Imidazolidine-4-one derivatives in the search for novel chemosensitizers of Staphylococcus aureus MRSA : synthesis, biological evaluation and molecular modeling studies

A series of amine derivatives of 5-aromatic imidazolidine-4-ones (7–19), representing three subgroups: piperazine derivatives of 5-arylideneimidazolones (7–13), piperazine derivatives of 5-arylideneimidazolidine-2,4-dione (14–16) and primary amines of 5-naphthyl-5-methylimidazolidine-2,4-diones (17–19), was evaluated for their ability to improve antibiotics effectiveness in two strains of Gram-positive Staphylococcus aureus: ATCC 25923 (a reference strain) and MRSA (methicillin resistant S. aureus) HEMSA 5 (a resistant clinical isolate). The latter compounds (17–19) were obtained by 4-step synthesis using Bucherer-Bergs condensation, two-phase bromoalkylation and Gabriel reactions. The naphthalen derivative: (Z)-5-(naphthalen-2-ylmethylene)-2-(piperazin-1-yl)-3H-imidazol-4(5H)-one (10) was the most potent in combination with β-lactam antibiotics and ciprofloxacin against the resistant strain. The high potency to increase efficacy of oxacillin was noted for (Z)-5-(anthracen-10-ylmethylene)-2-(piperazin-1-yl)-3H-imidazol-4(5H)one (12) too. In order to explain the mechanism of action of the compounds 10 and 12, docking studies with the use of crystal structures of a penicillin binding protein (PBP2a) and MecR1 were carried out. Their outcomes suggested that the most probable mechanism of action of the active compounds is the interaction with MecR1. Molecular dynamic experiments performed for the active compounds and compound 13 (structurally similar to 12) supported this hypothesis and provided possible explanation of activity dependencies of the tested compounds in terms of the restoration of antibiotic efficacy in S. aureus MRSA HEMSA 5

Low-basicity 5-HT7 receptor agonists synthesized using the van Leusen multicomponent protocol

A series of 5-aryl-1-alkylimidazole derivatives was synthesized using the van Leusen multicomponent reaction. The chemotype is the first example of low-basicity scaffolds exhibiting high affinity for 5-HT7 receptor together with agonist function. The chosen lead compounds 3-(1-ethyl-1H-imidazol-5-yl)-5- iodo-1H-indole (AGH-107, 1o, Ki 5-HT7=6nM, EC50=19nM, 176-fold selectivity over 5-HT1AR) and 1e (5-methoxy analogue, Ki 5-HT7=30nM, EC50=60nM) exhibited high selectivity over related CNS targets, high metabolic stability and low toxicity in HEK-293 and HepG2 cell cultures. A rapid absorption to the blood, high blood-brain barrier permeation and a very high peak concentration in the brain (Cmax=2723 ng/g) were found for 1o after i.p. (5mg/kg) administration in mice. The compound was found active in novel object recognition test in mice, at 0.5, 1 and 5mg/kg. Docking to 5-HT7R homology models indicated a plausible binding mode which explain the unusually high selectivity over the related CNS targets. Halogen bond formation between the most potent derivatives and the receptor is consistent with both the docking results and SAR. 5-Chlorine, bromine and iodine substitution resulted in a 13, 27 and 89-fold increase in binding affinities, respectively, and in enhanced 5-HT1AR selectivity

Selenocompounds as Novel Antibacterial Agents and Bacterial Efflux Pump Inhibitors

Bacterial multidrug resistance is becoming a growing problem for public health, due to the development and spreading of bacterial strains resistant to antimicrobials. In this study, the antibacterial and multidrug resistance reversing activity of a series of seleno-carbonyl compounds has been evaluated. The effects of eleven selenocompounds on bacterial growth were evaluated in Staphylococcus aureus, methicillin resistant S. aureus (MRSA), Enterococcus faecalis, Escherichia coli, and Chlamydia trachomatis D. The combination effect of compounds with antibiotics was examined by the minimum inhibitory concentration reduction assay. Their efflux pump (EP) inhibitory properties were assessed using real-time fluorimetry. Relative expressions of EP and quorum-sensing genes were studied by quantitative PCR. Results showed that a methylketone selenoester had remarkable antibacterial activity against Gram-positive bacteria and potentiated the activity of oxacillin in MRSA. Most of the selenocompounds showed significant anti-chlamydial effects. The selenoanhydride and the diselenodiester were active inhibitors of the AcrAB-TolC system. Based on these results it can be concluded that this group of selenocompounds can be attractive potential antibacterials and EP inhibitors. The discovery of new derivatives with a significant antibacterial activity as novel selenocompounds, is of high impact in the fight against resistant pathogen

