2C protein of Enterovirus: key protein of viral replication and antiviral target.

Enteroviruses (EVs) include many human pathogens of increasing public health concern. These EVs are often associated with mild clinical manifestations, but they can lead to serious complications such as encephalitis, meningitis, pneumonia, myocarditis or poliomyelitis. Despite significant advances, there is no approved antiviral therapy for the treatment of enterovirus infections. Due to the high genotypic diversity of EVs, molecules targeting highly conserved viral proteins may be considered for developing a pan-EV treatment. In this regard, the ATPase/Helicase 2C, which is a highly conserved non-structural protein among EVs, has essential functions for viral replication and is therefore an attractive antiviral target. Recent functional and structural studies on the 2C protein led to the identification of molecules showing ex vivo anti-EV activity and associated with resistance mutations on the coding sequence of the 2C protein. This review presents the current state of knowledge about the 2C protein from an antiviral target perspective and the mode of action of specific inhibitors for this therapeutic target.

Addition of Benzyl Halides to Aldehydes and Imines Using Photoactivated TDAE: Access to 3,4-Dihydroisocoumarins, 1,2-Diarylethanols, and 1,2-Diarylcarbamates under Metal-Free Conditions.

We describe herein the intermolecular addition reaction of benzyl halides to aldehydes and imines using photoactivated tetrakis(dimethylamino)ethylene (TDAE) as superphotoreductant. 3,4-Dihydroisocoumarins, 1,2-diarylethanols, and 1,2-diarylcarbamates were obtained with good functional group tolerance using simple, mild, and metal-free conditions.

Synthesis and Anti-Trypanosoma cruzi Biological Evaluation of Novel 2-Nitropyrrole Derivatives.

Human American trypanosomiasis, called Chagas disease, caused by T. cruzi protozoan infection, represents a major public health problem, with about 7000 annual deaths in Latin America. As part of the search for new and safe anti-Trypanosoma cruzi derivatives involving nitroheterocycles, we report herein the synthesis of ten 1-substituted 2-nitropyrrole compounds and their biological evaluation. After an optimization phase, a convergent synthesis methodology was used to obtain these new final compounds in two steps from the 2-nitropyrrole starting product. All the designed derivatives follow Lipinski's rule of five. The cytotoxicity evaluation on CHO cells showed no significant cytotoxicity, except for compound 3 (CC50 = 24.3 µM). Compound 18 appeared to show activity against T. cruzi intracellular amastigotes form (EC50 = 3.6 ± 1.8 µM) and good selectivity over the vero host cells. Unfortunately, this compound 18 showed an insufficient maximum effect compared to the reference drug (nifurtimox). Whether longer duration treatments may eliminate all parasites remains to be explored.

Quinoxaline Moiety: A Potential Scaffold against Mycobacterium tuberculosis.

Background. The past decades have seen numerous efforts to develop new antitubercular agents. Currently, the available regimens are lengthy, only partially effective, and associated with high rates of adverse events. The challenge is therefore to develop new agents with faster and more efficient action. The versatile quinoxaline ring possesses a broad spectrum of pharmacological activities, ensuring considerable attention to it in the field of medicinal chemistry. Objectives. In continuation of our program on the pharmacological activity of quinoxaline derivatives, this review focuses on potential antimycobacterial activity of recent quinoxaline derivatives and discusses their structure-activity relationship for designing new analogs with improved activity. Methods. The review compiles recent studies published between January 2011 and April 2021. Results. The final total of 23 studies were examined. Conclusions. Data from studies of quinoxaline and quinoxaline 1,4-di-N-oxide derivatives highlight that specific derivatives show encouraging perspectives in the treatment of Mycobacterium tuberculosis and the recent growing interest for these scaffolds. These interesting results warrant further investigation, which may allow identification of novel antitubercular candidates based on this scaffold.

Beyond-Use Dates Assignment for Pharmaceutical Preparations: Example of Low-Dose Amiodarone Capsules.

