Publications by authors named "Gniewomir Latacz"

87 Publications

Identification of New Compounds with Anticonvulsant and Antinociceptive Properties in a Group of 3-substituted (2,5-dioxo-pyrrolidin-1-yl)(phenyl)-Acetamides.

Int J Mol Sci 2021 Dec 3;22(23). Epub 2021 Dec 3.

Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland.

We report herein a series of water-soluble analogues of previously described anticonvulsants and their detailed in vivo and in vitro characterization. The majority of these compounds demonstrated broad-spectrum anticonvulsant properties in animal seizure models, including the maximal electroshock (MES) test, the pentylenetetrazole-induced seizure model (PTZ), and the psychomotor 6 Hz (32 mA) seizure model in mice. Compound showed the most robust anticonvulsant activity (ED MES = 49.6 mg/kg, ED 6 Hz (32 mA) = 31.3 mg/kg, EDPTZ = 67.4 mg/kg). Notably, it was also effective in the 6 Hz (44 mA) model of drug-resistant epilepsy (ED = 63.2 mg/kg). Apart from favorable anticonvulsant properties, compound revealed a high efficacy against pain responses in the formalin-induced tonic pain, the capsaicin-induced neurogenic pain, as well as in the oxaliplatin-induced neuropathic pain in mice. Moreover, compound showed distinct anti-inflammatory activity in the model of carrageenan-induced aseptic inflammation. The mechanism of action of compound is likely complex and may result from the inhibition of peripheral and central sodium and calcium currents, as well as the TRPV1 receptor antagonism as observed in the in vitro studies. This lead compound also revealed beneficial in vitro ADME-Tox properties and an in vivo pharmacokinetic profile, making it a potential candidate for future preclinical development. Interestingly, the in vitro studies also showed a favorable induction effect of compound on the viability of neuroblastoma SH-SY5Y cells.
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http://dx.doi.org/10.3390/ijms222313092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8658016PMC
December 2021

Histamine H Receptor Ligands-KSK-59 and KSK-73-Reduce Body Weight Gain in a Rat Model of Excessive Eating.

Pharmaceuticals (Basel) 2021 Oct 25;14(11). Epub 2021 Oct 25.

Department of Pharmacological Screening, Jagiellonian University Medical College, Medyczna 9, PL 30-688 Cracow, Poland.

Noting the worldwide rapid increase in the prevalence of overweight and obesity new effective drugs are now being sought to combat these diseases. Histamine H receptor antagonists may represent an effective therapy as they have been shown to modulate histamine synthesis and release and affect a number of other neurotransmitters (norepinephrine, acetylcholine, γ-aminobutyric acid, serotonin, substance P) thus influencing the food intake. Based on the preliminary studies determining affinity, intrinsic activity, and selected pharmacokinetic parameters, two histamine H receptor ligands were selected. Female rats were fed palatable food for 28 days and simultaneously administered the tested compounds intraperitoneally (i.p.) at a dose of 10 or 1 mg/kg b.w./day. Weight was evaluated daily and calorie intake was evaluated once per week. The plasma levels of cholesterol, triglycerides, leptin, adiponectin, ghrelin, corticosterone, CRP and IL-6 were determined at the end of experiment. The glucose tolerance test was also performed. To exclude false positives, the effect of tested compounds on spontaneous activity was monitored during the treatment, as well as the amount of consumed kaolin clay was studied as a reflection of possible gastrointestinal disturbances comparable to nausea. The histamine H receptor antagonists KSK-59 and KSK-73 administered i.p. at a dose of 10 mg/kg b.w. prevented weight gain in a rat model of excessive eating. They reduced adipose tissue deposits and improved glucose tolerance. Both compounds showed satisfying ability to penetrate through biological membranes determined in in vitro studies. Compound KSK-73 also reduced the caloric intake of the experimental animals what indicates its anorectic effect. These results show the pharmacological properties of histamine H receptor antagonists, (4-pyridyl)piperazine derivatives, as the compounds causing not only slower weight gain but also ameliorating some metabolic disorders in rats having the opportunity to overeat.
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http://dx.doi.org/10.3390/ph14111080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8622623PMC
October 2021

Design and synthesis of new potent 5-HT receptor ligands as a candidate for the treatment of central nervous system diseases.

Eur J Med Chem 2022 Jan 21;227:113931. Epub 2021 Oct 21.

Faculty of Chemical Engineering and Technology, Institute of Organic Chemistry and Technology, Cracow University of Technology, ul. Warszawska 24, 31-155, Kraków, Poland.

Owing to their multifunctional pharmacological profiles (including dual 5-HT/5-HT action), arylpiperazine derivatives are widely used for treating central nervous system diseases including the depression or neuropathic pain. Herein we describe the design, synthesis and evaluation of biological activity of novel 5-HT ligands derived of 2,4,6-triamino-1,3,5-triazine. The studied compounds showed affinity and high selectively towards 5-HT receptor with the two most active compounds 34 (K = 61 nM), 22 (K = 109 nM) showing good metabolic stability and moderate affinity to CYP3A4 isoenzyme. Compound 22 had high hepatotoxicity at a concentration below 50 μM, while compound 34 showed low hepatotoxicity even at a concentration above 50 μM.
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http://dx.doi.org/10.1016/j.ejmech.2021.113931DOI Listing
January 2022

The Phenoxyalkyltriazine Antagonists for 5-HT Receptor with Promising Procognitive and Pharmacokinetic Properties In Vivo in Search for a Novel Therapeutic Approach to Dementia Diseases.

Int J Mol Sci 2021 Oct 5;22(19). Epub 2021 Oct 5.

Faculty of Pharmacy, Medical College in Krakow, Jagiellonian University, PL 30-688 Kraków, Poland.

