ratos , Ratos Wistar , Receptores de Serotonina , Esquizofrenia/tratamento farmacológico , Esquizofrenia/metabolismoRESUMO
Haemonchus contortus is a parasitic nematode of ruminants which causes significant losses to many farmers worldwide. Since the drugs currently in use for the treatment of haemonchosis are losing their effectiveness due to the drug-resistance of this nematode, a new or repurposed drug is highly needed. As the antipsychotic drug sertraline (SRT) has been shown to be effective against the parasitic nematodes Trichuris muris, Ancylostoma caninum and Schistosoma mansoni, the aim of the present study was to evaluate the possible effect of SRT on H. contortus. The potential hepatotoxicity of SRT was tested in sheep, a common H. contortus host. In addition, the main metabolic pathways of SRT in H. contortus and the ovine liver were identified. While no effect of SRT on H. contortus egg hatching was observed, SRT was found to significantly decrease the viability of H. contortus adults in drug-sensitive and resistant strains, with its effect comparable to the commonly used anthelmintics levamisole and monepantel. Moreover, SRT in anthelmintically active concentrations showed no toxicity to the ovine liver. Biotransformation of SRT in H. contortus was weak, with most of the drug remaining unmetabolized. Production of the main metabolite hydroxy-SRT did not differ significantly between strains. Other minor metabolites such as SRT-O-glucoside, dihydroxy-SRT, and SRT-ketone were also identified in H. contorts adults. Compared to H. contortus, the ovine liver metabolized SRT more extensively, mainly via desmethylation and glucuronidation. In conclusion, the potency of SRT against H. contortus was proven, and it should be tested further toward possible repurposing.
Assuntos
Anti-Helmínticos , Hemoncose , Sertralina , Doenças dos Ovinos , Animais , Anti-Helmínticos/farmacologia , Anti-Helmínticos/toxicidade , Biotransformação , Hemoncose/tratamento farmacológico , Hemoncose/veterinária , Haemonchus/efeitos dos fármacos , Sertralina/farmacologia , Sertralina/toxicidade , Ovinos , Doenças dos Ovinos/tratamento farmacológicoRESUMO
Benzoxonium chloride belongs to the group of quaternary ammonium salts, which have been widely used for decades as disinfectants because of their high efficacy, low toxicity, and thermal stability. In this study, we have prepared the C10-C18 set of benzoxonium-like salts to evaluate the effect of their chemical and biological decontamination capabilities. In particular, biocidal activity against a panel of bacterial strains including Staphylococcus aureus in biofilm form was screened. In addition, the most promising compounds were successfully tested against Francisella tularensis as a representative of potential biological warfare agents. From a point of view of chemical warfare protection, the efficiency of BOC-like compounds to degrade the organophosphate simulant fenitrothion was examined. Notwithstanding that no single compound with universal effectiveness was identified, a mixture of only two compounds from this group would be able to satisfactorily cover the proposed decontamination spectrum. In addition, the compounds were evaluated for their cytotoxicity as a basic safety parameter for potential use in practice. In summary, the dual effect on chemical and biological agents of benzoxonium-like salts offer attractive potential as active components of decontamination mixtures in the case of a terrorist threat or chemical or biological accidents.
RESUMO
Alzheimers disease (AD) is the most common neurodegenerative disorder, characterized by neuronal loss and cognitive impairment. Currently, very few drugs are available for AD treatment, and a search for new therapeutics is urgently needed. Thus, in the current study, twenty-eight new derivatives of montanine-type Amaryllidaceae alkaloids were synthesized and evaluated for their ability to inhibit human recombinant acetylcholinesterase (hAChE) and butyrylcholinesterase (hBuChE). Three derivatives (1n, 1o, and 1p) with different substitution patterns demonstrated significant selective inhibitory potency for hAChE (IC50 < 5 µM), and one analog, 1v, showed selective hBuChE inhibition activity (IC50 = 1.73 ± 0.05 µM). The prediction of CNS availability, as disclosed by the BBB score, suggests that the active compounds in this survey should be able pass through the blood-brain barrier (BBB). Cytotoxicity screening and docking studies were carried out for the two most pronounced cholinesterase inhibitors, 1n and 1v.
Assuntos
Alcaloides/farmacologia , Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Isoquinolinas/farmacologia , Simulação de Acoplamento Molecular , Acetilcolinesterase/metabolismo , Alcaloides/síntese química , Alcaloides/química , Doença de Alzheimer/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Humanos , Isoquinolinas/síntese química , Isoquinolinas/química , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
In this pilot study, a series of new 3,4-dihydroquinolin-2(1H)-one derivatives as potential dopamine receptor D2 (D2R) modulators were synthesized and evaluated in vitro. The preliminary structure-activity relationship disclosed that compound 5e exhibited the highest D2R affinity among the newly synthesized compounds. In addition, 5e showed a very low cytotoxic profile and a high probability to cross the blood-brain barrier, which is important considering the observed affinity. However, molecular modelling simulation revealed completely different binding mode of 5e compared to USC-D301, which might be the culprit of the reduced affinity of 5e toward D2R in comparison with USC-D301.