Background: Beyond-use dates (BUDs) in compounding practice are assigned from stability studies. The United States Pharmacopoeia (USP 42 NF 37) suggested to assign a 6 months BUD for dry oral forms. A new pediatric formula of amiodarone capsules was implemented in our hospital, with 3 dosages (5 mg, 20 mg, and 50 mg). Objective: BUD of these new formulas had to be determined by stability study. Methods: The method for the determination of amiodarone content was validated to be stability indicating, and a stability study was performed. Different excipients commonly used for capsule compounding were compared. Results: We found that, with microcrystalline cellulose as excipient, 50 mg amiodarone capsules were stable for 1 year, whereas 5 mg and 20 mg capsules were not. This difference was studied, and lactose or mannitol were found to be better excipients for 5 mg amiodarone capsules, despite their potential side effects. A potential drug-excipient interaction between microcrystalline cellulose and amiodarone hydrochloride is described. Conclusion: Amiodarone hydrochloride/microcrystalline cellulose capsules have a BUD of 1 month for 5 mg capsules, 6 months for 20 mg, and 1 year for 50 mg.

Switching from Single to Simultaneous Free-Radical and Anionic Polymerization with Enamine-Based Organic Electron Donors.

Although most monomers can polymerize through different propagation pathways, polymerization-initiating systems that can switch from one mode to another are rare. In this study, we demonstrate that enamine-based organic electron donors (OEDs) constitute the first systems able to initiate either free-radical or anionic polymerization under simple, mild, and safe conditions. While direct electron-transfer reduction of monomers by OEDs results in the initiation of anionic chain-growth polymerization, introduction of a competing oxidant with a higher reduction potential than the monomer switches the former anionic propagation to a clean radical-propagation process. The benefit of this dual-mode activator is highlighted in the synthesis of an interpenetrating polymer network through simultaneous initiation of radical and anionic propagation processes.

Metal-Free Addition of Benzyl Halides to Aldehydes Using Super Electron Donors: Access to 3,4-Dihydroisocoumarins and 1,2-Diarylethanols.

We report here the intermolecular metal-free addition reaction of functionalized benzyl halides to aldehydes using a super electron donor (SED). The metal-free and mild conditions allowed the formation of 3,4-dihydroisocoumarins and 1,2-diarylethanols with unprecedented functional group tolerance.

Sequential Regioselective Diorganochalcogenations of Imidazo[1,2-a]pyrimidines Using I2/H3PO4 in Dimethylsulfoxide.

The dichalcogenation of imidazoheterocycles led to the first functionalization of imidazo[1,2-a]pyrimidine cores on the C6-position. The methodology, involving iodine/dimethylsulfoxide oxidation of diaryldichalcogenides, started with C3-chalcogenation, followed by C6 selanylation, activated in acidic medium. This novel sequential dichalcogenation strategy proceeded efficiently with excellent regioselectivity and yields.

Plasmodial Kinase Inhibitors Targeting Malaria: Recent Developments.

Recent progress in reducing malaria cases and ensuing deaths is threatened by factors like mutations that induce resistance to artemisinin derivatives. Multiple drugs are currently in clinical trials for malaria treatment, including some with novel mechanisms of action. One of these, MMV390048, is a plasmodial kinase inhibitor. This review lists the recently developed molecules which target plasmodial kinases. A systematic review of the literature was performed using CAPLUS and MEDLINE databases from 2005 to 2020. It covers a total of 60 articles and describes about one hundred compounds targeting 22 plasmodial kinases. This work highlights the strong potential of compounds targeting plasmodial kinases for future drug therapies. However, the majority of the Plasmodium kinome remains to be explored.

A Survey of Synthetic Routes and Antitumor Activities for Benzo[g]quinoxaline-5,10-diones.

Anthracycline antibiotics play an important role in cancer chemotherapy. The need to improve their therapeutic index has stimulated an ongoing search for anthracycline analogs with enhanced properties. This review aims to summarize the common synthetic approaches to benzo[g]quinoxaline-5,10-diones and their uses in heterocyclic chemistry. Because of the valuable biological activities of the 1,4-diazaanthraquinone compounds, a summary of the most promising heterocyclic quinones is provided together with their antitumor properties.

Quinoxaline Derivatives as Antiviral Agents: A Systematic Review.