Among the serotonin receptors, one of the most recently discovered 5-HT subtype is an important protein target and its ligands may play a key role in the innovative treatment of cognitive disorders. However, none of its selective ligands have reached the pharmaceutical market yet. Recently, a new chemical class of potent 5-HT receptor agents, the 1,3,5-triazine-piperazine derivatives, has been synthesized. Three members, the and dichloro- (,) and the unsubstituted phenyl () derivatives, proved to be of special interest due to their high affinities (,) and selectivity () toward 5-HT receptor. Thus, a broader pharmacological profile for , including comprehensive screening of the receptor selectivity and drug-like parameters in vitro as well as both, pharmacokinetic and pharmacodynamic properties in vivo, have been investigated within this study. A comprehensive analysis of the obtained results indicated significant procognitive-like activity together with beneficial drug-likeness in vitro and pharmacokinetics in vivo profiles for both, ()-4-[1-(2,3-dichlorophenoxy)propyl]-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine () and ()-4-(4-methylpiperazin-1-yl)-6-(1-phenoxypropyl)-1,3,5-triazin-2-amine (), but insensibly predominant for compound . Nevertheless, both compounds ( and ) seem to be good Central Nervous System drug candidates in search for novel therapeutic approach to dementia diseases, based on the 5-HT receptor target.
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http://dx.doi.org/10.3390/ijms221910773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8509428PMC
October 2021

Development and crystallography-aided SAR studies of multifunctional BuChE inhibitors and 5-HTR antagonists with β-amyloid anti-aggregation properties.

Eur J Med Chem 2021 Dec 27;225:113792. Epub 2021 Aug 27.

Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland. Electronic address:

The lack of an effective treatment makes Alzheimer's disease a serious healthcare problem and a challenge for medicinal chemists. Herein we report interdisciplinary research on novel multifunctional ligands targeting proteins and processes involved in the development of the disease: BuChE, 5-HT receptors and β-amyloid aggregation. Structure-activity relationship analyses supported by crystallography and docking studies led to the identification of a fused-type multifunctional ligand 50, with remarkable and balanced potencies against BuChE (IC = 90 nM) and 5-HTR (K = 4.8 nM), and inhibitory activity against Aβ aggregation (53% at 10 μM). In in vitro ADME-Tox and in vivo pharmacokinetic studies compound 50 showed good stability in the mouse liver microsomes, favourable safety profile and brain permeability with the brain to plasma ratio of 6.79 after p.o. administration in mice, thus being a promising candidate for in vivo pharmacology studies and a solid foundation for further research on effective anti-AD therapies.
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http://dx.doi.org/10.1016/j.ejmech.2021.113792DOI Listing
December 2021

Discovery of 1-(phenylsulfonyl)-1H-indole-based multifunctional ligands targeting cholinesterases and 5-HT receptor with anti-aggregation properties against amyloid-beta and tau.

Eur J Med Chem 2021 Dec 19;225:113783. Epub 2021 Aug 19.

Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland. Electronic address:

Multifunctional ligands as an essential variant of polypharmacology are promising candidates for the treatment of multi-factorial diseases like Alzheimer's disease. Based on clinical evidence and following the paradigm of multifunctional ligands we have rationally designed and synthesized a series of compounds targeting processes involved in the development of the disease. The biological evaluation led to the discovery of two compounds with favorable pharmacological characteristics and ADMET profile. Compounds 17 and 35 are 5-HTR antagonists (K = 13 nM and K = 15 nM respectively) and cholinesterase inhibitors with distinct mechanisms of enzyme inhibition. Compound 17, a tacrine derivative is a reversible inhibitor of acetyl- and butyrylcholinesterase (IC = 8 nM and IC = 24 nM respectively), while compound 35 with rivastigmine-derived phenyl N-ethyl-N-methylcarbamate fragment is a selective, pseudo-irreversible inhibitor of butyrylcholinesterase (IC = 455 nM). Both compounds inhibit aggregation of amyloid β in vitro (75% for compound 17 and 68% for 35 at 10 μM) moreover, compound 35 is a potent tau aggregation inhibitor in cellulo (79%). In ADMET in vitro studies both compounds showed acceptable metabolic stability on mouse liver microsomes (28% and 60% for compound 17 and 35 respectively), no or little effect on CYP3A4 and 2D6 up to a concentration of 10 μM and lack of toxicity on HepG2 cell line (IC values of 80 and 21 μM, for 17 and 35 respectively). Based on the pharmacological characteristics and favorable pharmacokinetic properties, we propose compounds 17 and 35 as an excellent starting point for further optimization and in-depth biological studies.
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http://dx.doi.org/10.1016/j.ejmech.2021.113783DOI Listing
December 2021

-Skatyltryptamines-Dual 5-HTR/DR Ligands with Antipsychotic and Procognitive Potential.

Molecules 2021 Jul 29;26(15). Epub 2021 Jul 29.

Department of Medicinal Chemistry, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Street, 31-343 Kraków, Poland.

A series of -skatyltryptamines was synthesized and their affinities for serotonin and dopamine receptors were determined. Compounds exhibited activity toward 5-HT, 5-HT, 5-HT, and D receptors. Substitution patterns resulting in affinity/activity switches were identified and studied using homology modeling. Chosen hits were screened to determine their metabolism, permeability, hepatotoxicity, and CYP inhibition. Several D receptor antagonists with additional 5-HTR antagonist and agonist properties were identified. The former combination resembled known antipsychotic agents, while the latter was particularly interesting due to the fact that it has not been studied before. Selective 5-HTR antagonists have been shown previously to produce procognitive and promnesic effects in several rodent models. Administration of 5-HTR agonists was more ambiguous-in naive animals, it did not alter memory or produce slight amnesic effects, while in rodent models of memory impairment, they ameliorated the condition just like antagonists. Using the identified hit compounds and , we tried to sort out the difference between ligands exhibiting the DR antagonist function combined with 5-HTR agonism, and mixed D/5-HTR antagonists in murine models of psychosis.
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http://dx.doi.org/10.3390/molecules26154605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8347595PMC
July 2021

Novel Functionalized Amino Acids as Inhibitors of GABA Transporters with Analgesic Activity.

ACS Chem Neurosci 2021 08 4;12(16):3073-3100. Epub 2021 Aug 4.

Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.

