RESUMO
Bis(benzimidazol-2-yl)amine scaffold is not present in dipeptidyl peptidase-4 (DPP-4) inhibitors published so far. Herein, the inhibitory potential of bis(benzimidazol-2-yl)amine derivatives against DPP-4 was evaluated. In non-competitive inhibition mode, three representatives 5, 6, and 7 inhibited DPP-4 in vitro with IC50 values below 50 µM. The assessed binding pocket of DPP-4 for these benzimidazoles includes the S2 extensive subsite's residues Phe357 and Arg358. None of the lead compounds showed cytotoxicity to human neuroblastoma SH-SY5Y cells at concentrations lower than 10 µM. None showed significant binding affinity for dopamine D2, D3, and histamine H1, H3 receptors, at concentrations lower than 10 µM, leading to preferable outcomes due to mutually opposite effects of these neurotransmitters on each other. The potential beneficial effects on dopamine synthesis and the survival of dopaminergic neurons could be mediated by DPP-4 inhibition. These effective noncompetitive DPP-4 inhibitors, with inhibitory potential better than reference diprotin A (relative inhibitory potency compared to diprotin A is 3.39 and 1.54 for compounds 7 and 5, respectively), with the absence of the cytotoxicity to SH-SY5Y cells, are valuable candidates for further evaluation for the treatment of diabetes and associated disruption of neuronal homeostasis.
RESUMO
Dopamine D2-like receptors, especially D2 and D3 receptor subtypes, are important targets of antipsychotic agents. Many of these antipsychotics share an aliphatic linker element between a protonable amine group and an acyl-like moiety. Here, we have modified this aliphatic linker into phenylmethyl and phenylethyl linkers substituted in different positions. The design, synthesis, and in vitro evaluation of 18 dopamine D2 and D3 receptor ligands were performed in this study. Using a radioligand displacement assay, all ligands were found to have modest nanomolar affinity to D2R and D3R. N-(4-{2-[4-(2-Methoxyphenyl)piperazin-1-yl]ethyl}phenyl)acetamide (6c) demonstrates the highest D3R and D2R affinity values (pKi values of 7.83 [D2R] and 8.04 [D3R]), featuring a slight preference to D3R. This derivative can be taken as a reference structure for the development of a new class of D2R and D3R ligands.
Assuntos
Receptores de Dopamina D2 , Receptores de Dopamina D3 , Ligantes , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Relação Estrutura-Atividade , Humanos , Estrutura Molecular , Ensaio Radioligante , Antipsicóticos/farmacologia , Antipsicóticos/síntese química , Antipsicóticos/química , Animais , Relação Dose-Resposta a DrogaRESUMO
Multitargeting ligands on enzymes and receptors may generate a profile for a potential treatment of cognitive impairment. Considering this, a set of 21 substituted aryl-alkyl-piperazines were designed, prepared and tested for their binding affinities at histamine H3 and dopamine D3 receptors (H3R and D3R, respectively) as well as acetyl- and butyrylcholinesterases (AChE/BChE) as potentially synergistic profile. Initial screening of the compounds at H3R and D3R was done at 1 or 10 µM and 100 µM at AChE and BChE assays. The most promising compounds were then evaluated in full concentration-response curves to estimate the Ki and IC50 values. Results showed that several compounds were ligands at H3R (n = 10), D3R (n = 6), AChE (n = 3), and BChE (n = 9). Compounds LINS05006 (Ki H3R 2.8 µM; D3R 0.7 µM; IC50 BChE 26.3 µM) and LINS05015 (Ki H3R 1.1 µM; D3R 3.1 µM; IC50 AChE 97.8 µM; BChE 43.7 µM) are highlighted since presented affinity in three different. These results suggest that methylpiperazine moiety led to balanced activity at all three classes of targets, and longer linker provided the best affinities. These compounds presented high ligand efficiency values (LE > 0.3) and may have adequate pharmacokinetic profile as suggested by calculated physicochemical properties.