BACKGROUND: In recent decades, several viruses have jumped from animals to humans, triggering sizable outbreaks. The current unprecedent outbreak SARS-COV-2 is prompting a search for new cost-effective therapies to combat this deadly pathogen. Suitably functionalized polysubstituted quinoxalines show very interesting biological properties (antiviral, anticancer, and antileishmanial), ensuring them a bright future in medicinal chemistry. OBJECTIVES: Focusing on the promising development of new quinoxaline derivatives as antiviral drugs, this review forms part of our program on the anti-infectious activity of quinoxaline derivatives. METHODS: Study compiles and discusses recently published studies concerning the therapeutic potential of the antiviral activity of quinoxaline derivatives, covering the literature between 2010 and 2020. RESULTS: A final total of 20 studies included in this review. CONCLUSIONS: This review points to a growing interest in the development of compounds bearing a quinoxaline moiety for antiviral treatment. This promising moiety with different molecular targets warrants further investigation, which may well yield even more encouraging results regarding this scaffold.

Synthesis and Antiplasmodial Evaluation of 4-Carboxamido- and 4-Alkoxy-2-Trichloromethyl Quinazolines.

From three previously identified antiplasmodial hit compounds (A-C) and inactive series (D), all based on a 2-trichloromethylquinazoline scaffold, we conducted a structure-activity relationship (SAR) study at position four of the quinazoline ring by synthesizing 42 novel derivatives bearing either a carboxamido- or an alkoxy-group, to identify antiplasmodial compounds and to enrich the knowledge about the 2-trichloromethylquinazoline antiplasmodial pharmacophore. All compounds were evaluated in vitro for their cytotoxicity towards the HepG2 cell line and their activity against the multiresistant K1 P. falciparum strain, using doxorubicin, chloroquine and doxycycline as reference drugs. Four hit-compounds (EC50 K1 P. falciparum ≤ 2 µM and SI ≥ 20) were identified among 4-carboxamido derivatives (2, 9, 16, and 24) and two among 4-alkoxy derivatives (41 and 44). Regarding the two most potent molecules (16 and 41), five derivatives without a 2-CCl3 group were prepared, evaluated, and appeared totally inactive (EC50 > 50 µM), showing that the 2-trichloromethyl group was mandatory for the antiplasmodial activity.

A review of melioidosis cases imported into Europe.

Melioidosis is a tropical bacterial infection, rarely encountered, and poorly known by clinicians. In non-endemic areas, a misdiagnosis can lead to a fatal outcome. This study aims to identify the main characteristics of imported and diagnosed melioidosis cases in Europe to increase clinician's awareness of this diagnosis. A literature review of imported and diagnosed human melioidosis cases in Europe was performed. PubMed and Web of Science search engines were used for retrieving articles from 2000 to November 2018. Seventy-seven cases of imported melioidosis into Europe described in the literature were identified. More than half of the cases were acquired in Thailand (53%) by men (73%). Patients were usually exposed to Burkholderia pseudomallei during a holiday stay (58%) of less than 1 month (23%) and were hospitalized during the month following their return to Europe (58%). Among travelers, melioidosis is less often associated with risk factor (16%), diabetes being the most frequently comorbidity related (19%). The clinical presentation was multifaceted, pneumonia being the most common symptom (52%), followed by cardiovascular form (45%) and skin and soft tissues damages (35%). The diagnosis was obtained by culture (92%), often supplemented by morphological, biochemical, and molecular identification (23%). Misdiagnoses were common (21%). Over half of the patients received a complete and adapted treatment (56%). Mortality is lower for returning traveler (6%). Imported melioidosis cases into Europe have their own characteristics. This possibility should be considered in patients with pneumonia, fever, and/or abscess returning from endemic areas even years after.

Management of adult Clostridium difficile digestive contaminations: a literature review.

Clostridium difficile infections (CDI) dramatically increased during the last decade and cause a major public health problem. Current treatments are limited by the high disease recurrence rate, severity of clinical forms, disruption of the gut microbiota, and colonization by vancomycin-resistant enterococci (VRE). In this review, we resumed current treatment options from official recommendation to promising alternatives available in the management of adult CDI, with regard to severity and recurring or non-recurring character of the infection. Vancomycin remains the first-line antibiotic in the management of mild to severe CDI. The use of metronidazole is discussed following the latest US recommendations that replaced it by fidaxomicin as first-line treatment of an initial episode of non-severe CDI. Fidaxomicin, the most recent antibiotic approved for CDI in adults, has several advantages compared to vancomycin and metronidazole, but its efficacy seems limited in cases of multiple recurrences. Innovative therapies such as fecal microbiota transplantation (FMT) and antitoxin antibodies were developed to limit the occurrence of recurrence of CDI. Research is therefore very active, and new antibiotics are being studied as surotomycin, cadazolid, and rinidazole.

