Investigating the C2 modulation of the imidazo[1,2-a]pyrazine-based hit compound CTN1122: synthesis, in vitro antileishmanial activity, cytotoxicity and casein kinase 1 inhibition.

Our research group previously discovered CTN1122, an imidazo[1,2-a]pyrazine compound with promising antileishmanial activity against intramacrophage amastigotes of Leishmania major and L. donovani strains. CTN1122 effectively targets Leishmania casein kinase 1 (L-CK1.

Enhancing public health response: a framework for topics and sentiment analysis of COVID-19 in the UK using Twitter and the embedded topic model.

Introduction: To protect citizens during the COVID-19 pandemic unprecedented public health restrictions were imposed on everyday life in the UK and around the world. In emergencies like COVID-19, it is crucial for policymakers to be able to gauge the public response and sentiment to such measures in almost real-time and establish best practices for the use of social media for emergency response.

Methods: In this study, we explored Twitter as a data source for assessing public reaction to the pandemic.

Molecular mechanisms in Alzheimer's disease and related potential treatments such as structural target convergence of antibodies and simple organic molecules.

The amyloid cascade is the most frequently accepted hypothesis of Alzheimer's Disease (AD). According to this hypothesis, the formation of plaques precedes the appearance of fibrillary tangles. Therapeutic agents able to inhibit the formation of plaques are therefore considered as potential disease-modifying treatments (DMT) that could prevent or limit the progression of AD.

In vitro identification of imidazo[1,2-a]pyrazine-based antileishmanial agents and evaluation of L. major casein kinase 1 inhibition.

Leishmaniasis constitutes a severe public health problem, with an estimated prevalence of 12 million cases. This potentially fatal disease has a worldwide distribution and in 2012, the fatal Visceral Leishmaniasis (VL) was declared as new emerging disease in Europe, mainly due to global warming, with expected important public health impact. The available treatments are toxic, costly or lead to parasite resistance, thus there is an urgent need for new drugs with new mechanism of action.

Synthesis and Antimalarial Activity of 1,4-Disubstituted Piperidine Derivatives.

In order to prepare, at low cost, new compounds active against , and with a less side-effects, we have designed and synthesized a library of 1,4-disubstituted piperidine derivatives from 4-aminopiperidine derivatives . The resulting compound library has been evaluated against chloroquine-sensitive (3D7) and chloroquine-resistant (W2) strains of The most active molecules-compounds (13.64 nM (3D7)), (4.

GDP-Mannose Pyrophosphorylase: A Biologically Validated Target for Drug Development Against Leishmaniasis.

Leishmaniases are neglected tropical diseases that threaten about 350 million people in 98 countries around the world. In order to find new antileishmanial drugs, an original approach consists in reducing the pathogenic effect of the parasite by impairing the glycoconjugate biosynthesis, necessary for parasite recognition and internalization by the macrophage. Some proteins appear to be critical in this way, and one of them, the GDP-Mannose Pyrophosphorylase (GDP-MP), is an attractive target for the design of specific inhibitors as it is essential for survival and it presents significant differences with the host counterpart.

In Silico Drug-Target Profiling.

Pharmacological science is trying to establish the link between chemicals, targets, and disease-related phenotypes. A plethora of chemical proteomics and structural data have been generated, thanks to the target-based approach that has dominated drug discovery at the turn of the century. There is an invaluable source of information for in silico target profiling.

In Silico Target Druggability Assessment: From Structural to Systemic Approaches.

This chapter will focus on today's in silico direct and indirect approaches to assess therapeutic target druggability. The direct approach tries to infer from the 3D structure the capacity of the target protein to bind small molecule in order to modulate its biological function. Algorithms to recognize and characterize the quality of the ligand interaction sites whether within buried protein cavities or within large protein-protein interface will be reviewed in the first part of the paper.

Biochemical analysis of leishmanial and human GDP-Mannose Pyrophosphorylases and selection of inhibitors as new leads.

Leishmaniases are an ensemble of diseases caused by the protozoan parasite of the genus Leishmania. Current antileishmanial treatments are limited and present main issues of toxicity and drug resistance emergence. Therefore, the generation of new inhibitors specifically directed against a leishmanial target is an attractive strategy to expand the chemotherapeutic arsenal.