Neuropathic pain resistance to pharmacotherapy has encouraged researchers to develop effective therapies for its treatment. γ-Aminobutyric acid (GABA) transporters 1 and 4 (mGAT1 and mGAT4) have been increasingly recognized as promising drug targets for neuropathic pain (NP) associated with imbalances in inhibitory neurotransmission. In this context, we designed and synthesized new functionalized amino acids as inhibitors of GABA uptake and assessed their activities toward all four mouse GAT subtypes (mGAT1-4). According to the obtained results, compounds 2,4- (pIC (mGAT4) = 5.36), (pIC (mGAT2) = 5.43), and (with moderate subtype selectivity that favored mGAT4, pIC (mGAT4) = 5.04) were of particular interest and were therefore evaluated for their cytotoxic and hepatotoxic effects. In a set of experiments, both compounds and showed antinociceptive properties in three rodent models of NP, namely, chemotherapy-induced neuropathic pain models (the oxaliplatin model and the paclitaxel model) and the diabetic neuropathic pain model induced by streptozotocin; however compound demonstrated predominant activity. Since impaired motor coordination is also observed in neuropathic pain conditions, we have pointed out that none of the test compounds induced motor deficits in the rotarod test.
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http://dx.doi.org/10.1021/acschemneuro.1c00351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8397297PMC
August 2021

Cyanobiphenyls: Novel H receptor ligands with cholinesterase and MAO B inhibitory activity as multitarget compounds for potential treatment of Alzheimer's disease.

Bioorg Chem 2021 09 28;114:105129. Epub 2021 Jun 28.

Department of Physicochemical Drug Analysis, Jagiellonian University Medical College, Medyczna 9, Krakow 30-688, Poland. Electronic address:

Alzheimer's disease (AD) is a complex and incurable illness that requires the urgent approval of new effective drugs. However, since 2003, no new molecules have shown successful results in clinical trials, thereby making the common "one compound - one target" paradigm questionable. Recently, the multitarget-directed ligand (MTDL) approach has gained popularity, as compounds targeting at least two biological targets may be potentially more effective in treating AD. On the basis of these findings, we designed, synthesized, and evaluated through biological assays a series of derivatives of alicyclic amines linked by an alkoxy bridge to an aromatic lipophilic moiety of [1,1'-biphenyl]-4-carbonitrile. The research results revealed promising biological activity of the obtained compounds toward the chosen targets involved in AD pathophysiology; the compounds showed high affinity (mostly low nanomolar range of K values) for human histamine H receptors (hHR) and good nonselective inhibitory potency (micromolar range of IC values) against acetylcholinesterase from electric eel (eeAChE) and equine serum butyrylcholinesterase (eqBuChE). Moreover, micromolar/submicromolar potency against human monoamine oxidase B (hMAO B) was detected for some compounds. The study identified compound 5 as a multiple hHR/eeAChE/eqBuChE/hMAO B ligand (5: hHR K = 9.2 nM; eeAChE IC = 2.63 µM; eqBuChE IC = 1.30 µM; hMAO B IC = 0.60 µM). Further in vitro studies revealed that compound 5 exhibits a mixed type of eeAChE and eqBuChE inhibition, good metabolic stability, and moderate hepatotoxicity effect on HepG2 cells. Finally, compound 5 showed a beneficial effect on scopolamine-induced memory impairments, as assessed by the passive avoidance test, thus revealing the potential of this compound as a promising agent for further optimization for AD treatment.
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http://dx.doi.org/10.1016/j.bioorg.2021.105129DOI Listing
September 2021

Development of tricyclic N-benzyl-4-hydroxybutanamide derivatives as inhibitors of GABA transporters mGAT1-4 with anticonvulsant, antinociceptive, and antidepressant activity.

Eur J Med Chem 2021 Oct 4;221:113512. Epub 2021 May 4.

Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna St, 30-688, Kraków, Poland.

γ-Aminobutyric acid (GABA) neurotransmission has a significant impact on the proper functioning of the central nervous system. Numerous studies have indicated that inhibitors of the GABA transporters mGAT1-4 offer a promising strategy for the treatment of several neurological disorders, including epilepsy, neuropathic pain, and depression. Following our previous results, herein, we report the synthesis, biological evaluation, and structure-activity relationship studies supported by molecular docking and molecular dynamics of a new series of N-benzyl-4-hydroxybutanamide derivatives regarding their inhibitory potency toward mGAT1-4. This study allowed us to identify compound 23a (N-benzyl-4-hydroxybutanamide bearing a dibenzocycloheptatriene moiety), a nonselective GAT inhibitor with a slight preference toward mGAT4 (pIC = 5.02 ± 0.11), and compound 24e (4-hydroxy-N-[(4-methylphenyl)-methyl]butanamide bearing a dibenzocycloheptadiene moiety) with relatively high inhibitory activity toward mGAT2 (pIC = 5.34 ± 0.09). In a set of in vivo experiments, compound 24e successively showed predominant anticonvulsant activity and antinociception in the formalin model of tonic pain. In contrast, compound 23a showed significant antidepressant-like properties in mice. These results were consistent with the available literature data, which indicates that, apart from seizure control, GABAergic neurotransmission is also involved in the pathophysiology of several psychiatric diseases, however alternative mechanisms underlying this action cannot be excluded. Finally, it is worth noting that the selected compounds showed unimpaired locomotor skills that have been indicated to give reliable results in behavioral assays.
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http://dx.doi.org/10.1016/j.ejmech.2021.113512DOI Listing
October 2021

Computer-Aided Search for 5-Arylideneimidazolone Anticancer Agents Able To Overcome ABCB1-Based Multidrug Resistance.

ChemMedChem 2021 Aug 7;16(15):2386-2401. Epub 2021 Jun 7.

Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688, Kraków, Poland.

ABCB1 modulation is an interesting strategy in the search for new anticancer agents that can overcome multidrug resistance (MDR). Hence, 17 new 5-arylideneimidazolones containing an amine moiety, as potential ABCB1 inhibitors, were designed, synthesized, and investigated. The series was tested in both parental (PAR) and multidrug-resistant (MDR) ABCB1-overexpressing T-lymphoma cancer cells using cytotoxicity assays. The ABCB1-modulating activity was examined in rhodamine 123 accumulation tests, followed by Pgp-Glo™ Assay to determine the influence of the most active compounds on ATPase activity. Lipophilic properties were assessed both, in silico and experimentally (RP-TLC). Pharmacophore-based molecular modelling toward ABCB1 modulation was performed. The studies allowed the identification of anticancer agents (p-fluorobenzylidene derivatives) more potent than doxorubicin, with highly selective action on MDR T-lymphoma cells (selectivity index >40). Most of the investigated compounds showed ABCB1-modulating action; in particular, two 5-benzyloxybenzylidene derivatives displayed activity nearly as strong as that of tariquidar.
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http://dx.doi.org/10.1002/cmdc.202100252DOI Listing
August 2021

Discovery of multifunctional anti-Alzheimer's agents with a unique mechanism of action including inhibition of the enzyme butyrylcholinesterase and γ-aminobutyric acid transporters.

