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The serotonin type 6 receptor (5-HT 6 R) displays a strong constitutive activity, suggesting it participates largely in the physiological and pathological processes controlled by the receptor. The active states of 5-HT 6 R engage particular signal transduction pathways that lead to different biological responses. In this study, we present the development of 5-HT 6 R neutral antagonists at Gs signaling built upon the 2-phenylpyrrole scaffold. Using molecular dynamics simulations, we outline the relationship between the exposure of the basic center of the molecules and their ability to target the agonist-activated state of the receptor. Our study identifies compound 30 as a potent and selective neutral antagonist at 5-HT 6 R-operated Gs signaling. Furthermore, we demonstrate the cytoprotective effects of 30 and structurally diverse 5-HT 6 R neutral antagonists at Gs signaling in C8-D1A cells and human astrocytes exposed to rotenone. This effect is not observed for 5-HT 6 R agonists or inverse agonists. In light of these findings, we propose compound 30 as a valuable molecular probe to study the biological effects associated with the agonist-activated state of 5-HT 6 R and provide insight into the glioprotective properties of 5-HT 6 R neutral antagonists at Gs signaling., Competing Interests: Declaration of competing interest All authors disclose no financial or personal relationships that may be perceived as influencing their work., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The alarming increase in the resistance of bacteria to the currently available antibiotics necessitates the development of new effective antimicrobial agents that are active against bacterial pathogens causing major public health problems. For this purpose, our in-house libraries were screened against a wide panel of clinically relevant Gram-positive and Gram-negative bacteria, based on which compound I was selected for further optimization. Synthetic efforts in a group of arylurea derivatives of aryloxy(1-phenylpropyl) alicyclic diamines, followed with an in vitro evaluation of the activity against multidrug-resistant strains identified compound 44 (1-(3-chlorophenyl)-3-(1-{3-phenyl-3-[3-(trifluoromethyl)phenoxy] propyl}piperidin-4-yl)urea). Compound 44 showed antibacterial activity against Gram-positive bacteria including fatal drug-resistant strains i.e., Staphylococcus aureus (methicillin-resistant, MRSA; vancomycin-intermediate, VISA) and Enterococcus faecium (vancomycin-resistant, VREfm) at low concentrations (0.78-3.125 μg/mL) comparable to last resort antibiotics (i.e., vancomycin and linezolid). It is also potent against biofilm-forming S. aureus and Staphylococcus epidermidis (including linezolid-resistant, LRSE) strains, but with no activity against Gram-negative bacteria (Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa). Compound 44 showed strong bactericidal properties against susceptible and drug-resistant Gram-positive bacteria. Depolarization of the bacterial cytoplasmic membrane induced by compound 44 suggests a dissipation of the bacterial membrane potential as its mechanism of antibacterial action. The high antimicrobial activity of compound 44, along with its selectivity over mammalian cells (lung MCR-5 and skin BJ fibroblast cell lines) and no hemolytic properties toward horse erythrocytes, proposes arylurea derivatives of aryloxy(1-phenylpropyl) alicyclic diamines for development of novel antibacterial agents., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Masson SAS.)