Structure Prediction, Evaluation, and Validation of GPR18 Lipid Receptor Using Free Programs

The GPR18 receptor, often referred to as the N-arachidonylglycine receptor, although assigned (along with GPR55 and GPR119) to the new class A GPCR subfamily-lipid receptors, officially still has the status of a class A GPCR orphan. While its signaling pathways and biological significance have not yet been fully elucidated, increasing evidence points to the therapeutic potential of GPR18 in relation to immune, neurodegenerative, and cancer processes to name a few. Therefore, it is necessary to understand the interactions of potential ligands with the receptor and the influence of particular structural elements on their activity. Thus, given the lack of an experimentally solved structure, the goal of the present study was to obtain a homology model of the GPR18 receptor in the inactive state, meeting all requirements in terms of protein structure quality and recognition of active ligands. To increase the reliability and precision of the predictions, different contemporary protein structure prediction methods and software were used and compared herein. To test the usability of the resulting models, we optimized and compared the selected structures followed by the assessment of the ability to recognize known, active ligands. The stability of the predicted poses was then evaluated by means of molecular dynamics simulations. On the other hand, most of the best-ranking contemporary CADD software/platforms for its full usability require rather expensive licenses. To overcome this down-to-earth obstacle, the overarching goal of these studies was to test whether it is possible to perform the thorough CADD experiments with high scientific confidence while using only license-free/academic software and online platforms. The obtained results indicate that a wide range of freely available software and/or academic licenses allow us to carry out meaningful molecular modelling/docking studies

Low basicity as a characteristic for atypical ligands of serotonin receptor 5-HT2

Serotonin receptors are extensively examined by academic and industrial researchers, due to their vital roles, which they play in the organism and constituting therefore important drug targets. Up to very recently, it was assumed that the basic nitrogen in compound structure is a necessary component to make it active within this receptor system. Such nitrogen interacts in its protonated form with the aspartic acid from the third transmembrane helix (D3x32) forming a hydrogen bond tightly fitting the ligand in the protein binding site. However, there are several recent studies that report strong serotonin receptor affinity also for compounds without a basic moiety in their structures. In the study, we carried out a comprehensive in silico analysis of the low-basicity phenomenon of the selected serotonin receptor ligands. We focused on the crystallized representatives of the proteins of 5-HT1B, 5-HT2A, 5-HT2B, and 5-HT2C receptors, and examined the problem both from the ligand- and structure-based perspectives. The study was performed for the native proteins, and for D3x32A mutants. The investigation resulted in the determination of nonstandard structural requirements for activity towards serotonin receptors, which can be used in the design of new nonbasic ligands

N-Substituted piperazine derivatives as potential multitarget agents acting on histamine H3 receptor and cancer resistance proteins

Taking into account that multidrug resistance (MDR) is the main cause for chemotherapeutic failure in cancer treatment, the ability of novel histamine H3 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 H3 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. © 2020 Elsevier Lt

N-skatyltryptamines - dual 5-HT6R/D2R ligands with antipsychotic and procognitive potential

A series of N-skatyltryptamines was synthesized and their affinities for serotonin and dopamine receptors were determined. Compounds exhibited activity toward 5-HT(1A), 5-HT(2A), 5-HT(6), and D(2) 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(2) receptor antagonists with additional 5-HT(6)R 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-HT(6)R antagonists have been shown previously to produce procognitive and promnesic effects in several rodent models. Administration of 5-HT(6)R 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 15 and 18, we tried to sort out the difference between ligands exhibiting the D(2)R antagonist function combined with 5-HT(6)R agonism, and mixed D(2)/5-HT(6)R antagonists in murine models of psychosis