Eur J Med Chem 2021 Jun 31;218:113397. Epub 2021 Mar 31.

Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland. Electronic address:

Looking for an effective anti-Alzheimer's agent is very challenging; however, a multifunctional ligand strategy may be a promising solution for the treatment of this complex disease. We herein present the design, synthesis and biological evaluation of novel hydroxyethylamine derivatives displaying unique, multiple properties that have not been previously reported. The original mechanism of action combines inhibitory activity against disease-modifying targets: β-secretase enzyme (BACE1) and amyloid β (Aβ) aggregation, along with an effect on targets associated with symptom relief - inhibition of butyrylcholinesterase (BuChE) and γ-aminobutyric acid transporters (GATs). Among the obtained molecules, compound 36 exhibited the most balanced and broad activity profile (eeAChE IC = 2.86 μM; eqBuChE IC = 60 nM; hBuChE IC = 20 nM; hBACE1 IC = 5.9 μM; inhibition of Aβ aggregation = 57.9% at 10 μM; mGAT1 IC = 10.96 μM; and mGAT2 IC = 19.05 μM). Moreover, we also identified 31 as the most potent mGAT4 and hGAT3 inhibitor (IC = 5.01 μM and IC = 2.95 μM, respectively), with high selectivity over other subtypes. Compounds 36 and 31 represent new anti-Alzheimer agents that can ameliorate cognitive decline and modify the progress of disease.
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http://dx.doi.org/10.1016/j.ejmech.2021.113397DOI Listing
June 2021

2-Phenyl-1-pyrrole-3-carboxamide as a New Scaffold for Developing 5-HT Receptor Inverse Agonists with Cognition-Enhancing Activity.

ACS Chem Neurosci 2021 04 11;12(7):1228-1240. Epub 2021 Mar 11.

Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Str., 30-688 Kraków, Poland.

Serotonin type 6 receptor (5-HTR) has gained particular interest as a promising target for treating cognitive deficits, given the positive effects of its antagonists in a wide range of memory impairment paradigms. Herein, we report on degradation of the 1-pyrrolo[3,2-]quinoline scaffold to provide the 2-phenyl-1-pyrrole-3-carboxamide, which is devoid of canonical indole-like skeleton and retains recognition of 5-HTR. This modification has changed the compound's activity at 5-HTR-operated signaling pathways from neutral antagonism to inverse agonism. The study identified compound that behaves as an inverse agonist of the 5-HTR at the Gs and Cdk5 signaling pathways. Compound showed high selectivity and metabolic stability and was brain penetrant. Finally, reversed scopolamine-induced memory decline in the novel object recognition test and exhibited procognitive properties in the attentional set-shifting task in rats. In light of these findings, might be considered for further evaluation as a new cognition-enhancing agent, while 2-phenyl-1-pyrrole-3-carboxamide might be used as a template for designing 5-HTR inverse agonists.
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http://dx.doi.org/10.1021/acschemneuro.1c00061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041276PMC
April 2021

Molecular Insights into an Antibiotic Enhancer Action of New Morpholine-Containing 5-Arylideneimidazolones in the Fight against MDR Bacteria.

Int J Mol Sci 2021 Feb 19;22(4). Epub 2021 Feb 19.

Department of Technology and Biotechnology of Drugs, Jagiellonian University, Medical College, ul. Medyczna 9, 30-688 Krakow, Poland.

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 (-) were tested for oxacillin adjuvant properties in the Methicillin-susceptible (MSSA) strain ATCC 25923 and Methicillin-resistant MRSA 19449. Compounds - 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 to determine the potential of compounds - to block the multidrug efflux pump AcrAB-TolC. Drug-like properties were determined experimentally. Two compounds (, ) containing non-condensed aromatic rings, significantly reduced oxacillin MICs in MRSA 19449, while 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% (). The 4-phenylbenzylidene derivative () demonstrated significant MDR-reversal "dual action" for -lactam antibiotics in MRSA and inhibited AcrAB-TolC in . displayed also satisfied solubility and safety towards CYP3A4 in vitro.
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http://dx.doi.org/10.3390/ijms22042062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7922564PMC
February 2021

Asymmetric synthesis and in vivo/in vitro characterization of new hybrid anticonvulsants derived from (2,5-dioxopyrrolidin-1-yl)phenylacetamides.

Bioorg Chem 2021 04 19;109:104751. Epub 2021 Feb 19.

Jagiellonian University Medical College, Faculty of Pharmacy, Department of Medicinal Chemistry, Medyczna 9, 30-688 Krakow, Poland. Electronic address:

In the current studies we carried out an optimized multistep asymmetric synthesis of R-enantiomers (eutomers) for a previously identified series of racemic hybrid anticonvulsants. The spatial structure of selected enantiomers was solved by the use of crystallographic methods. The compound (R)-16 was identified as a lead, which revealed broad-spectrum protective activity in a range of epilepsy models with the following ED values: the maximal electroshock (MES) test (36.0 mg/kg), the 6 Hz (32 mA) seizure model (39.2 mg/kg), and the pentylenetetrazole-induced seizure model (scPTZ) (54.8 mg/kg). Furthermore, (R)-16 displayed a low potency for the induction of motor impairment in the rotarod test (TD = 468.5 mg/kg), resulting in potentially very beneficial therapeutic window. Finally, (R)-16 showed satisfying ADME-Tox properties in the in vitro assays. Therefore, the data obtained in the current studies justify the further preclinical development of (R)-16 as candidate for potentially broad-spectrum and safe anticonvulsant.
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http://dx.doi.org/10.1016/j.bioorg.2021.104751DOI Listing
April 2021

An insight into the structure of 5-spiro aromatic derivatives of imidazolidine-2,4-dione, a new group of very potent inhibitors of tumor multidrug resistance in T-lymphoma cells.

