Non-Polio Enterovirus Inhibitors: Scaffolds, Targets, and Potency─What's New?

Enterovirus (EV) is a genus that includes a large diversity of viruses spread around the world. They are the main cause of numerous diseases with seasonal clusters, like hand-foot-mouth disease (HFMD). A vaccine is marketed in China for the prevention of HFMD caused by EV-A71.

Improving Aqueous Solubility and In Vitro Pharmacokinetic Properties of the 3-Nitroimidazo[1,2-]pyridine Antileishmanial Pharmacophore.

An antileishmanial structure−activity relationship (SAR) study focused on positions 2 and 8 of the imidazo[1,2-a]pyridine ring was conducted through the synthesis of 22 new derivatives. After being screened on the promatigote and axenic amastigote stages of Leishmania donovani and L. infantum, the best compounds were tested against the intracellular amastigote stage of L.

Stability Studies of Fludrocortisone Acetate Capsules and Fludrocortisone Acetate Titrated Powders (Powder Triturates).

Fludrocortisone acetate is a drug used to treat adrenal insufficiencies which can be prescribed to hospitalized or ambulatory pediatric patients at dosages not commercially available. For these patients, 10-µg fludrocortisone capsules are currently compounded from a pre-compounded titrated powder (powder triturate). Fludrocortisone stability studies were carried out to ensure a valid beyond-use date.

Antikinetoplastid SAR study in 3-nitroimidazopyridine series: Identification of a novel non-genotoxic and potent anti-T. b. brucei hit-compound with improved pharmacokinetic properties.

To study the antikinetoplastid 3-nitroimidazo[1,2-a]pyridine pharmacophore, a structure-activity relationship study was conducted through the synthesis of 26 original derivatives and their in vitro evaluation on both Leishmania spp and Trypanosoma brucei brucei. This SAR study showed that the antitrypanosomal pharmacophore was less restrictive than the antileishmanial one and highlighted positions 2, 6 and 8 of the imidazopyridine ring as key modulation points. None of the synthesized compounds allowed improvement in antileishmanial activity, compared to previous hit molecules in the series.

8-Alkynyl-3-nitroimidazopyridines display potent antitrypanosomal activity against both T. b. brucei and cruzi.

An antikinetoplastid pharmacomodulation study was done at position 8 of a previously identified pharmacophore in 3-nitroimidazo[1,2-a]pyridine series. Twenty original derivatives bearing an alkynyl moiety were synthesized via a Sonogashira cross-coupling reaction and tested in vitro, highlighting 3 potent (40 nM ≤ EC blood stream form≤ 70 nM) and selective (500 ≤ SI ≤ 1800) anti-T. brucei brucei molecules (19, 21 and 22), in comparison with four reference drugs.

Development and evaluation of an elective course of pharmacist's roles in disaster management in France.

Purpose: To describe Faculty of Pharmacy experience in the development of an elective course of pharmacist's roles in disaster management for third-year pharmacy students and to evaluate the effectiveness of this innovative teaching module in students' knowledge and their perception of the introduction of this specific course into their curriculum.

Methods: An expert team of physicians, surgeons and pharmacists of the Service de Santé des Armées, pharmacists teaching at the Faculty and pharmacists of Bataillon des Marins Pompiers de Marseille defined the program of a 30-hour module in disaster response in line with previously published recommendations, literature analysis and international guidelines on disaster response training. Students' knowledge of key competencies was assessed after each teaching session through a multiple-choice questionnaire.

Nongenotoxic 3-Nitroimidazo[1,2-]pyridines Are NTR1 Substrates That Display Potent Antileishmanial Activity.

Twenty nine original 3-nitroimidazo[1,2-]pyridine derivatives, bearing a phenylthio (or benzylthio) moiety at position 8 of the scaffold, were synthesized. evaluation highlighted compound as an antiparasitic hit molecule displaying low cytotoxicity for the human HepG2 cell line (CC > 100 μM) alongside good antileishmanial activities (IC = 1-2.1 μM) against , , and ; and good antitrypanosomal activities (IC = 1.

8-Aryl-6-chloro-3-nitro-2-(phenylsulfonylmethyl)imidazo[1,2-a]pyridines as potent antitrypanosomatid molecules bioactivated by type 1 nitroreductases.

Based on a previously identified antileishmanial 6,8-dibromo-3-nitroimidazo[1,2-a]pyridine derivative, a Suzuki-Miyaura coupling reaction at position 8 of the scaffold was studied and optimized from a 8-bromo-6-chloro-3-nitroimidazo[1,2-a]pyridine substrate. Twenty-one original derivatives were prepared, screened in vitro for activity against L. infantum axenic amastigotes and T.

