Non-imidazole-based histamine H3 receptor antagonists with anticonvulsant activity in different seizure models in male adult rats

A series of twelve novel non-imidazole-based ligands (3-14) was developed and evaluated for its in vitro binding properties at the human histamine H3 receptor (hH3R). The novel ligands were investigated for their in vivo protective effects in different seizure models in male adult rats. Among the H3R ligands (3-14) tested, ligand 14 showed significant and dose-dependent reduction in the duration of tonic hind limb extension in maximal electroshock (MES)-induced seizure model subsequent to acute systemic administration (5, 10, and 20 mg/kg, intraperitoneally), whereas ligands 4, 6, and 7 without appreciable protection in MES model were most promising in pentylenetetrazole (PTZ) model. Moreover, the protective effect observed for ligand 14 in MES model was lower than that observed for the reference drug phenytoin and was entirely abrogated when rats were co-administered with the brain-penetrant H1R antagonist pyrilamine (PYR) but not the brain-penetrant H2R antagonist zolantidine (ZOL), demonstrating that histaminergic neurotransmission by activation of postsynaptically located H1Rs seems to be involved in the protective action. On the contrary, PYR and ZOL failed to abrogate the full protection provided by 4 in PTZ model and the moderate protective effect by 14 in strychnine (STR) model. Moreover, the experimental and in silico estimation of properties such as metabolism was performed for five selected test compounds. Also, lipophilicity using planar reversed-phase thin-layer chromatography method was included for better understanding of the molecular properties of the tested compounds. Additionally, the absorption, distribution, metabolism, and elimination and toxicity parameters were evaluated for the most promising compounds 2, 4, 6, 7, and 14 utilizing in vitro methods. These interesting results highlight the potential of H3R ligands as new antiepileptic drugs or as adjuvants to available epilepsy medications

Dual target ligands with 4-tert-butylphenoxy scaffold as histamine H3 receptor antagonists and monoamine oxidase B inhibitors

Dual target ligands are a promising concept for the treatment of Parkinson’s disease (PD). A combination of monoamine oxidase B (MAO B) inhibition with histamine H3 receptor (H3R) antagonism could have positive effects on dopamine regulation. Thus, a series of twenty-seven 4-tert-butylphenoxyalkoxyamines were designed as potential dual-target ligands for PD based on the structure of 1-(3-(4-tert-butylphenoxy)propyl)piperidine (DL76). Probed modifications included the introduction of different cyclic amines and elongation of the alkyl chain. Synthesized compounds were investigated for human H3R (hH3R) affinity and human MAO B (hMAO B) inhibitory activity. Most compounds showed good hH3R affinities with Ki values below 400 nM, and some of them showed potent inhibitory activity for hMAO B with IC50 values below 50 nM. However, the most balanced activity against both biological targets showed DL76 (hH3R: Ki = 38 nM and hMAO B: IC50 = 48 nM). Thus, DL76 was chosen for further studies, revealing the nontoxic nature of DL76 in HEK293 and neuroblastoma SH-SY5Ycells. However, no neuroprotective effect was observed for DL76 in hydrogen peroxide-treated neuroblastoma SH-SY5Y cells. Furthermore, in vivo studies showed antiparkinsonian activity of DL76 in haloperidol-induced catalepsy (Cross Leg Position Test) at a dose of 50 mg/kg body weight

Selenazolinium salts as "small molecule catalysts" with high potency against ESKAPE bacterial pathogens

In view of the pressing need to identify new antibacterial agents able to combat multidrug-resistant bacteria, we investigated a series of fused selenazolinium derivatives (1–8) regarding their in vitro antimicrobial activities against 25 ESKAPE-pathogen strains. Ebselen was used as reference compound. Most of the selenocompounds demonstrated an excellent in vitro activity against all S. aureus strains, with activities comparable to or even exceeding the one of ebselen. In contrast to ebselen, some selenazolinium derivatives (1, 3, and 7) even displayed significant actions against all Gram-negative pathogens tested. The 3-bromo-2-(1-hydroxy-1-methylethyl)[1,2]selenazolo[2,3-a]pyridinium chloride (1) was particularly active (minimum inhibitory concentrations, MICs: 0.31–1.24 µg/mL for MRSA, and 0.31–2.48 µg/mL for Gram-negative bacteria) and devoid of any significant mutagenicity in the Ames assay. Our preliminary mechanistic studies in cell culture indicated that their mode of action is likely to be associated with an alteration of intracellular levels of glutathione and cysteine thiols of different proteins in the bacterial cells, hence supporting the idea that such compounds interact with the intracellular thiolstat. This alteration of pivotal cysteine residues is most likely the result of a direct or catalytic oxidative modification of such residues by the highly reactive selenium species (RSeS) employed

Quantitative analysys of amine-derived compounds against Helicobacter pylori clinical strains.