Bioorg Chem 2021 04 18;109:104735. Epub 2021 Feb 18.

Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland. Electronic address:

A series of 17 arylpiperazine derivatives of the 5-spiroimidazolidine-2,4-diones (6-22) has been explored, including variations in (i) the number of aromatic rings at position 5, (ii) the length of the linker, as well as (iii) the kind and position of the linked arylpiperazine terminal fragment. Synthesis (6-16) and X-ray crystallographic studies for representative compounds (8, 10, 14 and 18) have been performed. The ability to inhibit the tumor multidrug resistance (MDR) efflux pump P-glycoprotein (P-gp, ABCB1) overexpressed in mouse T-lymphoma cells was investigated. The cytotoxic and antiproliferative actions of the compounds on both the reference and the ABCB1-overproducing cells were also examined. The pharmacophore-based molecular modeling studies have been performed. ADMET properties in vitro of selected most active derivatives (6, 11 and 12) have been determined. All compounds, excluding 18, inhibited the cancer P-gp efflux pump with higher potency than that of reference verapamil. The spirofluorene derivatives with amine alkyl substituents at position 1, and the methyl group at position 3 (6-16), occurred the most potent P-gp inhibitors in the MDR T-lymphoma cell line. In particular, compounds 7 and 12 were 100-fold more potent than verapamil. Crystallography-supported pharmacophore-based SAR analysis has postulated specific structural properties that could explain this excellent cancer MDR-inhibitory action.
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http://dx.doi.org/10.1016/j.bioorg.2021.104735DOI Listing
April 2021

Design and Synthesis of Novel Aminoalkanamides Targeting Neurodegeneration and Symptoms of Alzheimer's Disease.

Curr Med Chem 2021 ;28(29):6082-6094

Jagiellonian University Medical College, Faculty of Pharmacy, Department of Medicinal Chemistry, 9 Medyczna Street, 30-688 Krakow, Poland.

Background: There is currently no drug that slows the process of neurodegeneration or alleviates the cognitive and depressive symptoms in patients with Alzheimer's disease. Due to the increasing number of Alzheimer's patients, there is an urgent need to develop novel drugs with neuroprotective, procognitive, and antidepressant properties.

Objective: The aim of this study was to design, synthesize, and evaluate novel aminoalkanamides with serotonin 5-HT/5-HT receptor affinity and phosphodiesterase (PDE) inhibitory activity as a new approach to combat neurodegeneration and symptoms of Alzheimer's disease.

Methods: The newly designed compounds were synthesized using classical methods of organic chemistry and tested in vitro for their receptor affinity, functional profile, enzyme inhibition, and ADME properties. The neuroprotective effect against HO-induced increase of reactive oxygen species level was tested in SH-SY5Y cells. The novel object recognition and forced swimming tests were used to evaluate the procognitive and antidepressant activity, respectively.

Results: Synthesized aminoalkanamides were characterized as potent 5-HTreceptor antagonists with additional 5-HT7 receptor antagonistic properties and PDE4B inhibitory activity. Selected compound 15 showed neuroprotective, procognitive, and antidepressant properties. In addition, compound 15 revealed suitable ADME properties expressed as good membrane permeability and high metabolic stability.

Conclusion: This study revealed a new class of compounds that may be useful in the search for an effective drug in the alleviation of neurodegeneration and symptoms of Alzheimer's disease.
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http://dx.doi.org/10.2174/0929867328666210215113346DOI Listing
September 2021

Characterization of In Vitro and In Vivo Metabolism of Antazoline Using Liquid Chromatography-Tandem Mass Spectrometry.

Int J Mol Sci 2020 Dec 18;21(24). Epub 2020 Dec 18.

Department of Social Pharmacy, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland.

Antazoline (ANT) was recently shown to be an effective and safe antiarrhythmic drug in the termination of atrial fibrillation. However, the drug is still not listed in clinical guidelines. No data on ANT metabolism in humans is available. We used liquid chromatography coupled with tandem mass spectrometry to identify and characterize metabolites of ANT. We analyzed plasma of volunteers following a single intravenous administration of 100 mg of ANT mesylate and in in vitro cultures of human hepatocytes. We revealed that ANT was transformed into at least 15 metabolites and we investigated the role of cytochrome P450 isoforms. CYP2D6 was the main one involved in the fast metabolism of ANT. The biotransformation of ANT by CYP2C19 was much slower. The main Phase I metabolite was M1 formed by the removal of phenyl and metabolite M2 with hydroxyl in the position of phenyl. Glucuronidation was the leading Phase II metabolism. Further study on pharmacokinetics of the metabolites would allow us to better understand the activity profile of ANT and to predict its potential clinical applications. Ultimately, further investigation of the activity profile of the new hydroxylated M2 metabolite of ANT might result in an active substance with a different pharmacological profile than the parent molecule, and potentially a new drug candidate.
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http://dx.doi.org/10.3390/ijms21249693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766522PMC
December 2020

Structural modifications in the distal, regulatory region of histamine H receptor antagonists leading to the identification of a potent anti-obesity agent.

Eur J Med Chem 2021 Mar 24;213:113041. Epub 2020 Nov 24.

Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, Kraków, 30-688, Poland. Electronic address:

A series of 4-pyridylpiperazine derivatives with varying regulatory region substituents proved to be potent histamine H receptor (HR) ligands in the nanomolar concentration range. The most influential modification that affected the affinity toward the HR appeared by introducing electron-withdrawing moieties into the distal aromatic ring. In order to finally discuss the influence of the characteristic 4-pyridylpiperazine moiety on HR affinity, two Ciproxifan analogues 2 and 3 with a slight modification in their basic part were obtained. The replacement of piperazine in 3 with piperidine in compound 2, led to slightly reduced affinity towards the HR (K = 3.17 and 7.70 nM, respectively). In fact, 3 showed the highest antagonistic properties among all compounds in this series, hence affirming our previous assumptions, that the 4-pyridylpiperazine moiety is the key element for suitable interaction with the human histamine H receptor. While its structural replacement to piperidine is also tolerated for HR binding, the heteroaromatic 4-pyridyl moiety seems to be essential for proper ligand-receptor interaction. The putative protein-ligand interactions responsible for their high affinity were demonstrated using molecular modeling techniques. Furthermore, selectivity, intrinsic activity at the HR, as well as drug-like properties of ligands were evaluated using in vitro methods. Moreover, pharmacological in vivo test results of compound 9 (structural analogue of Abbott's A-331440) clearly indicate that it may affect the amount of calories consumed, thus act as an anorectic compound.
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http://dx.doi.org/10.1016/j.ejmech.2020.113041DOI Listing
March 2021

The relationship between stereochemical and both, pharmacological and ADME-Tox, properties of the potent hydantoin 5-HTR antagonist MF-8.