Assuntos
Disfunção Cognitiva , Receptores Histamínicos H3 , Humanos , Histamina , Dopamina , Ligantes , Butirilcolinesterase/metabolismo , Receptores Histamínicos H3/metabolismo , Disfunção Cognitiva/tratamento farmacológico , Inibidores da Colinesterase/química , Relação Estrutura-AtividadeRESUMO
The chromane ring system is widely distributed in nature and has proven to be a highly potent pharmacophore in medicinal chemistry, which includes the area of Alzheimer's and Parkinson's diseases. We report on the development of a gem-dimethylchroman-4-ol family that was shown to give good inhibition of equine serum butyrylcholinesterase (eqBuChE) (in the range 2.9 - 7.3 µM) and in the same range of currently used drugs. We also synthesized a small library of gem-dimethylchroman-4-amine compounds, via a simple reductive amination of the corresponding chromanone precursor, that were also selective for eqBuChE presenting inhibitions in the range 7.6 - 67 µM. Kinetic studies revealed that they were mixed inhibitors. Insights into their mechanism of action were obtained through molecular docking and STD-NMR experiments, and the most active examples showed excellent drug-likeness and pharmacological properties predicted using Swiss-ADME. We also prepared a set of propargyl gem-dimethylchromanamines, for monoamine oxidase (MAO) inhibition but they were only moderately active (the best being 28% inhibition at 1 µM on MAO-B). Overall, our compounds were found to be best suited as inhibitors for BuChE.
Assuntos
Doença de Alzheimer , Doença de Alzheimer/tratamento farmacológico , Animais , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Cavalos , Cinética , Simulação de Acoplamento Molecular , Estrutura Molecular , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/química , Inibidores da Monoaminoxidase/farmacologia , Relação Estrutura-AtividadeRESUMO
During the past decades, histamine H3 receptors have received widespread attention in pharmaceutical research due to their involvement in pathophysiology of several diseases such as neurodegenerative disorders. In this context, blocking of these receptors is of paramount importance in progression of such diseases. In the current investigation, novel histamine H3 receptor ligands were designed by exploiting scaffold-hopping drug-design strategy. We inspected the designed molecules in terms of ADME properties, drug-likeness, as well as toxicity profiles. Additionally molecular docking and dynamics simulation studies were performed to predict binding mode and binding free energy calculations, respectively. Among the designed structures, we selected compound d2 and its demethylated derivative as examples for synthesis and affinity measurement. In vitro binding assays of the synthesized molecules demonstrated that d2 has lower binding affinity (Ki = 2.61 µM) in radioligand displacement assay to hH3R than that of demethylated form (Ki = 12.53 µM). The newly designed compounds avoid of any toxicity predictors resulted from extended in silico and experimental studies, can offer another scaffold for histamine H3R antagonists for further structure-activity relationship studies.
Assuntos
Desenho de Fármacos , Histamínicos/química , Histamínicos/farmacologia , Receptores Histamínicos H3/metabolismo , Descoberta de Drogas , Agonistas dos Receptores Histamínicos/química , Agonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos/química , Antagonistas dos Receptores Histamínicos/farmacologia , Humanos , Ligantes , Modelos MolecularesRESUMO
In search of new dual-acting histamine H3/sigma-1 receptor ligands, we designed a series of compounds structurally based on highly active in vivo ligands previously studied and described by our team. However, we kept in mind that within the previous series, a pair of closely related compounds, KSK67 and KSK68, differing only in the piperazine/piperidine moiety in the structural core showed a significantly different affinity at sigma-1 receptors (σ1Rs). Therefore, we first focused on an in-depth analysis of the protonation states of piperazine and piperidine derivatives in the studied compounds. In a series of 16 new ligands, mainly based on the piperidine core, we selected three lead structures (3, 7, and 12) for further biological evaluation. Compound 12 showed a broad spectrum of analgesic activity in both nociceptive and neuropathic pain models based on the novel molecular mechanism.