The incorporation of the fluorine motif is a strategy widely applied in drug design for modulating the activity, physicochemical parameters, and metabolic stability of chemical compounds. In this study, we attempted to reduce the affinity for ether-à-go-go-related gene (hERG) channel by introducing fluorine atoms in a group of 1H-pyrrolo[3,2-c]quinolines that are capable of inhibiting monoamine oxidase type B (MAO-B). A series of structural modifications guided by in vitro evaluation of MAO-B inhibition and antitargeting for hERG channels were performed, which led to the identification of 1-(3-chlorobenzyl)-4-(4,4-difluoropiperidin-1-yl)-1H-pyrrolo[3,2-c]quinoline (26). Compound 26 acted as a reversible MAO-B inhibitor exhibiting selectivity over 45 targets, enzymes, transporters, and ion channels, and showed potent glioprotective properties in cultured astrocytes. In addition, the compound demonstrated good metabolic stability in rat liver microsomes assay, a favorable safety profile, and brain permeability. It also displayed procognitive effects in the novel object recognition test in rats and antidepressant-like activity in forced swim test in mice. The findings of the study suggest that reversible MAO-B inhibitors can have potential therapeutic applications in Alzheimer's disease., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The 5-HT 1A receptors are an important biological target in the treatment of CNS diseases. Recently, their importance in the context of non-CNS disease entities has also been postulated. In the light of these reports, we designed a new group of urea derivatives of N-aryl-N'-aryl-/(thio)ureido-/sulfamoylamino-derivatives of alkyl/alkylcarbamoyl piperazines as 5-HT 1A R ligands, focusing on increasing receptor selectivity. We made structural modifications in three areas of the molecule. In the course of our research, we obtained a ligand with reduced basicity (6f), which, despite the loss of the protonable nitrogen atom, did not lose its affinity for the 5-HT 1A R (K i  = 35 nM) with a simultaneous increase in selectivity. In particular, a decrease in affinity for D 2 R (K i  = 1940 nM) was observed, which was analyzed using molecular modeling methods, including FMO and molecular dynamics. Basic ADME-Tox parameters were characterized for 6f, confirming its potential applicability in pharmacotherapy., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Przemyslaw Zareba reports financial support was provided by National Center for Research and Development. Przemyslaw Zareba reports financial support was provided by Polish Ministry of Science and Higher Education. Przemyslaw Zareba reports computing resources provided by AGH University of Science and Technology Academic Computer Centre CYFRONET., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Herein, we describe the rapid synthesis of a focused library of trisubstituted imidazo[4,5-b]pyridines and imidazo[4,5-c]pyridines from 2,4-dichloro-3-nitropyridine using the combination of solution-phase/solid-phase chemistry as new potential anti-inflammatory agents in the treatment of autoimmune diseases. Structure-activity relationship studies, followed by the structure optimization, provided hit compounds (17 and 28) which inhibited phosphodiesterase 4 (PDE4) with IC 50 values comparable to rolipram and displayed different inhibitory potency against phosphodiesterase 7 (PDE7). Among them, compound 17 showed a beneficial effect in all the studied animal models of inflammatory and autoimmune diseases (concanavalin A-induced hepatitis, lipopolysaccharide-induced endotoxemia, collagen-induced arthritis, and MOG 35-55 -induced encephalomyelitis). In addition, compound 17 showed a favorable pharmacokinetic profile after intraperitoneal administration; it was characterized by a fast absorption from the peritoneal cavity and a relatively long terminal half-life in rats. It was found to penetrate brain barrier in mice. The performed experiments sheds light on the impact of PDE7A inhibition for the efficacy of PDE4 inhibitors in these disease conditions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

The complex etiology of Alzheimer's disease has initiated a quest for multi-target ligands to address the multifactorial causes of this neurodegenerative disorder. In this context, we designed dual-acting 5-HT 6 receptor (5-HT 6 R) antagonists/MAO-B inhibitors using pharmacophore hybridization strategy. Our approach involved linking priviliged scaffolds of 5-HT 6 R with aryloxy fragments derived from reversible and irreversible MAO-B inhibitors. The study identified compound 48 that acts as an inverse agonist of 5-HT 6 R at G s signaling and an irreversible MAO-B inhibitor. Compound 48 showed moderate metabolic stability in rat microsomal assay, artificial membrane permeability, no hepatotoxicity, and it was well distributed to the brain. Additionally, 48 showed glioprotective properties in a model of cultured astrocytes using 6-OHDA as the cytotoxic agent. Finally, compound 48 (MED = 1 mg/kg, p.o.) fully reversed memory deficits in the NOR task induced by scopolamine in rats. A better understanding of effects exerted by dual-acting 5-HT 6 R/MAO-B modulators may impact the future development of neurodegenerative-directed treatment strategies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

