Investigation of Ln complexation by a DOTA derivative substituted by an imidazothiadiazole: synthesis, solution structure, luminescence and relaxation properties.

We investigated the coordination properties of original macrocyclic Ln complexes comprising an imidazothiadiazole heterocycle. The thermodynamic stability of the Gd complex was determined by a combination of potentiometric and photophysical measurements. The kinetic inertness was assessed in highly acidic media.

Tetrahydropyridine LIMK inhibitors: Structure activity studies and biological characterization.

LIM Kinases, LIMK1 and LIMK2, have become promising targets for the development of inhibitors with potential application for the treatment of several major diseases. LIMKs play crucial roles in cytoskeleton remodeling as downstream effectors of small G proteins of the Rho-GTPase family, and as major regulators of cofilin, an actin depolymerizing factor. In this article we describe the conception, synthesis, and biological evaluation of novel tetrahydropyridine pyrrolopyrimidine LIMK inhibitors.

Access and Modulation of Substituted Pyrrolo[3,4-]pyrazole-4,6-(2,5)-diones.

The first access to polyfunctionnalized pyrrolo[3,4-]pyrazole-4,6-(2,5)-dione derivatives is reported. The series were generated from diethyl acetylenedicarboxylate and arylhydrazines, which afforded the key intermediates bearing two functional positions. The annellation to generate the maleimide moiety of the bicycle was studied.

Development and preclinical evaluation of [F]FBVM as a new potent PET tracer for vesicular acetylcholine transporter.

Age-related neurodegenerative diseases have in common the occurrence of cognitive impairment, a highly incapacitating process that involves the cholinergic neurotransmission system. The vesicular acetylcholine transporter (VAChT) positron emission tomography (PET) tracer [F]fluoroethoxybenzovesamicol ((-)-[F]FEOBV) has recently demonstrated its high value to detect alterations of the cholinergic system in Alzheimer's disease, Parkinson's disease and dementia with Lewy body. We present here the development of the new vesamicol derivative tracer (-)-(R,R)-5-[F]fluorobenzovesamicol ((-)[F]FBVM) that we compared to (-)[F]FEOBV in the same experimental conditions.

Selection of Bis-Indolyl Pyridines and Triphenylamines as New Inhibitors of SARS-CoV-2 Cellular Entry by Modulating the Spike Protein/ACE2 Interfaces.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the infectious agent that has caused the current coronavirus disease (COVID) pandemic. Viral infection relies on the viral S (spike) protein/cellular receptor ACE2 interaction. Disrupting this interaction would lead to early blockage of viral replication.

LIM Kinases, Promising but Reluctant Therapeutic Targets: Chemistry and Preclinical Validation In Vivo.

LIM Kinases are important actors in the regulation of cytoskeleton dynamics by controlling microtubule and actin filament turnover. The signaling pathways involving LIM kinases for actin filament remodeling are well established. They are downstream effectors of small G proteins of the Rho-GTPases family and have become promising targets for the treatment of several major diseases because of their position at the lower end of these signaling cascades.

Modeling Temperature and Species Concentration Profiles on a Continuous-Flow Reactor Applied to Aldol Condensation.

This paper presents the modeling of a continuous-flow reactor used for the synthesis of organic products. The finite element method software, COMSOL Multiphysics, was used to model transport phenomena and reaction kinetics. The temperature is one of the most important kinetic factors that may modify the reaction.

Design and biological evaluation of substituted 5,7-dihydro-6-indolo[2,3-]quinolin-6-one as novel selective Haspin inhibitors.

A library of substituted indolo[2,3-]quinolone-6-ones was developed as simplified Lamellarin isosters. Synthesis was achieved from indole after a four-step pathway sequence involving iodination, a Suzuki-Miyaura cross-coupling reaction, and a reduction/lactamization sequence. The inhibitory activity of the 22 novel derivatives was assessed on Haspin kinase.

Aminations and arylations by direct C-O activation for the design of 7,8-dihydro-6-5,8-ethanopyrido[3,2-]pyrimidines.

The design of some novel disubstituted 7,8-dihydro-6-5,8-ethanopyrido[3,2-]pyrimidine derivatives is reported. The series was developed from quinuclidinone, which afforded versatile platforms bearing one lactam function in position -2 that were then used to create C-N or C-C bonds for S Ar or palladium-catalyzed cross-coupling reactions by C-O activation. The reaction conditions were optimized under microwave irradiation, and a wide range of amines or boronic acids were used to determine the scope and limitations of each method.

