A One-Step, Versatile Synthesis of Dibenzo [n.2.2] Macrobicyclic Compounds via a Conformation-Directed Macrocyclization Reaction

A series of dibenzo [n.2.2] bicyclic compounds (n = 2–20) were prepared in one step and good yields starting from dimethyl anthracene-9,10-dicarboxylate. Reduction of the aromatic diester using lithium/naphthalene led to a bis-enolate that was cyclized with a variety of bis-electrophiles. The ease of the cyclization is probably due to the puckered conformation of the intermediate formed after the first alkylation step, in which the newly introduced chain that will become the bridge portion occupies a pseudoaxial position, positioning the leaving group close to the enolate nucleophile in the macrocyclization stepThis work was supported by the Ministerio de Economía y Competitividad of Spain (CTQ2011-22436) and Xunta de Galicia (PGIDIT10-PXIB209113PR, 10PXIB209155PR, and 2007/085)S

Pharmacological insights emerging from the characterization of a large collection of synthetic cannabinoid receptor agonists designer drugs

Synthetic cannabinoid receptor agonists (SCRAs) constitute the largest and most defiant group of abuse designer drugs. These new psychoactive substances (NPS), developed as unregulated alternatives to cannabis, have potent cannabimimetic effects and their use is usually associated with episodes of psychosis, seizures, dependence, organ toxicity and death. Due to their ever-changing structure, very limited or nil structural, pharmacological, and toxicological information is available to the scientific community and the law enforcement offices. Here we report the synthesis and pharmacological evaluation (binding and functional) of the largest and most diverse collection of enantiopure SCRAs published to date. Our results revealed novel SCRAs that could be (or may currently be) used as illegal psychoactive substances. We also report, for the first time, the cannabimimetic data of 32 novel SCRAs containing an (R) configuration at the stereogenic center. The systematic pharmacological profiling of the library enabled the identification of emerging Structure-Activity Relationship (SAR) and Structure-Selectivity Relationship (SSR) trends, the detection of ligands exhibiting incipient cannabinoid receptor type 2 (CB2R) subtype selectivity and highlights the significant neurotoxicity of representative SCRAs on mouse primary neuronal cells. Several of the new emerging SCRAs are currently expected to have a rather limited potential for harm, as the evaluation of their pharmacological profiles revealed lower potencies and/or efficacies. Conceived as a resource to foster collaborative investigation of the physiological effects of SCRAs, the library obtained can contribute to addressing the challenge posed by recreational designer drugsThis work was financially supported by the Consellería de Cultura, Educación e Ordenación Universitaria of the Galician Government: (grant: ED431B 2020/43), Centro Singular de Investigación de Galicia accreditation 2019–2022 (ED431G 2019/03), Ministerio de Ciencia e Innovación (PID2020-113430RB-I00) and the European Regional Development Fund (ERDF)S

Computer-Aided Structure-Based Design of Multitarget Leads for Alzheimer’s Disease

Alzheimer’s disease is a neurodegenerative pathology with unmet clinical needs. A highly desirable approach to this syndrome would be to find a single lead that could bind to some or all of the selected biomolecules that participate in the amyloid cascade, the most accepted route for Alzheimer disease genesis. In order to circumvent the challenge posed by the sizable differences in the binding sites of the molecular targets, we propose a computer-assisted protocol based on a pharmacophore and a set of required interactions with the targets that allows for the automated screening of candidates. We used a combination of docking and molecular dynamics protocols in order to discard nonbinders, optimize the best candidates, and provide a rationale for their potential as inhibitors. To provide a proof of concept, we proceeded to screen the literature and databases, a task that allowed us to identify a set of carbazole-containing compounds that initially showed affinity only for the cholinergic targets in our experimental assays. Two cycles of design based on our protocol led to a new set of analogues that were synthesized and assayed. The assay results revealed that the designed inhibitors had improved affinities for BACE-1 by more than 3 orders of magnitude and also displayed amyloid aggregation inhibition and affinity for AChE and BuChE, a result that led us to a group of multitarget amyloid cascade inhibitors that also could have a positive effect at the cholinergic levelFinancial support from the Ministerio de Economia y Competitividad of Spain (Project CTQ2011-22436) and the Xunta de Galicia (CN2011/047 and 10CSA209063PR) is gratefully acknowledgedS