In Vitro Screening of the Antibacterial and Anti-Candida Properties of Crushed Nonantimicrobial Drugs Frequently Prescribed in Nursing Homes.

Frail older adults often experience swallowing disorders, prompting nursing staff to crush tablets, open capsules, and mix drugs into their meals or gelled water. However, crushing drugs can lead to pharmacological and gustatory problems. As crushed drugs can stay in prolonged contact with oral microbial biofilm, the current study aimed to investigate their antimicrobial properties.

Body image and psychological distress in women with breast cancer: a French online survey on patients' perceptions and expectations.

Background: Altered body image caused by alopecia, loss of eyebrows or eyelashes, or mastectomy is a major source of psychological distress in women with breast cancer.

Objective: To identify and to assess patients' perceptions and expectations regarding altered body image.

Method: Opinion survey conducted among patients treated for breast cancer and member of French online support groups.

Factors limiting adherence to antiepileptic treatment: A French online patient survey.

What Is Known And Objective: There are various reasons why antiepileptic treatment can fail. One is drug-resistant epilepsies, but non-adherence, or poor adherence, to treatment may make some patients' treatment ineffective. The consequences of poor adherence include treatment failure or introduction of more complex treatments involving greater toxicity with uncertain prognosis.

Discovery of new hit-molecules targeting Plasmodium falciparum through a global SAR study of the 4-substituted-2-trichloromethylquinazoline antiplasmodial scaffold.

From 4 antiplasmodial hit-molecules identified in 2-trichloromethylquinazoline series, we conducted a global Structure-Activity relationship (SAR) study involving 26 compounds and covering 5 molecular regions (I - V), aiming at defining the corresponding pharmacophore and identifying new bioactive derivatives. Thus, after studying the aniline moiety in detail, thienopyrimidine, quinoline and quinoxaline bio-isosters were synthesized and tested on the K1 multi-resistant P. falciparum strain, along with a cytotoxicity evaluation on the human HepG2 cell line, to define selectivity indecies.

[Pertinence of Off-label Prescriptions of Innovating and Expensive Drugs in a University Hospital].

Objectives: Pertinence of off-label prescriptions of innovative and expensive drugs needs a strict scientific appraisal to prevent adverse reaction risks and financial drift.

Methods: Pertinence of such prescriptions has been analyzed in a University Hospital by bibliometric methods. Scientific publications issued from this clinical activity have been also evaluated.

Antileishmanial pharmacomodulation in 8-nitroquinolin-2(1H)-one series.

An antileishmanial pharmacomodulation at position 4 of 8-nitroquinolin-2(1H)-one was conducted by using the Sonogashira and Suzuki-Miyaura coupling reactions. A series of 25 derivatives was tested in vitro on the promastigote stage of Leishmania donovani along with an in vitro cytotoxicity evaluation on the human HepG2 cell line. Only the derivatives bearing a phenyl moiety at position 4 of the quinoline ring displayed interesting biologic profile, when the phenyl moiety was substituted at the para position by a Br or Cl atom, or by a CF3 group.

Discovery of new thienopyrimidinone derivatives displaying antimalarial properties toward both erythrocytic and hepatic stages of Plasmodium.

A preliminary in vitro screening of compounds belonging to various chemical families from our library revealed the thieno[3,2-d]pyrimidin-4(3H)-one scaffold displayed a promising profile against Plasmodium falciparum. Then, 120 new derivatives were synthesized and evaluated in vitro; compared to drug references, 40 showed good activity toward chloroquine sensitive (IC50 35-344 nM) and resistant (IC50 45-800 nM) P. falciparum strains.

Looking for new antileishmanial derivatives in 8-nitroquinolin-2(1H)-one series.

From a recently identified antileishmanial pharmacophore, a structure-activity relationship study was conducted by introducing various aminated, phenoxy or thiophenoxy moieties at position 4 of the 8-nitroquinolin-2(1H)-one scaffold, using SNAr reactions. Thus a series of 47 derivatives was synthesized and evaluated in vitro on the promastigote stage of Leishmania donovani. In parallel, the cytotoxicity of the active molecules was tested on the human HepG2 cell line.

Synthesis and in vitro evaluation of 4-trichloromethylpyrrolo[1,2-a]quinoxalines as new antiplasmodial agents.