A virtual screening campaign aimed at finding structurally new compounds active at 5-HT 6 R provided a set of candidates. Among those, one structure, 4-(5-{[(2-{5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl)amino]methyl}furan-2-yl)phenol (1, 5-HT 6 R K i  = 91 nM), was selected as a hit for further optimization. As expected, the chemical scaffold of selected compound was significantly different from all the serotonin receptor ligands published to date. Synthetic efforts, supported by molecular modelling, provided 43 compounds representing different substitution patterns. The derivative 42, 4-(5-{[(2-{5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl)amino]methyl}furan-2-yl)phenol (5-HT 6 R K i  = 25, 5-HT 2A R K i  = 32 nM), was selected as a lead and showed a good brain/plasma concentration profile, and it reversed phencyclidine-induced memory impairment. Considering the unique activity profile, the obtained series might be a good starting point for the development of a novel antipsychotic or antidepressant with pro-cognitive properties., (Copyright © 2019 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

This article provides an overview of compounds based on imidazo[1,2-a]pyridine, imidazo[1,5-a]pyridine, imidazo[4,5-b]pyridine and imidazo[4,5-c]pyridine scaffolds, which act as potent ligands of diverse molecular targets localized in the central nervous system. A literature survey revealed that various imidazopyridines can be powerful modulators of several diseases associated with CNS dysfunction including Alzheimer's disease, Parkinson's disease, schizophrenia, depression or sleeping disorders. A description of target enzymes (e.g., β-secretase, γ-secretase, fatty acid amide hydrolase - FAAH, leucine-rich repeat kinase 2 - LRRK2) and selected receptors (e.g., GABA-A, histamine H 3 , serotonin 5-HT 3 , 5-HT 4 , 5-HT 6 , dopamine D 4 , adenosine A 2A , orexin), modes of action of imidazopyridine-based ligands and their therapeutic importance is discussed., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

A new strategy in the design of aminergic GPCR ligands is proposed - the use of aromatic, heterocyclic basic moieties in place of the evergreen piperazine or alicyclic and aliphatic amines. This hypothesis has been tested using a benchmark series of 5-HT 6 R antagonists obtained by coupling variously substituted 2-aminoimidazole moieties to the well established 1-benzenesulfonyl-1H-indoles, which served as the ligands cores. The crystallographic studies revealed that upon protonation, the 2-aminoimidazole fragment triggers a resonance driven conformational change leading to a form of higher affinity. This molecular switch may be responsible for the observed differences in 5-HT 6 R activity of the studied chemotypes with different amine-like fragments. Considering the multiple functionalization sites of the embedded guanidine fragment, diverse libraries were constructed, and the relationships between the structure and activity, metabolic stability, and solubility were established. Compounds from the N-(1H-imidazol-2-yl)acylamide chemotype (10a-z) exhibited high affinity for 5-HT 6 R and very high selectivity over 5-HT 1A , 5-HT 2A , 5-HT 7 and D 2 receptors (negligible binding), which was attributed to their very weak basicity. The lead compound in the series 4-methyl-5-[1-(naphthalene-1-sulfonyl)-1H-indol-3-yl]-1H-imidazol-2-amine (9i) was shown to reverse the cognitive impairment caused by the administration of scopolamine in rats indicating procognitive potential., (Copyright © 2019. Published by Elsevier Masson SAS.)

Currently used antipsychotics are characterized by multireceptor mode of action. While antagonism of dopamine D 2 receptors is responsible for the alleviation of "positive" symptoms of schizophrenia and the effects at other, particularly serotonergic receptors are necessary for their additional therapeutic effects, there is no consensus regarding an "ideal" target engagement. Here, a detailed SAR analysis in a series of 45 novel azinesulfonamides of cyclic amine derivatives, involving the aryl-piperazine/piperidine pharmacophore, central alicyclic amine and azinesulfonamide groups has led to the selection of (S)-4-((2-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)pyrrolidin-1-yl)sulfonyl)isoquinoline (62). The polypharmacology profile of 62, characterized by partial 5-HT 1A R agonism, 5-HT 2A /5-HT 7 /D 2 /D 3 R antagonism, and blockade of SERT, reduced the "positive"-like, and "negative"-like symptoms of psychoses. Compound 62 produced no catalepsy, demonstrated a low hyperprolactinemia liability and displayed pro-cognitive effects in the novel object recognition task and attentional set-shifting test. While association of in vitro features with the promising in vivo profile of 62 is still not fully established, its clinical efficacy should be verified in further stages of development., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