Synthesis of novel series of 3,5-disubstituted imidazo[1,2-] [1,2,4]thiadiazoles involving SAr and Suzuki-Miyaura cross-coupling reactions.

The first access to 3,5-disubstituted imidazo[1,2-][1,2,4]thiadiazole derivatives is reported. The series were generated from 2-mercaptoimidazole, which afforded the key intermediate bearing two functional positions. The SAr reactivity toward tosyl release at the C-3 position was investigated and a regioselective electrophilic iodination in C-5 position was performed to allow a novel C-C bond using Suzuki-Miyaura reaction.

Probe drug T-1032 N-oxygenation mediated by cytochrome P450 3A5 in human hepatocytes in vitro and in humanized-liver mice in vivo.

Polymorphic cytochrome P450 3A5 (CYP3A5) expression contributes to individual differences in the pharmacokinetics of probe drugs. The identification of suitable in vivo CYP3A5 probes would benefit drug metabolism and drug interaction studies using chimeric mice with humanized liver. In this study, we investigated the pharmacokinetic profiles of T-1032, which is known as an in vitro CYP3A5 probe substrate, using humanized-liver mice.

Design, Synthesis and SAR in 2,4,7-Trisubstituted Pyrido[3,2-]Pyrimidine Series as Novel PI3K/mTOR Inhibitors.

This work describes the synthesis, enzymatic activities on PI3K and mTOR, in silico docking and cellular activities of various uncommon 2,4,7 trisubstituted pyrido[3,2-]pyrimidines. The series synthesized offers a chemical diversity in C-7 whereas C-2 (3-hydroxyphenyl) and C-4 groups (morpholine) remain unchanged, in order to provide a better understanding of the molecular determinants of PI3K selectivity or dual activity on PI3K and mTOR. Some C-7 substituents were shown to improve the efficiency on kinases compared to the 2,4-di-substituted pyrimidopyrimidine derivatives used as references.

Design, Synthesis, In Silico and In Vitro Studies for New Nitric Oxide-Releasing Indomethacin Derivatives with 1,3,4-oxadiazole-2-thiol Scaffold.

Starting from indomethacin (IND), one of the most prescribed non-steroidal anti-inflammatory drugs (NSAIDs), new nitric oxide-releasing indomethacin derivatives with 1,3,4-oxadiazole-2-thiol scaffold (NO-IND-OXDs, ) have been developed as a safer and more efficient multitarget therapeutic strategy. The successful synthesis of designed compounds (intermediaries and finals) was proved by complete spectroscopic analyses. In order to study the interaction of NO-IND-OXDs with cyclooxygenase isoenzymes, a molecular docking study, using AutoDock 4.

Development of PET Radioligands Targeting COX-2 for Colorectal Cancer Staging, a Review of and Preclinical Imaging Studies.

Colorectal cancer (CRC) is the second most common cause of cancer death, making early diagnosis a major public health challenge. The role of inflammation in tumorigenesis has been extensively explored, and among the identified markers of inflammation, cyclooxygenase-2 (COX-2) expression seems to be linked to lesions with a poor prognosis. Until now, COX-2 expression could only be accessed by invasive methods, mainly by biopsy.

Prodromal neuroinflammatory, cholinergic and metabolite dysfunction detected by PET and MRS in the TgF344-AD transgenic rat model of AD: a collaborative multi-modal study.

Mouse models of Alzheimer's disease (AD) are valuable but do not fully recapitulate human AD pathology, such as spontaneous Tau fibril accumulation and neuronal loss, necessitating the development of new AD models. The transgenic (TG) TgF344-AD rat has been reported to develop age-dependent AD features including neuronal loss and neurofibrillary tangles, despite only expressing and mutations, suggesting an improved modelling of AD hallmarks. Alterations in neuronal networks as well as learning performance and cognition tasks have been reported in this model, but none have combined a longitudinal, multimodal approach across multiple centres, which mimics the approaches commonly taken in clinical studies.

[ F]-labeled positron emission tomography ligand for the histamine H4 receptor.

We synthesized 5-[ F]-fluoro-1H-indol-2-yl)(4-methyl-1-piperazinyl)methanone ([ F]5) via a Suzuki approach starting from a protected pinacol borane precursor followed by acidic hydrolysis of the t-Boc protecting group. The non-optimized radiochemical yield was 5.7 ± 1.

New nitric oxide-releasing indomethacin derivatives with 1,3-thiazolidine-4-one scaffold: Design, synthesis, in silico and in vitro studies.