Helicobacter pylori is one of the most common pathogenic microorganism in the world. The association between Helicobacter pylori infection and gastroduodenal diseases such as inflammation or ulceration of stomach and duodenum has been proved. Helicobacter pylori infection treatment is recommended for patients suffering from these diseases. Increased resistance of Helicobacter pylori strains to recommended drugs has led to a search for alternatives to this antimicrobial agents effective for Helicobacter pylori infection treatment.In this research, we have studied the anti-Helicobacter pylori effect of 46 newly synthesized amine-derived compounds. These substances were synthesized in Department of Bioorganic Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College. The disc-diffusion method was used to screen tested compounds against Helicobacter pylori ATCC 43504, Helicobacter pylori J99, Helicobacter pylori 488, and Staphylococcus aureus ATCC 25923, Escherichia coli ATCC 25922 as control. In preliminary studies 46 amine-derived compounds were used in 10mg/ml solution. The higher activity against Helicobacter pylori strains than against Staphylococcus aureus and Escherichia coli was proved on the basis of size of growth inhibition zones. 45 compounds were active against Helicobacter pylori ATCC 43504 (size of growth inhibition zone was more than 8mm) and 29 compounds were high active against this strain (size of growth inhibition zone was more than 30mm). From all of newly synthesized amino-derived compounds 44 compounds were active against Helicobacter pylori J99 (size of growth inhibition zone was more than 8mm) and 23 compounds were high active against this strain (size of growth inhibition zone was more than 30mm). Against Helicobacter pylori 488 45 compounds were active (size of growth inhibition zone was more than 8mm) and 26 compounds were high active against this strain (size of growth inhibition zone was more than 30mm).15 compounds from the most active against Helicobacter pylori strains, were selected to measurement Minimal Inhibition Concentration (MIC) against Helicobacter pylori ATCC 43504. The strongest growth inhibition against Helicobacter pylori (MIC=50) were proved in 11 from 15 tested compounds. The structure-activity relationship wasn't proved in this research. Xanthone amine-derived had stronger anti-Helicobacter pylori activity than other compounds. This study was a screening test.Helicobacter pylori jest jednym z najbardziej rozpowszechnionych drobnoustrojów chorobotwórczych na świecie. Antybiotykoterapia zakażenia H. pylori stała się jednym z głównych elementów leczenia schorzeń, takich jak wrzody żołądka i dwunastnicy, czy zapalenie żołądka typu B. Jednak wśród izolowanych szczepów, coraz częściej potwierdzana jest ich oporność na rekomendowane leki przeciwbakteryjne, co przyczynia się do nieskuteczności terapii oraz nasuwa konieczność poszukiwania nowych leków aktywnych wobec H. pylori. Przebadano aktywność 46 nowych pochodnych aminowych zsyntetyzowanych w Zakładzie Chemii Bioorganicznej Katedry Chemii Organicznej UJCM, wobec szczepów Helicobacter pylori ATCC 43504, Helicobacter pylori J99, Helicobacter pylori 488 a także kontrolnie wobec Staphylococcus aureus ATCC 25923 i Escherichia coli ATCC 25922. W badaniu wstępnym zastosowano metodę dyfuzyjno-krążkową, przy użyciu bibułowych krążków nasączonych uprzednio roztworem badanych związków w stężeniu 10mg/ml. Na podstawie wielkości stref zahamowania wzrostu szczepów, potwierdzono silną aktywność przeciwbakteryjną większości badanych związków w stężeniu 10mg/ml wobec H. pylori, w porównaniu do niskiej ich aktywności wobec Staphylococcus aureus i Escherichia coli. Wśród badanych pochodnych amin w stężeniu 10mg/ml, aktywność przeciwbakteryjną (strefa zahamowania wzrostu powyżej 8mm) potwierdzono dla 46 związków i szczepu H. pylori ATCC 43504, 45 związków i H. pylori J99 oraz 45 związków i szczepu H. pylori 488, co stanowi odpowiednio 100%, 97,83% i 97,83% wszystkich badanych związków. Natomiast silną aktywność przeciwbakteryjną oraz strefy zahamowania wzrostu powyżej 30 mm, potwierdzono dla 29 związków i H. pylori ATCC 43504, 23 związków i H. pylori J99 oraz 26 związków i H.pylori 488, co stanowi odpowiednio 63,04%, 50%, i 56,52% wszystkich badanych pochodnych amin. Badanie ilościowe przeprowadzono wobec jednego szczepu H. pylori tj. H. pylori ATCC 43504 i 15 wybranych związków spośród 46 badanych , które w badaniu jakościowym wykazały dużą aktywność a strefa zahamowania wzrostu H. pylori dla tych związków przekraczała 30 mm. Badanie ilościowe pozwoliło na określenie wartości minimalnego stężenia związku, hamującego wzrost badanego szczepu (Minimal Inhibitory Concentration – MIC). Dobrą aktywność wobec szczepu H. pylori ATCC 43504 potwierdzono w przypadku 11 związków spośród 15 wybranych do badania. Wartość MIC dla tych związków to 50,0μg/ml. Po przeanalizowaniu struktur związków, biorąc pod uwagę wartość MIC, nie znaleziono zależności pomiędzy budową związków a ich aktywnością.Jednak w całej grupie 46 przebadanych pochodnych amin najlepszą aktywność wobec szczepów Helicobacter pylori wykazały związki posiadające w swojej strukturze układ dibenzo-γ-pironu (ksantonu).Przeprowadzone badania aktywności przeciwbakteryjnej pochodnych amin mają charakter skriningowy. Przebadano związki należące do różnorodnych grup chemicznych, aby wyciągnąć wnioski o ewentualnym elemencie farmakoforowym.Wyselekcjonowanie nowej grupy syntetycznych związków o aktywności przeciwdrobnoustrojowej może mieć w przyszłości duże znaczenie w leczeniu zakażeń patogennymi, opornymi na stosowane antybiotyki szczepami Helicobacter pylori i ich następstwami, które nie leczone w konsekwencji mogą prowadzić do choroby nowotworowej żołądka