Bioorg Chem 2021 01 10;106:104466. Epub 2020 Nov 10.

Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland. Electronic address:

This study concerns synthesis and evaluation of pharmacodynamic and pharmacokinetic profile for all four stereoisomers of MF-8 (5-(4-fluorophenyl)-3-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl)-5-methylimidazolidine-2,4-dione), the previously described, highly potent 5-HTR ligand with antidepressant activity on mice. The combination of DFT calculations of H NMR chemical shifts with docking and dynamic simulations, in comparison to experimental screening results, provided prediction of the configuration for one of two present stereogenic centers. The experimental data for stereoisomers (MF-8A-MF-8D) confirmed the significant impact of stereochemistry on both, 5-HTR affinity and antagonistic action, with K and K values in the range of 3-366 nM and 0.024-99 μM, respectively. We also indicated the stereochemistry-dependent influence of the tested compounds on P-glycoprotein efflux, absorption in Caco-2 model, metabolic pathway as well as CYP3A4 and CYP2C9 activities.
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http://dx.doi.org/10.1016/j.bioorg.2020.104466DOI Listing
January 2021

The Search for New Anticonvulsants in a Group of (2,5-Dioxopyrrolidin-1-yl)(phenyl)Acetamides with Hybrid Structure-Synthesis and In Vivo/In Vitro Studies.

Int J Mol Sci 2020 Nov 20;21(22). Epub 2020 Nov 20.

Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Cracow, Poland.

Epilepsy belongs to the most common and debilitating neurological disorders with multifactorial pathophysiology and a high level of drug resistance. Therefore, with the aim of searching for new, more effective, and/or safer therapeutics, we discovered a focused series of original hybrid pyrrolidine-2,5-dione derivatives with potent anticonvulsant properties. We applied an optimized coupling reaction yielding several hybrid compounds that showed broad-spectrum activity in widely accepted animal seizure models, namely, the maximal electroshock (MES) test and the psychomotor 6 Hz (32 mA) seizure model in mice. The most potent anticonvulsant activity and favorable safety profile was demonstrated for compound (median effective dose (ED) MES = 45.6 mg/kg, ED 6 Hz (32 mA) = 39.5 mg/kg, median toxic dose (TD) (rotarod test) = 162.4 mg/kg). Anticonvulsant drugs often show activity in pain models, and compound was also proven effective in the formalin test of tonic pain, the capsaicin-induced pain model, and the oxaliplatin (OXPT)-induced neuropathic pain model in mice. Our studies showed that the most plausible mechanism of action of involves inhibition of calcium currents mediated by Cav (L-type) channels. Importantly, revealed high metabolic stability on human liver microsomes, negligible hepatotoxicity, and relatively weak inhibition of CYP3A4, CYP2D6, and CYP2C9 isoforms of cytochrome P450, compared to reference compounds. The promising in vivo activity profile and drug-like properties of compound make it an interesting candidate for further preclinical development.
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http://dx.doi.org/10.3390/ijms21228780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699745PMC
November 2020

and ADME-Tox Profiling and Safety Significance of Multifunctional Monoamine Oxidase Inhibitors Targeting Neurodegenerative Diseases.

ACS Chem Neurosci 2020 11 3;11(22):3793-3801. Epub 2020 Nov 3.

Laboratory of Medicinal Chemistry (IQOG, CSIC), C/Juan de la Cierva 3, 28006 Madrid, Spain.

Herein we report metabolic stability in human liver microsomes (HLMs), interactions with cytochrome P450 isoenzymes (CYP3A4, CYP2D6, and CYP2C9), and cytotoxicity analyses on HEK-293, HepG2, Huh7, and WTIIB cell lines of our most recent multitarget directed ligands PF9601N, ASS234, and contilisant. Based on these results, we conclude that (1) PF9601N and contilisant are metabolically stable in the HLM assay, in contrast to the very unstable ASS234; (2) CYP3A4 activity was decreased by PF9601N at all the tested concentrations and by ASS234 and contilisant only at the highest concentration; CYP2D6 activity was reduced by ASS234 at 1, 10, and 25 μM and by PF9601N at 10 and 25 μM, whereas contilisant increased its activity at the same concentrations; CYP2C9 was inhibited by the three compounds; (3) contilisant did not affect cell viability in the widest range of concentrations: up to 10 μM on HEK-293 cells, up to 30 μM on Huh7 cells, up to 50 μM on HepG2 cells, and up to 30 or 100 μM on WTIIB cells. Based on these results, we selected contilisant as a metabolically stable and nontoxic lead compound for further studies in Alzheimer's disease therapy.
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http://dx.doi.org/10.1021/acschemneuro.0c00489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677930PMC
November 2020

Eosinophils adhesion assay as a tool for phenotypic drug screening - The pharmacology of 1,3,5 - Triazine and 1H-indole like derivatives against the human histamine H receptor.

Eur J Pharmacol 2021 Jan 2;890:173611. Epub 2020 Oct 2.