A small library of novel 3H-imidazo[4,5-b]pyridine and 1H-imidazo[4,5-c]pyridine derivatives was designed and synthesized as non-sulfonamide 5-HT 6 receptor ligands. In vitro evaluation allowed to identify compound 17 (2-ethyl-3-(3-fluorobenzyl)-7-(piperazin-1-yl)-3H-imidazo[4,5-b]pyridine) as potent 5-HT 6 receptor partial inverse agonist in G s signaling (K i  = 6 nM, IC 50  = 17.6 nM). Compound 17 displayed high metabolic stability, favorable cytochrome P450 isoenzyme (2D6, 3A4) profile, did not affect PgP-protein binding, without evoking mutagenic effects. It was orally bioavailable and brain penetrant. In contrast to intepirdine (SB-742457), which prevented 5-HT 6 R-elicited neurite growth and behaved as an inverse agonist of cyclin-dependent kinase 5 (Cdk5), compound 17 has no influence on neuronal differentiation. Compound 17 exerted significant pro-cognitive properties in novel object recognition (NOR) task in rats reversing both phencyclidine- and scopolamine-induced memory deficits (MED = 1 and 0.3 mg/kg, p.o, respectively). These effects were similar to those produced by intepirdine. Additionally, combination of inactive doses of compound 17 (0.1 mg/kg) and donepezil (0.3 mg/kg) produced synergistic effect to reverse scopolamine-induced memory deficits. Accordingly, investigating putative divergence between inverse agonists and neutral antagonists as cognitive enhancers in neurodegenerative and psychiatric disorders is certainly of utmost interest., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

A series of 39 arylsulfonamide/amide derivatives of (aryloxy)ethyl alkyl amines, was designed with the support of the Virtual Combinatorial Library-Virtual Screening protocol, and synthesized using solid-phase methodologies. Representative compounds were biologically evaluated for their affinity for 5-HT7Rs and for their selectivity over related 5-HTRs (5-HT1ARs, 5-HT2ARs, 5-HT6Rs), dopamine D2Rs and adrenergic α1Rs. The study identified the derivatives 27 (3-fluoro-N-{1-[2-(2-cyclopentylphenoxy)ethyl]piperidin-4-yl}-benzenesulfonamide; PZ-1417) and 35 (4-fluoro-N-(1-{2-[(propan-2-yl)phenoxy]ethyl}-8-azabicyclo[3.2.1]octan-3-yl)-benzenesulfonamide; PZ-1150) as being potent 5-HT7R antagonists with antidepressant and anxiolytic properties in the forced swim test (0.625-5 mg/kg and 0.625 mg/kg, respectively), the tail suspension test (0.625 mg/kg and 0.625 mg/kg, respectively), and in four plate test (0.625 mg/kg and 1.25-2.5 mg/kg, respectively) in mice. It has to be stressed that new compounds displayed higher activity than that of SB-269970, a reference 5-HT7R antagonist. Finally, the study provided valuable insight into the development of potential therapeutic agents for the treatment of CNS disorders., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