Phenylalanine-based AMPA receptor antagonist as the anticonvulsant agent with neuroprotective activity - in vitro and in vivo studies

Trying to meet the multitarget-directed ligands strategy, a series of previously described aryl-substituted phenylalanine derivatives, reported as competitive antagonists of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, were screened in vitro for their free-radical scavenging and antioxidant capacity in two different assays: ferric reducing antioxidant power (FRAP) and oxygen radical absorbance capacity fluorescent (ORAC-FL) assays. The most active antioxidants 1 and 8 were further examined to evaluate their neuroprotective properties in vitro. In this study, compound 1 showed a significant neuroprotective effect against the neurotoxin 6-hydroxydopamine in neuroblastoma SH-SY5Y and IMR-32 cell lines. Both compounds also showed prevention from high levels of reactive oxygen species (ROS) in SH-SY5Y cells. Furthermore, the desired monoamine oxidase B (MAO-B) inhibition effect (IC50 = 278 ± 29 nM) for 1 was determined. No toxic effects up to 100 µM of 1 and 8 against neuroblastoma cells were observed. Furthermore, in vivo studies showed that compound 1 demonstrated significant anticonvulsant potential in 6-Hz test, but in neuropathic pain models its antiallodynic and antihyperalgesic properties were not observed. Concluding, the compound 1 seems to be of higher importance as a new phenylalanine-based lead candidate due to its confirmed promise in in vitro and in vivo anticonvulsant activity

2-{5-[(Z,2Z)-2-Chloro-3-(4-nitrophenyl)-2-propenylidene]-4-oxo-2-thioxothiazolidin-3-yl -3-methylbutanoic acid as a potential anti-breast cancer molecule

It was established that the synthesis of hybrid molecules containing a thiazolidinone and a (2Z)-2-chloro-3-(4-nitrophenyl)prop-2-ene structural fragments is an effective approach for the design of potential anticancer agents. Given the results of the previous SAR-analysis, the aim of the study was to synthesize a novel 4-thiazolidinone derivative Les-3331 and investigate its molecular mechanism of action in MCF-7 and MDA-MB-231 breast cancer cells. The cytotoxic properties and antiproliferative potential of Les-3331 were determined. The effect of the tested compound on apoptosis induction and mitochondrial membrane potential was checked by flow cytometry. ELISA was used to determine caspase-8 and caspase-9, LC3A, LC3B, Beclin-1, and topoisomerase II concentration. Additionally, PAMPA, in silico or in vitro prediction of metabolism, CYP3A4/2D6 inhibition, and an Ames test were performed. Les-3331 possesses high cytotoxic and antiproliferative activity in MCF-7 and MDA-MB-231 breast cancer cells. Its molecular mechanism of action is associated with apoptosis induction, decreased mitochondrial membrane potential, and increased caspase-9 and caspase-8 concentrations. Les-3331 decreased LC3A, LC3B, and Beclin-1 concentration in tested cell lines. Topoisomerase II concentration was also lowered. The most probable metabolic pathways and no DDIs risk of Les-3331 were confirmed in in vitro assays. Our studies confirmed that a novel 4-thiazolidinone derivative represents promising anti-breast cancer activity