20 research outputs found
Pharmaceutical and Safety Profile Evaluation of Novel Selenocompounds with Noteworthy Anticancer Activity
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
Are the hydantoin-1,3,5-triazine ligands a hope to a find new procognitive and anti-obesity drug? : considerations based on primary in vivo assays and ADME-Tox profile in vitro
Though the serotonin receptor is an important target giving both agonists and
antagonists similar therapeutic potency in the treatment of topic CNS-diseases, no ligand
has reached the pharmaceutical market yet due to the too narrow chemical space of the known
agents and insuffcient "drugability." Recently, a new group of non-indole and non-sulfone
hydantoin-triazine ligands was found, where 3-((4-amino-6-(4-methylpiperazin-1-yl)-
1,3,5-triazin-2-yl)methyl)-5-methyl-5-(naphthalen-2-yl)imidazolidine-2,4-dione (KMP-10) was the
most active member. This study is focused on wider pharmacological and "druglikeness"
characteristics for KMP-10. A computer-aided insight into molecular interactions with
has been performed. "Druglikeness" was examined using an eight-test panel in vitro, i.e., a parallel
artificial membrane permeability assay (PAMPA), and Caco-2 permeability-, P-glycoprotein (Pgp)
affnity-, plasma protein binding-, metabolic stability- and drug–drug interaction-assays, as well
as mutagenicity- and HepG2-hepatotoxicity risk tests. Behavioral studies in vivo, i.e., elevated
plus-maze (EPM) and novel object recognition (NOR) tests, were performed. Extended studies on
the influence of KMP-10 on rats' metabolism, including biochemical tests, were conducted in vivo.
Results indicated significant anxiolytic and precognitive properties, as well as some anti-obesity
properties in vivo, and it was found to satisfy the "druglikeness" profile in vitro for KMP-10. The
compound seems to be a good lead-structure and candidate for wider pharmacological studies in
search for new CNS-drugs acting via
Molecular Insights into an Antibiotic Enhancer Action of New Morpholine-Containing 5-Arylideneimidazolones in the Fight against MDR Bacteria
In the search for an effective strategy to overcome antimicrobial resistance, a series of
new morpholine-containing 5-arylideneimidazolones differing within either the amine moiety or at
position five of imidazolones was explored as potential antibiotic adjuvants against Gram-positive
and Gram-negative bacteria. Compounds (7–23) were tested for oxacillin adjuvant properties in
the Methicillin-susceptible S. aureus (MSSA) strain ATCC 25923 and Methicillin-resistant S. aureus
MRSA 19449. Compounds 14–16 were tested additionally in combination with various antibiotics.
Molecular modelling was performed to assess potential mechanism of action. Microdilution and
real-time efflux (RTE) assays were carried out in strains of K. aerogenes to determine the potential
of compounds 7–23 to block the multidrug efflux pump AcrAB-TolC. Drug-like properties were
determined experimentally. Two compounds (10, 15) containing non-condensed aromatic rings,
significantly reduced oxacillin MICs in MRSA 19449, while 15 additionally enhanced the effectiveness
of ampicillin. Results of molecular modelling confirmed the interaction with the allosteric site of
PBP2a as a probable MDR-reversing mechanism. In RTE, the compounds inhibited AcrAB-TolC even
to 90% (19). The 4-phenylbenzylidene derivative (15) demonstrated significant MDR-reversal “dual
action” for β-lactam antibiotics in MRSA and inhibited AcrAB-TolC in K. aerogenes. 15 displayed also
satisfied solubility and safety towards CYP3A4 in vitro
Molecular insights into an antibiotic enhancer action of new morpholine-containing 5-arylideneimidazolones in the fight against MDR bacteria
Chlorine substituents and linker topology as factors of activity for novel highly active 1,3,5-triazine derivatives with procognitive properties in vivo
Hydrophobicity modulation via the substituents at positions 2 and 4 of 1,3,5-triazine to enhance therapeutic ability against Alzheimer's disease for potent serotonin 5-HT6R agents
Pharmaceutical and safety profile evaluation of novel selenocompounds with noteworthy anticancer activity
Prior studies have reported the potent and selective cytotoxic, pro-apoptotic, and chemopreventive activities of a cyclic selenoanhydride and of a series of selenoesters. Some of these selenium derivatives demonstrated multidrug resistance (MDR)-reversing activity in different resistant cancer cell lines. Thus, the aim of this study was to evaluate the pharmaceutical and safety profiles of these selected selenocompounds using alternative methods in silico and in vitro. One of the main tasks of this work was to determine both the physicochemical properties and metabolic stability of these selenoesters. The obtained results proved that these tested selenocompounds could become potential candidates for novel and safe anticancer drugs with good ADMET parameters. The most favorable selenocompounds turned out to be the phthalic selenoanhydride (EDA-A6), two ketone-containing selenoesters with a 4-chlorophenyl moiety (EDA-71 and EDA-73), and a symmetrical selenodiester with a pyridine ring and two selenium atoms (EDA-119)