In this study we present design and synthesis of nineteen new nitric oxide-releasing indomethacin derivatives with 1,3-thiazolidine-4-one scaffold (NO-IND-TZDs) (6a-s), as a new safer and efficient multi-targets strategy for inflammatory diseases. The chemical structure of all synthesized derivatives (intermediaries and finals) was proved by NMR and mass spectroscopic analysis. In order to study the selectivity of NO-IND-TZDs for COX isoenzymes (COX-1 and COX-2) a molecular docking study was performed using AutoDock 4.

New ibuprofen derivatives with thiazolidine-4-one scaffold with improved pharmaco-toxicological profile.

Background: Aryl-propionic acid derivatives with ibuprofen as representative drug are very important for therapy, being recommended especially for anti-inflammatory and analgesic effects. On other hand 1,3-thiazolidine-4-one scaffold is an important heterocycle, which is associated with different biological effects such as anti-inflammatory and analgesic, antioxidant, antiviral, antiproliferative, antimicrobial etc. The present study aimed to evaluated the toxicity degree and the anti-inflammatory and analgesic effects of new 1,3-thiazolidine-4-one derivatives of ibuprofen.

Neuroprotective and anti-inflammatory effects of a therapy combining agonists of nicotinic α7 and σ1 receptors in a rat model of Parkinson's disease.

To date there is no treatment able to stop or slow down the loss of dopaminergic neurons that characterizes Parkinson's disease. It was recently observed in a rodent model of Alzheimer's disease that the interaction between the a7 subtype of nicotinic acetylcholine receptor (a7-nAChR) and sigma-1 receptor (s1-R) could exert neuroprotective effects through the modulation of neuroinflammation which is one of the key components of the pathophysiology of Parkinson's disease. In this context, the aim of the present study was to assess the effects of the concomitant administration of N-(3R)-1-azabicyclo[2.

Design of new disubstituted imidazo[1,2-]pyridazine derivatives as selective Haspin inhibitors. Synthesis, binding mode and anticancer biological evaluation.

Haspin is a mitotic protein kinase required for proper cell division by modulating Aurora B kinase localisation and activity as well as histone phosphorylation. Here a series of imidazopyridazines based on the CHR-6494 and Structure Activity Relationship was established. An assessment of the inhibitory activity of the lead structures on human Haspin and several other protein kinases is presented.

Gold(I)-Catalyzed Intramolecular Hydroamination and Hydroalkoxylation of Alkynes: Access to Original Heterospirocycles.

We report here a simple and robust gold-catalyzed annulation reaction, giving - and -spirocycles in good to excellent yields. We have prepared a library of protected amines and tertiary alcohols that give, upon cyclization with alkynes, a representative set of heterospirocycles and illustrate reaction compatibility with diverse functional groups. A change in catalytic activity is possible by modifying the solvent, and two original tricyclic spirocycles were synthesized in a tandem reaction.

Longitudinal PET Imaging of α7 Nicotinic Acetylcholine Receptors with [F]ASEM in a Rat Model of Parkinson's Disease.

Purpose: The nicotinic acetylcholine alpha-7 receptors (α7R) are involved in a number of neuropsychiatric and neurodegenerative brain disorders such as Parkinson's disease (PD). However, their specific pathophysiologic roles are still unclear. In this context, we studied the evolution of these receptors in vivo by positron emission tomography (PET) imaging using the recently developed tracer 3-(1,4-diazabicyclo[3.

Bis(het)aryl-1,2,3-triazole quinuclidines as α7 nicotinic acetylcholine receptor ligands: Synthesis, structure affinity relationships, agonism activity, [F]-radiolabeling and PET study in rats.

In this paper we describe the design and synthesis of bis(Het)Aryl-1,2,3-triazole quinuclidine α7R ligands using an efficient three-step sequence including a Suzuki-Miyaura cross coupling reaction with commercially available and home-made boron derivatives. The exploration of SAR required the preparation of uncommon boron derivatives. Forty final drugs were tested for their ability to bind the target and nine of them exhibited Ki values below nanomolar concentrations.

Preparation, Characterization and Wound Healing Effects of New Membranes Based on Chitosan, Hyaluronic Acid and Arginine Derivatives.

New membranes based on chitosan and chitosan-hyaluronic acid containing new arginine derivatives with thiazolidine-4-one scaffold have been prepared using the ionic cross-linking method. The presence of the arginine derivatives with thiazolidine-4-one scaffold into the polymer matrix was proved by Fourier-transform infrared spectroscopy (FT-IR). The scanning electron microscopy (SEM) revealed a micro-porous structure that is an important characteristic for the treatment of burns, favoring the exudate absorption, the rate of colonization, the cell structure, and the angiogenesis process.