Simple and efficient synthesis of 5'-aryl-5'-deoxyguanosine analogs by azide-alkyne click reaction and their antileishmanial activities.

A series of non-hydrolysable 5'-aryl substituted GDP analogs has been synthesized by reacting 5'-azido-5'-deoxyguanosine with different aryl- and benzyloxy-alkynes. Cu(I) nanoparticles in water were found to be the most efficient catalyst, producing the desired 5'-arylguanosines with good yields. The synthesized compounds were screened for in vitro antileishmanial activity against Leishmania donovani axenic amastigotes and intramacrophage amastigotes stages.

Comparative study of structural models of Leishmania donovani and human GDP-mannose pyrophosphorylases.

Leishmania is the parasite responsible for the neglected disease leishmaniasis. Its virulence and survival require biosynthesis of glycoconjugates, whose guanosine diphospho-d-mannose pyrophosphorylase (GDP-MP) is a key player. However, experimentally resolved structures of this enzyme are still lacking.

Asymmetric reduction of β-ketoesters and chiral β-iminoesters: impact of a α-quaternary stereocenter.

Diastereomeric reduction of nonactivated, hindered β-keto and chiral β-iminoesters are described. The influence of a α-stereocontrolled center on the efficiency and stereoselectivity of the reduction was studied. Reaction conditions were optimized to synthesize β-hydroxy- and β-aminoesters in good yields.

Auditory-tactile speech perception in congenitally blind and sighted adults.

The present study investigated whether manual tactile information from a speaker's face modulates the intelligibility of speech when audio-tactile perception is compared with audio-only perception. Since more elaborated auditory and tactile skills have been reported in the blind, two groups of congenitally blind and sighted adults were compared. Participants performed a forced-choice syllable decision task across three conditions: audio-only and congruent/incongruent audio-tactile conditions.

Are eyebrow movements linked to voice variations and turn-taking in dialogue? An experimental investigation.

Following our work on the relationship between eyebrow movements and the fundamental frequency of the voice, this article presents the results of a study on this phenomenon, and also on the temporal location of rapid eyebrow movements with respect to speaking turns during dialogue. We used an automatic movement-acquisition system coupled with the simultaneous, synchronized recording of the vocal production. This procedure permits an objective analysis of eyebrow movements in relation to the vocal production.

Asymmetric Michael reaction involving chiral imines/secondary enamines: stereocontrolled synthesis of 2,2-disubstituted tetrahydrothiophen-3-ones.

[reaction: see text] The asymmetric Michael reaction involving a chiral imine derived from 2-methyltetrahydrothiophenone-3-one and enantiopure (R)-1-phenylethylamine with a variety of electrophilic alkenes furnished 2,2-disubstituted tetrahydrothiophenone-3-ones with good yields and excellent stereoselectivity.

Regio- and diastereocontrolled preparative oxidation of methyloctalones by a biomimetic porphyrin catalyst.

Both enantiomers of methyloctalone were oxidized by a biomimetic manganese/porphyrin/imidazole catalytic system in order to obtain sufficient amounts of various model metabolites. The double bond proved to be less sensitive than the ring methylenes. Hydroxylation occurred mainly in the allylic position (position 8) and also at positions 7 and 6.

Stereochemical Aspects in the Asymmetric Michael Addition of Chiral Imines to Substituted Electrophilic Alkenes.

The Michael-type addition of chiral imines, derived from racemic alpha-substituted cyclanones and optically active 1-phenylethylamine, to electrophilic alkenes, in neutral conditions, constitutes one of the most efficient methods for the stereocontrolled construction of quaternary carbon centers. In order to create an additional stereogenic center at the alpha- or beta-position to the quaternary one, the behavior of a variety of alpha- and beta-substituted alkenyl acceptors was examined. In general, these additions are highly regioselective, the alkylation taking place predominantly, if not exclusively, at the more substituted alpha-side of the imine function; however, in some cases (electrophilic alkenes 28 and 49), significant amounts (10-15%) of regioisomeric adducts were obtained.