Thanks to a preliminary in vitro screening of several CCl3-substituted-nitrogen containing heterocycles belonging to our chemical library, the 2-trichloromethylquinoxaline scaffold appeared to be of potential interest for developing new antiplasmodial agents. Then, combining these experimental results to the antimalarial properties reported for various pyrrolo[1,2-a]quinoxaline derivatives, an original series of fifteen 7-substituted-4-trichoromethylpyrrolo[1,2-a]quinoxalines was synthesized in a 4 to 5 reaction steps pathway. All molecules were evaluated in vitro toward both their antiplasmodial activity on the K1 multi-resistant Plasmodium falciparum strain and their cytotoxicity on the HepG2 human cell line.

[mediEVAL: a new evaluating tool for the medication-use system].

Purposes: A new methodology to evaluate the medication-use system based on a risk cartography tool, has been developed. This work has been promoted by the Observatoire du médicament et des dispositifs médicaux stériles et de l'innovation thérapeutique (OMEDIT) from Provence-Alpes-Côte d'Azur (PACA)-Corse regions.

Methods: This new methodology has been developed with Excel (Microsoft(®)) and has led to the mediEVAL tool.

Targeting the human parasite Leishmania donovani: discovery of a new promising anti-infectious pharmacophore in 3-nitroimidazo[1,2-a]pyridine series.

We report herein the discovery of antileishmanial molecules based on the imidazo[1,2-a]pyridine ring. In vitro screenings of imidazopyridines belonging to our chemical library, toward the promastigotes stage of Leishmania donovani, J774A.1 murine and HepG2 human cells, permitted to identify three selective hit-compounds (12, 20 and 28).

Efficacy and toxicity of factor Xa inhibitors.

Venous thromboembolism (VTE) is a serious disease that is often neglected, and effective and safe antithrombotic treatments are a public health priority. New antithrombotics such as rivaroxaban, apixaban, betrixaban, edoxaban, darexaban, TAK-442, LY517717, eribaxaban, otamixaban are being developed to overcome current therapeutic limitations. The new oral anticoagulants and parenteral otamixaban are under evaluation in clinical trials for VTE treatment, for VTE prevention in orthopedic surgery, for stroke prevention in patients with atrial fibrillation and for cardiovascular event prevention in patients with acute coronary syndrome.

Synthesis and promising in vitro antiproliferative activity of sulfones of a 5-nitrothiazole series.

 The synthesis in water of new sulfone derivatives under microwave irradiation is described. This eco-friendly process leads to the expected products in good yields by reaction of various substituted sulfinates (commercially available or obtained by reduction of the corresponding sulfonyl chlorides) with 4-chloromethyl-2-methyl-5-nitro-1,3-thiazole. In order to evaluate the antiproliferative effect of these compounds, several sulfone derivatives are also dichlorinated on the Cα next to the sulfonyl group.

[Targeted based therapies in metastatic breast cancer: future evolution].

Research on molecular alteration process mechanisms leading to cancerogenesis permitted the elaboration of many targeted therapies. Some therapeutic classes appeared recently and are currently being tested, including HER-2 dimerization inhibitors. However, most of these therapies are mostly ineffective with monotherapy.

Tandem synthesis and in vitro antiplasmodial evaluation of new naphtho[2,1-d]thiazole derivatives.

A series of naphtho[2,1-d]thiazoles was prepared in good yields under microwave irradiation with an original protocol combining tandem direct arylation and intramolecular Knoevenagel reaction on 1,3-thiazole derivatives. Antiplasmodial evaluation of this series highlighted two hit compounds (compounds 11 and 13) displaying promising in vitro activity on the multiresistant K1 Plasmodium falciparum strain. Structure-toxicity and structure-activity relationships are also discussed and reveal the importance of the R(1) and R(4) substituents of the naphthyl moiety for the biological profile of the series.

A new synthetic route to original sulfonamide derivatives in 2-trichloromethylquinazoline series: a structure-activity relationship study of antiplasmodial activity.

We report herein a simple and efficient two-step synthetic approach to new 2-trichloromethylquinazolines possessing a variously substituted sulfonamide group at position 4 used to prepare new quinazolines with antiparasitic properties. Thus, an original series of 20 derivatives was synthesized, which proved to be less-toxic than previously synthesized hits on the human HepG2 cell line, but did not display significant antiplasmodial activity. A brief Structure-Activity Relationship (SAR) evaluation shows that a more restricted conformational freedom is probably necessary for providing antiplasmodial activity.