Jagiellonian University Medical College, Faculty of Pharmacy, Department of Technology and Biotechnology of Drugs, Medyczna 9, 30-688, Kraków, Poland. Electronic address:

Histamine is a pleiotropic biogenic amine, having affinity towards four distinct histamine receptors. The existing pharmacological studies suggest the usefulness of histamine H receptor ligands in the treatment of many inflammatory and immunomodulatory diseases, including allergic rhinitis, asthma, atopic dermatitis, colitis or pruritus. Up to date, several potent histamine H receptor ligands were developed, none of which was registered as a drug yet. In this study, a series of potent indole-like and triazine derivatives were tested, in radioligand displacement and functional assays at histamine H receptor, as well as in human eosinophils adhesion assay to endothelium. For selected compounds permeability, cytotoxicity, metabolic and in vivo studies were conducted. Adhesion assay differentiated the activity of different groups of compounds with a known affinity towards the histamine H receptor. Most of the tested compounds downregulated the number of adherent cells. However, adhesion assay revealed additional properties of tested compounds that had not been detected in radioligand displacement and aequorin-based functional assays. Furthermore, for some tested compounds, these abnormal effects were confirmed during the in vivo studies. In conclusion, eosinophils adhesion assay uncovered pharmacological activity of histamine H receptor ligands that has been later confirmed in vivo, underscoring the value of well-suited cell-based phenotypic screening approach in drug discovery.
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http://dx.doi.org/10.1016/j.ejphar.2020.173611DOI Listing
January 2021

KA-104, a new multitargeted anticonvulsant with potent antinociceptive activity in preclinical models.

Epilepsia 2020 10 14;61(10):2119-2128. Epub 2020 Sep 14.

Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Cracow, Poland.

Objective: The main objective of the present work was to assess the utility of KA-104 as potential therapy for drug-resistant seizures and neuropathic pain, and to characterize its druglike properties in a series of absorption, distribution, metabolism, excretion and toxicity (ADME-Tox) studies. We also aimed to establish its mechanism of action in electrophysiological studies.

Methods: The activity of KA-104 against drug-resistant seizures was tested in the mouse 6-Hz (44-mA) model, whereas the antinociceptive activity was assessed with the capsaicin- and oxaliplatin-induced pain models in mice. The patch-clamp technique was used to study the influence of KA-104 on fast voltage-gated sodium currents in rat prefrontal cortex pyramidal neurons. The pharmacokinetic profile was determined after intraperitoneal (ip) injection in mice. The in vitro ADME-Tox properties were studied by applying routine testing procedures.

Results: KA-104 was effective in the 6-Hz (44-mA) model (median effective dose [ED ] = 73.2 mg/kg) and revealed high efficacy in capsaicin-induced neurogenic pain as well as in oxaliplatin-induced neuropathic pain in mice. Patch-clamp technique showed that KA-104 reversibly inhibits voltage-gated sodium currents. KA-104 was rapidly absorbed after the ip injection and showed relatively good penetration through the blood-brain barrier. This molecule was also characterized by high passive permeability, moderate influence on CYP2C9, and negligible hepatotoxicity on HepG2 cells.

Significance: The results reported herein indicate that KA-104 is a new wide-spectrum multitargeted anticonvulsant with favorable in vitro ADME-Tox properties. Importantly, this compound may also prove to become an interesting and hopefully more effective therapeutic option for treatment of neuropathic pain.
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http://dx.doi.org/10.1111/epi.16669DOI Listing
October 2020

Aminotriazines with indole motif as novel, 5-HT receptor ligands with atypical binding mode.

Bioorg Chem 2020 11 2;104:104254. Epub 2020 Sep 2.

Faculty of Chemical Engineering and Technology, Institute of Organic Chemistry and Technology, Cracow University of Technology, 24 Warszawska Street, 31-155 Kraków, Poland.

Developing new and selective 5-HTR ligands may have a key impact on the treatment of central nervous system diseases including depression. We have found that indoleaminotriazine core fused with alkyl aryl moiety exhibits high affinity and selectivity to 5-HTR. SAR analysis demonstrated that the ethyl or ethoxy group (5c 5-HTR K = 8 nM; 5d 5-HTR K = 55 nM) is the optimal carbon linker between triazine and aryl moiety. The results of the molecular dynamics simulations show stable interaction with E7.34 upon binding to a 5-HTR. Compounds 5c and 5d were tested for early ADMET parameters. Compounds are not hepatotoxic and exhibit moderate potential interaction with other drugs metabolized by CYP3A4 or CYP2D6.
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http://dx.doi.org/10.1016/j.bioorg.2020.104254DOI Listing
November 2020

Discovery of Novel pERK1/2- or β-Arrestin-Preferring 5-HT Receptor-Biased Agonists: Diversified Therapeutic-like versus Side Effect Profile.

J Med Chem 2020 10 23;63(19):10946-10971. Epub 2020 Sep 23.

Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.

Novel 1-(1-benzoylpiperidin-4-yl)methanamine derivatives with high affinity and selectivity for serotonin 5-HT receptors were obtained and tested in four functional assays: ERK1/2 phosphorylation, adenylyl cyclase inhibition, calcium mobilization, and β-arrestin recruitment. Compounds and (2-methylaminophenoxyethyl and 2-(1-indol-4-yloxy)ethyl derivatives, respectively) were selected as biased agonists with highly differential "signaling fingerprints" that translated into distinct profiles. , showed biased agonism for ERK1/2 phosphorylation and, , it preferentially exerted an antidepressant-like effect in the Porsolt forced swimming test in rats. In contrast, compound exhibited a first-in-class profile: it preferentially and potently activated β-arrestin recruitment and potently elicited lower lip retraction , a component of "serotonergic syndrome". Both compounds showed promising developability properties. The presented 5-HT receptor-biased agonists, preferentially targeting various signaling pathways, have the potential to become drug candidates for distinct central nervous system pathologies and possessing accentuated therapeutic activity and reduced side effects.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586344PMC
October 2020

Rational design of new multitarget histamine H receptor ligands as potential candidates for treatment of Alzheimer's disease.

Eur J Med Chem 2020 Dec 21;207:112743. Epub 2020 Aug 21.

Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna Str. 9, 30-688, Kraków, Poland.