8‐Aminomethyl‐7‐hydroxy‐4‐methylcoumarins as Multitarget Leads for Alzheimer's Disease

This is the peer reviewed version of the following article: Domínguez, J., Fernández-Nieto, F., Brea, J., Catto, M., Paleo, M., & Porto, S. et al. (2016). 8-Aminomethyl-7-hydroxy-4-methylcoumarins as Multitarget Leads for Alzheimer's Disease. Chemistryselect, 1(11), 2742-2749, which has been published in final form at https://doi.org/10.1002/slct.201600735. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived VersionsThis work is part of our ongoing research in the discovery of multitarget therapeutic agents for Alzheimer's disease (AD). A literature screening, based on our recently proposed pharmacophore, led to the identification of 8‐aminomethyl‐7‐hydroxy‐4‐methyl coumarins as potential multitarget leads for AD. The results of a computer‐assisted protocol developed by us to validate multitarget hits for AD indicated that our coumarin candidates were viable leads only for AChE inhibition as later validated by biological assays. The results of BChE binding and propidium displacement assays indicate that our first generation compounds bind to the PAS site in AChE. We designed new generations of coumarin derivatives with a longer substituent at position 8 aimed at leads with more efficient interaction at the catalytic anionic site (CAS). Inhibition data and docking simulations indicated that an anilino‐capping group reached the CAS region of AChE and determined also a higher inhibitory potency towards BChE. The best compound obtained, with a N‐benzylpiperidine fragment, displayed sub‐micromolar affinity for AChE, affinity for BChE, and precluded Aβ‐amyloid aggregation with a potency similar to that of 9,10‐anthraquinone, making it a multitarget lead viable for further improvementFinancial support from the Ministerio de Economia y Competitividad of Spain (Project CTQ2014‐55208‐P) and the Xunta de Galicia (10CSA209063PR and GRC2014/029) is gratefully acknowledged. The Italian authors thank the University of Bari for partial financial support (Fondi di Ateneo 2014–2015)S

Exploring Biginelli-based scaffolds as A2B adenosine receptor antagonists: Unveiling novel structure-activity relationship trends, lead compounds, and potent colorectal anticancer agents

Antagonists of the A(2B) adenosine receptor have recently emerged as targeted anticancer agents and immune checkpoint inhibitors within the realm of cancer immunotherapy. This study presents a comprehensive evaluation of novel Biginelli-assembled pyrimidine chemotypes, including mono-, bi-, and tricyclic derivatives, as A(2B)AR antagonists. We conducted a comprehensive examination of the adenosinergic profile (both binding and functional) of a large compound library consisting of 168 compounds. This approach unveiled original lead compounds and enabled the identification of novel structure-activity relationship (SAR) trends, which were supported by extensive computational studies, including quantum mechanical calculations and free energy perturbation (FEP) analysis. In total, 25 molecules showed attractive affinity (K-i < 100 nM) and outstanding selectivity for A(2B)AR. From these, five molecules corresponding to the new benzothiazole scaffold were below the K-i < 10 nM threshold, in addition to a novel dual A(2A)/A(2B) antagonist. The most potent compounds, and the dual antagonist, showed enantiospecific recognition in the A(2B)AR. Two A(2B)AR selective antagonists and the dual A(2A)AR/A(2B)AR antagonist reported in this study were assessed for their impact on colorectal cancer cell lines. The results revealed a significant and dose-dependent reduction in cell proliferation. Notably, the A(2B)AR antagonists exhibited remarkable specificity, as they did not impede the proliferation of non-tumoral cell lines. These findings support the efficacy and potential that A(2B)AR antagonists as valuable candidates for cancer therapy, but also that they can effectively complement strategies involving A(2A)AR antagonism in the context of immune checkpoint inhibition