AiCuris (Germany)

Abstract Several strategies to synthesize desired 1,2,4‐triazolo[1,5‐a]pyridine‐2‐carboxylate targets have been reported over the years. The most convenient way features the preparation of the precursor triazolopyridine‐N‐oxide through a condensation step between sulfilimines and a nitrile oxide species, followed by a deoxygenation step. This paper presents a detailed work on the synthesis of [1,2,4]triazolo[1,5‐a]pyridine‐2‐carboxylate‐N‐oxide, featuring a synergistic experimental‐theoretical approach. Herein, we report the development of an efficient and straightforward method to prepare ethyl [1,2,4]triazolo[1,5‐a]pyridine‐2‐carboxylate 3‐oxide in continuous flow. The transfer from batch to flow processing resulted in a significant boost in isolated yield (53 % vs. 31 %) and a decrease in the simultaneous presence of starting materials and product in the reaction media from 4 hours to 3.5 minutes. An in‐depth mechanistic study of the reaction using density functional theory provided a deeper understanding of the whole reaction manifold and key indications on how to further improve the process in flow.

Este artículo buscó promover una reflexión sistemática sobre la Asistencia Jurídica Gratuita y la gratuidad de la justicia en el Proceso Civil. En ese contexto, se adoptó la siguiente pregunta orientadora: qué dificulta, facilita o interfiere en el otorgamiento de los beneficios de Asistencia Jurídica Gratuita y Justicia Gratuita, en sentido amplio y en sentido estricto, en la concepción procesal sistemática, de cara a de decisiones judiciales de diferimiento, denegación y revocación del otorgamiento del beneficio? Con el objetivo de abordar los conceptos, definiciones, su aspecto procesal y su aplicación en la fase de ejecución de la sentencia. Por ello, se utilizó el método inductivo como herramienta de investigación para la Doctrina y la Jurisprudencia, con el fin de identificar qué dificulta, facilita o interfiere en el otorgamiento de los beneficios de la Asistencia Jurídica. Así, a través de esta investigación, fue posible observar que la garantía de la gratuidad de la justicia implica únicamente gastos procesales y honorarios de abogados, siendo otorgados a la parte siempre que estos acrediten la precariedad de recursos. Por ello, el Código de Procedimiento Civil promueve la aplicación de la igualdad procesal para hacer justicia a todas aquellas personas desfavorecidas y en exclusión social que puedan necesitar apoyo jurisdiccional estatal.

To date, hepatitis B virus (HBV) capsid assembly modulators (CAMs), which target the viral core protein and induce the formation of non-functional viral capsids, have been identified and characterized in microtiter plate-based biochemical or cell-based in vitro assays. In this work, we developed an automated microfluidic screening assay, which uses convection-dominated Taylor-Aris dispersion to generate high-resolution dose-response curves, enabling the measurements of compound EC50 values at very short incubation times. The measurement of early kinetics down to 7.7 seconds in the microfluidic format was utilized to discriminate between the two different classes of CAMs known so far. The CAM (-N), leading to the formation of morphologically normal capsids and the CAM (-A), leading to aberrant HBV capsid structures. CAM-A compounds like BAY 41-4109 and GLS4 showed rapid kinetics, with assembly rates above 80% of the core protein after only a 7 second exposure to the compound, whereas CAM-N compounds like ABI-H0731 and JNJ-56136379 showed significantly slower kinetics. Using our microfluidic system, we characterized two of our in-house screening compounds. Interestingly, one compound showed a CAM-N/A intermediate behavior, which was verified with two standard methods for CAM classification, size exclusion chromatography, and anti-HBc immunofluorescence microscopy. With this proof-of-concept study, we believe that this microfluidic system is a robust primary screening tool for HBV CAM drug discovery, especially for the hit finding and hit-to-lead optimization phases. In addition to EC50 values, this system gives valuable first information about the mode of action of novel CAM screening compounds.

Critical Care Medicine: January 2022 - Volume 50 - Issue 1 - p 329 doi: 10.1097/01.ccm.0000809008.98544.95

Human cytomegalo virus (CMV) is widespread in the human population (prevalence 50% to close to 100%) and can cause severe, often life-threatening diseases in all conditions with a missing or weak immune system. Patients at risk include recipients of stem cells or solid organs, newborns, AIDS patients, and potentially also patients in intensive care or patients treated aggressively against certain autoimmune disorders and cancers. Until 2017, all licensed low molecular weight drugs against CMV addressed the viral polymerase as their target and – by interaction with human polymerases – are burdened with significant side effects like bone marrow toxicity, kidney toxicity, mutagenicity, or carcinogenicity. In addition, cross-resistance between these drugs developed, leaving patients without therapeutic options. In this chapter, the discovery of inhibitors of the CMV viral terminase will be described. Based on the fact that this target does not have any counterpart in humans, these drugs have proven to be very well tolerated. They exert high efficacy and by addressing a different target show no cross-resistance to polymerase inhibitors against CMV. For the first time, therefore, prophylaxis against CMV reactivation is now possible for recipients of hematopoietic stem cells. The use of letermovir for CMV prophylaxis in kidney recipients is currently being investigated. Furthermore, the role as a potential co-pathogen, which this widespread virus is suspected to play in a number of the conditions mentioned above, can now be characterized by clinical studies. In cases, where an important role of CMV as co-pathogen becomes evident, this may allow to introduce treatment against CMV as part of the management of the condition.