Design and development of multitarget-directed ligands (MTDLs) has become a very important approach in the search of new therapies for Alzheimer's disease (AD). In our present research, a number of xanthone derivatives were first designed using a pharmacophore model for histamine H receptor (HR) antagonists/inverse agonists, and virtual docking was then performed for the enzyme acetylcholinesterase. Next, 23 compounds were synthesised and evaluated in vitro for human HR (hHR) affinity and inhibitory activity on cholinesterases. Most of the target compounds showed hHR affinities in nanomolar range and exhibited cholinesterase inhibitory activity with IC values in submicromolar range. Furthermore, the inhibitory effects of monoamine oxidases (MAO) A and B were investigated. The results showed low micromolar and selective human MAO B (hMAO B) inhibition. Two azepane derivatives, namely 23 (2-(5-(azepan-1-yl)pentyloxy)-9H-xanthen-9-one) and 25 (2-(5-(azepan-1-yl)pentyloxy)-7-chloro-9H-xanthen-9-one), were especially very promising and showed high affinity for hHR (K = 170 nM and 100 nM respectively) and high inhibitory activity for acetylcholinesterase (IC = 180 nM and 136 nM respectively). Moreover, these compounds showed moderate inhibitory activity for butyrylcholinesterase (IC = 880 nM and 394 nM respectively) and hMAO B (IC = 775 nM and 897 nM respectively). Furthermore, molecular docking studies were performed for hHR, human cholinesterases and hMAO B to describe the mode of interactions with these biological targets. Next, the two most promising compounds 23 and 25 were selected for in vivo studies. The results showed significant memory-enhancing effect of compound 23 in dizocilpine-induced amnesia in rats in two tests: step-through inhibitory avoidance paradigm (SIAP) and transfer latency paradigm time (TLPT). In addition, favourable analgesic effects of compound 23 were observed in neuropathic pain models. Therefore, compound 23 is a particularly promising structure for further design of new MTDLs for AD.
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http://dx.doi.org/10.1016/j.ejmech.2020.112743DOI Listing
December 2020

N-Substituted piperazine derivatives as potential multitarget agents acting on histamine H receptor and cancer resistance proteins.

Bioorg Med Chem Lett 2020 11 29;30(22):127522. Epub 2020 Aug 29.

Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, Kraków 30-688, Poland.

Taking into account that multidrug resistance (MDR) is the main cause for chemotherapeutic failure in cancer treatment, the ability of novel histamine H receptor ligands to reverse the cancer MDR was evaluated, using the ABCB1 efflux pump inhibition assay in mouse MDR T-lymphoma cells. The most active compounds displayed significant cytotoxic and antiproliferative effects as well as a very potent MDR efflux pump inhibitory action, 3-5-fold stronger than that of reference inhibitor verapamil. Although these compounds possess weak antagonistic properties against histamine H receptors, they are valuable pharmacological tools in the search for novel anticancer molecules. Furthermore, for the most active compounds, an insight into mechanisms of action using either, the luminescent Pgp-Glo™ Assay in vitro or docking studies to human Pgp, was performed.
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http://dx.doi.org/10.1016/j.bmcl.2020.127522DOI Listing
November 2020

Phenylpiperazine 5,5-Dimethylhydantoin Derivatives as First Synthetic Inhibitors of Msr(A) Efflux Pump in .

Molecules 2020 Aug 20;25(17). Epub 2020 Aug 20.

Department of Technology and Biotechnology of Drugs, Jagiellonian University, Medical College, ul. Medyczna 9, 30-688 Krakow, Poland.

Herein, 15 phenylpiperazine 3-benzyl-5,5-dimethylhydantoin derivatives (-) were screened for modulatory activity towards Msr(A) efflux pump present in bacteria. Synthesis, crystallographic analysis, biological studies in vitro and structure-activity relationship (SAR) analysis were performed. The efflux pump inhibitory (EPI) potency was determined by employing ethidium bromide accumulation assay in both Msr(A) efflux pump overexpressed (K/14/1345) and deficient (ATCC 12228) strains. The series of compounds was also evaluated for the capacity to reduce the resistance of K/14/1345 strain to erythromycin, a known substrate of Msr(A). The study identified five strong modulators for Msr(A) in . The 2,4-dichlorobenzyl-hydantoin derivative was found as the most potent EPI, inhibiting the efflux activity in K/14/1345 at a concentration as low as 15.63 µM. Crystallography-supported SAR analysis indicated structural properties that may be responsible for the activity found. This study identified the first synthetic compounds able to inhibit Msr(A) efflux pump transporter in . Thus, the hydantoin-derived molecules found can be an attractive group in search for antibiotic adjuvants acting via Msr(A) transporter.
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http://dx.doi.org/10.3390/molecules25173788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7503621PMC
August 2020

Chlorine substituents and linker topology as factors of 5-HTR activity for novel highly active 1,3,5-triazine derivatives with procognitive properties in vivo.

Eur J Med Chem 2020 Oct 6;203:112529. Epub 2020 Jul 6.

Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University, Medical College, Medyczna 9, PL 30-688, Kraków, Poland. Electronic address:

In the light of recent lines of evidence, 5-HTR ligands are a promising tool for future treatment of memory impairment. Hence, this study has supplied highly potent 5-HTR agents with procognitive effects, which represent an original chemical class of 1,3,5-triazines, different from widely studied sulfone and indole-like 5-HTR ligands. The new compounds were rationally designed as modifications of lead, 4-(1-(2-chlorophenoxy)ethyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (1), involving an introduction of: (i) two chlorines at benzene ring and (ii) varied linkers joining the triazine ring to aromatic ethers. Synthesis, in vitro and in vivo biological tests and computer-aided SAR analysis for 19 new compounds were carried out. Most of the new triazines displayed high affinity (K < 100 nM) and selectivity towards 5-HTR, with respect to 5-HTR, 5-HTR and DR. The crystallography-supported docking studies, including quantum-polarized ligand docking (QPLD), indicated that chlorine atoms may be involved in different type of halogen bonding, however, the linker properties seem to predominately affect the 5-HTR affinity. 4-[1-(2,5-Dichlorophenoxy)propyl]-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (9), which displayed: the highest affinity (K = 6 nM), very strong 5-HTR antagonistic action (K = 27 pM), procognitive effects in vivo in novel object recognition (NOR) test in rats, a very good permeability in PAMPA model and satisfying safety in vitro, was identified as the most potent 1,3,5-triazine agent so far, useful as a new lead for further research.
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http://dx.doi.org/10.1016/j.ejmech.2020.112529DOI Listing
October 2020
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