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. This study contributes to a critical research area focused on antiepileptic drug adherence and aims to assess the main factors limiting adherence, as well as psychosocial factors influencing on risk of non-adherence. METHODS: An opinion survey was conducted among patients and parents of children treated for epilepsy and members of a French online support group. RESULTS AND DISCUSSION: A total of 263 questionnaires were collected. Of the patients, 79% said they never forget their medication, whereas 21% admitted occasional or frequent omissions. The main treatment-related factors that can limit adherence were adverse effects (limiting factors reported for 70% of patients) and number of tablets or number of intake per day (limiting factors reported for 32% of patients). Galenic (liquid) formulation (18%), drug taste (18%), tablet size (14%) and concern about the perception of others (17%) were cited in roughly equivalent terms as limiting adherence to treatment. Among the 55 patients who were genuinely non-adherent to their treatment, the occupational difficulties induced by following the treatment were a main cause of non-adherence. WHAT IS NEW AND CONCLUSION: Improving adherence in patients with epilepsy is a difficult and complex problem. Community pharmacists could play a major role in the determination of patients' adherence and should be aware of the risk of non-adherence.

Anticancer and Anti-Inflammatory Activities of Some New Pyrazolo[3,4-b]pyrazines.

New derivatives of pyrazolo[3,4-b]pyrazines and related heterocycles were synthesized using 5-amino-3-methyl-4-nitroso-1-phenyl-pyrazole (1) as a starting material. The 5-acetyl derivative 15 was shown to be a useful key intermediate for the synthesis of several derivatives of pyrazolopyrazines. Some of the prepared compounds were evaluated for their anti-inflammatory and anti-breast cancer MCF-7 cell line activities. SAR study showed that compounds 15 and 29 exhibited remarkable anti-inflammatory activity, where 15 showed the same activity as that of the reference drug indomethacin. On the other hand, compounds 25i, 25j showed very significant inhibitory activity (p < 0.001) against MCF-7 breast cancer cell line.

Base-Free Generation of Organic Electron Donors from Air-Stable Precursors.

Organic electron donors (OEDs) are powerful reducing agents recognized for their potential in the reduction of challenging substrates and in original applications. Nonetheless, their low stability in atmospheric oxygen or over time complicates their manipulation and storage. To overcome these constraints and enhance OED practicality, new air- and moisture-stable aminopyridinium carboxylate and carbonate precursors were synthesized and thermally activated to generate the potent electron donor in situ. Carboxylate adducts proved to be excellent latent OED systems, enabling the facile and efficient reduction of challenging substrates. Their reduction properties were correlated to their structural characteristics by thermogravimetric and spectroscopic analysis.

Metal-Free Regiodivergent Addition of Carbon Nucleophiles to α,ß-Unsaturated Electrophiles.

A mild and metal-free regiodivergent addition of carbon nucleophiles to α,ß-unsaturated electrophiles was developed. Total 1,2-regioselectivity was observed in the addition of nitrobenzyl chloride derivative 1 to α,ß-unsaturated aldehydes 2 in the presence of TDAE. Moreover, the reaction between p-nitrobenzyl chloride 1a and α,ß-unsaturated iminium salts 4 led to the formation of the 1,4-adduct with total regioselectivity.

An Efficient One-Pot Catalyzed Synthesis of 2,4-Disubstituted 5-Nitroimidazoles Displaying Antiparasitic and Antibacterial Activities.

A one-pot regioselective bis-Suzuki-Miyaura or Suzuki-Miyaura/Sonogashira reaction on 2,4-dibromo-1-methyl-5-nitro-1H-imidazole under microwave heating was developed. This method is applicable to a wide range of (hetero)arylboronic acids and terminal alkynes. Additionally, this approach provides a simple and efficient way to synthesize 2,4-disubstituted 5-nitroimidazole derivatives with antibacterial and antiparasitic properties.