Hospital readmissions following severe infections are a major economic burden on the health care system and have a negative influence on patients' quality of life. Understanding the risk factors for readmission, particularly the extent to which they could be prevented, is of a great importance. In this study we evaluated potentially preventable risk factors for 60-day readmission in patients surviving hospitalization for complicated urinary tract infection (cUTI). This was a multinational, multicentre retrospective cohort study conducted in Europe and the Middle East. Our cohort included survivors of hospitalization due to cUTI during the years 2013–2014. The primary outcome was 60-day readmission following index hospitalization. Patient characteristics that could have influenced readmission: demographics, infection presentation and management, microbiological and clinical data; were collected via computerized medical records from infection onset up to 60 days after hospital discharge. Overall, 742 patients were included. The cohort median age was 68 years (interquartile range, (IQR) 55–80) and 43.3% (321/742) of patients were males. The all-cause 60-day readmission rate was 20.1% (149/742) and more than half were readmitted for infection [57.1%, (80/140)]. Recurrent cUTI was the most frequent cause for readmission [46.4% (65/140)]. Statistically significant risk factors associated with 60-day readmission in multivariable analysis were: older age (odds ratio (OR) 1.02 for an one-year increment, confidence interval (CI) 1.005–1.03), diabetes mellitus (OR 1.63, 95% CI 1.04–2.55), cancer (OR 1.7, 95% CI 1.05–2.77), previous urinary tract infection (UTI) in the last year (OR 1.8, 95% CI: 1.14–2.83), insertion of an indwelling bladder catheter (OR 1.62, 95% CI 1.07–2.45) and insertion of percutaneous nephrostomy (OR 3.68, 95% CI 1.67–8.13). In conclusion, patients surviving hospitalization for cUTI are frequently re-hospitalized, mostly for recurrent urinary infections associated with a medical condition that necessitated urinary interventions. Interventions to avoid re-admissions should target these patients.

Pritelivir (AIC316, BAY 57-1293) was discovered as a highly potent drug against herpes simplex viruses with a novel mode of action, i.e. inhibition of the viral helicase-primase. A side by side comparison of the oral form against Valtrex™ in patients with genital herpes, showed superiority in phase II testing for Pritelivir. A number of different solid forms have been generated for additional, e.g. systemic, or topical applications.

Antibiotic resistance (ABR) is a global public health threat. Despite the emergence of highly resistant organisms and the huge medical need for new drugs, the development of antibacterials has slowed to an unacceptable level worldwide. Numerous government and non-government agencies have called for public-private partnerships and innovative funding mechanisms to address this problem. To respond to this public health crisis, the Innovative Medicines Initiative Joint Undertaking programme has invested more than €660 million, with a goal of matched contributions from the European Commission and the European Federation of Pharmaceutical Industries and Associations, in the development of new antibacterial strategies. The New Drugs for Bad Bugs (ND4BB) programme, an Innovative Medicines Initiative, has the ultimate goal to boost the fight against ABR at every level from basic science and drug discovery, through clinical development to new business models and responsible use of antibiotics. Seven projects have been launched within the ND4BB programme to achieve this goal. Four of them will include clinical trials of new anti-infective compounds, as well as epidemiological studies on an unprecedented scale, which will increase our knowledge of ABR and specific pathogens, and improve the designs of the clinical trials with new investigational drugs. The need for rapid concerted action has driven the funding of seven topics, each of which should add significantly to progress in the fight against ABR. ND4BB unites expertise and provides a platform where the commitment and resources required by all parties are streamlined into a joint public-private partnership initiative of unprecedented scale.

The spread of MDR bacteria represents a serious threat to human society and novel antibiotic drugs, preferably from new chemical classes, are urgently needed. Closthioamide was isolated from the strictly anaerobic bacterium Clostridium cellulolyticum and belongs to a new class of natural products, the polythioamides. Here, we investigated the antimicrobial activity and mechanism of action of closthioamide. For assessing the antimicrobial activity of closthioamide, MIC values and killing kinetics were determined. To identify its target pathway, whole-cell-based assays were used including analysis of macromolecular synthesis and recording the susceptibility profile of a library of clones with down-regulated potential target genes. Subsequently, the inhibitory effect of closthioamide on the activity of isolated target enzymes, e.g. DNA gyrase and topoisomerase IV, was evaluated. Closthioamide had broad-spectrum activity against Gram-positive bacteria. Notably, closthioamide was very potent against MRSA and VRE strains. Closthioamide impaired DNA replication and inhibited DNA gyrase activity, in particular the ATPase function of gyrase and of topoisomerase IV, whereas there was little effect on the cleavage-rejoining function. Closthioamide also inhibited the relaxation activity of DNA gyrase, which does not require ATP hydrolysis, and thus may allosterically rather than directly interfere with the ATPase activity of gyrase. Cross-resistance to ciprofloxacin and novobiocin could not be detected in experimental mutants and clinical isolates. Closthioamide, a member of an unprecedented class of antibiotics, is a potent inhibitor of bacterial DNA gyrase; however, its molecular mechanism differs from that of the quinolones and aminocoumarins.