Assuntos
Neuralgia , Receptores Histamínicos H3 , Receptores sigma , Humanos , Histamina , Receptores Histamínicos H3/química , Ligantes , Nociceptividade , Piperazina , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Piperidinas/química , Neuralgia/tratamento farmacológico , Relação Estrutura-Atividade , Receptor Sigma-1RESUMO
Continuing with our program to obtain new histamine H3 receptor (H3R) ligands, in this work we present the synthesis, H3R affinity and in silico studies of a series of eight new synthetically accessible purine derivatives. These compounds are designed from the isosteric replacement of the scaffold presented in our previous ligand, pyrrolo[2,3-d]pyrimidine ring, by a purine core. This design also considers maintaining the fragment of bipiperidine at C-4 and aromatic rings with electron-withdrawing groups at N-9, as these fragments are part of the proposed pharmacophore. The in vitro screening results show that two purine derivatives, 3d and 3h, elicit high affinities to the H3R (Ki values of 2.91 and 5.51 nM, respectively). Both compounds are more potent than the reference drug pitolisant (Ki 6.09 nM) and show low toxicity with in vitro models (IC50 > 30 µM on HEK-293, SH-SY5Y and HepG2 cell lines). Subsequently, binding modes of these ligands are obtained using a model of H3R by docking and molecular dynamics studies, thus determining the importance of the purine ring in enhancing affinity due to the hydrogen bonding of Tyr374 to the N-7 of this heterocycle. Finally, in silico ADME properties are predicted, which indicate a promising future for these molecules in terms of their physical−chemical properties, absorption, oral bioavailability and penetration in the CNS.
RESUMO
A library of 31 butyrylcholinesterase (BChE) and cathepsin B (CatB) inhibitors was screened inâ vitro for inhibition of deoxyribonuclease I (DNase I). Compounds 22, 8 and 7 are among the most potent synthetic non-peptide DNase I inhibitors reported to date. Three 8-hydroxyquinoline analogues inhibited both DNase I and BChE with IC50 values below 35â µM and 50â nM, respectively, while two nitroxoline derivatives inhibited DNase I and Cat B endopeptidase activity with IC50 values below 60 and 20â µM. Selected derivatives were screened for various co-target binding affinities at dopamine D2 and D3 , histamine H3 and H4 receptors and inhibition of 5-lipoxygenase. Compound 8 bound to the H3 receptor and is highlighted as the most promising multifunctional ligand with a favorable pharmacokinetic profile and one of the most potent non-peptide DNase I inhibitors. The present study demonstrates that 8-hydroxyquinoline is a structural fragment critical for DNase I inhibition in the presented series of compounds.
Assuntos
Butirilcolinesterase , Catepsina B , Acetilcolinesterase/metabolismo , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Desoxirribonuclease I/química , Desoxirribonuclease I/farmacologia , Ligantes , Simulação de Acoplamento Molecular , Oxiquinolina , Relação Estrutura-AtividadeRESUMO
Molecular hybridization is a valuable approach in drug discovery. Combining it with multicomponent reactions is highly desirable, since structurally diverse libraries can be attained efficiently in an eco-friendly manner. In this work, isatin is used as the key building block for the Ugi 4-center 3-component reaction synthesis of oxindole-lactam hybrids, under catalyst-free conditions. The resulting oxindole-ß-lactam and oxindole-γ-lactam hybrids were evaluated for their potential to inhibit relevant central nervous system targets, namely cholinesterases and monoamine oxidases. Druglikeness evaluation was also performed, and compounds 4eca and 5dab exhibited great potential as selective butyrylcholinesterase inhibitors, at the low micromolar range, with an interesting predictive pharmacokinetic profile. Our findings herein reported suggest oxindole-lactam hybrids as new potential agents for the treatment of Alzheimer's disease.