A 26-membered library of novel long-chain arylpiperazines, which contained primary and tertiary amides of cyclic amino acids (proline and 1,2,3,4-tetrahydroisoquinoline-3-carboxamide) in the terminal fragment was synthesized and biologically evaluated for binding affinity for 5-HT7 and 5-HT1A receptors. Docking studies confirmed advantages of Tic-amide over Pro-amide fragment for interaction with 5-HT7 receptors. Selected compounds 32 and 28, which behaved as 5-HT7Rs antagonist and 5-HT1A partial agonist, respectively, produced antidepressant-like effects in the forced swim test in mice after acute treatment in doses of 10 mg/kg (32) and 1.25 mg/kg (28). Compound 32 reduced immobility in a manner similar to the selective 5-HT7 antagonist SB-269970., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

A 47-membered library of novel long-chain arylpiperazines, which contained cyclic amino acid amides in the terminal fragment (pyrrolidine-2-carboxamide and 1,2,3,4-tetrahydroisoquinoline-3-carboxamide), was synthesized on Rink-amide resin and biologically evaluated for binding affinity for 5-HT7 and 5-HT1A receptors. Surprisingly, members of the designed series containing piperidine-2-carboxamide fragments underwent hydrolysis, which occurred during the acidic treatment for release from the solid-support, to their respective pipecolic acid analogs. Representative compounds from the library displayed high-to-low affinity for 5-HT7 (Ki = 18-3134 nM) and 5-HT1A (Ki = 0.5-6307 nM) sites. The possible interactions implicated in binding of the studied compounds to the 5-HT7 receptor were supported by molecular modeling. Research was also applied to support the exploration of the influence of the amide fragment, the length of alkylene spacer, and arylpiperazine substituents on the receptor's affinity and selectivity., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

A series of new quinoline- and isoquinoline-sulfonamide analogs of aripiprazole was synthesized to explore the influence of two structural features - replacement of ether/amide moiety with sulfonamide one, and localization of a sulfonamide group in the azine moiety. In contrast to aripiprazole, compound 33 (N-(3-(4-(2,3-dichlorophenyl)piperazin-1-yl)propyl)quinoline-7-sulfonamide) and 39 (N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)isoquinoline-3-sulfonamide) displaying multireceptor 5-HT(1A)/5-HT(2A)/5-HT(7)/D(2)/D(3) profile, and behaving as 5-HT(1A) agonists, D(2) partial agonists, and 5-HT(2A)/5-HT(7) antagonists, produced significant antidepressant activity in FST in mice. On the other hand, their 4-isoquinolinyl analog 40 (N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)isoquinoline-4-sulfonamide), with similar receptor binding and functional profile, additionally displayed remarkable antipsychotic properties in the MK-801-induced hyperlocomotor activity in mice., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

An analysis of the virtual combinatorial library was used for refining a pilot set of 34 derivatives and designing a targeted 38-member library of the arylamide and arylsulfonamide derivatives of aryloxyethyl- and arylthioethyl- piperidines and pyrrolidines. All compounds 24-95 were synthesized according to an elaborated parallel solid-phase method and were biologically evaluated for their affinity for 5-HT(7)R. Additionally, the targeted library members were tested for 5-HT(1A), 5-HT(6), and D(2) receptors. Selected compounds of particular interest were examined for their intrinsic activity at 5-HT(7)R in vitro employing a cAMP assay. The study allowed us to identify compound 68 (4-fluoro-N-(1-{2-[(propan-2-yl)phenoxy]ethyl}piperidin-4-yl) benzenesulfonamide) as a potent 5-HT(7)R ligand (K(i) = 0.3 nM) with strong antagonistic properties (K(b) = 1 nM) and a 1450-fold selectivity over 5-HT(1A)Rs., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

A library of ethylene analogs of the previously described arylpiperazines with N-acylated amino acids was synthesized on SynPhase Lanterns and the library representatives were evaluated for their 5-HT(1A) and 5-HT(2A) receptor affinities. The obtained results were compared with those reported for compounds containing propylene and a butylene spacer and they revealed that 5-HT(1A) receptor affinity decreased proportionally with the length of the alkyl chain. Furthermore, the synthesized 3-cycloalkyl derivatives containing two methylene group spacers showed that the 3-position of pyrrolidine-2,5-dione preferred substituents of hydrophobic character.