Towards Antibiotic Synthesis in Continuous-Flow Processes

Continuous-flow chemistry has become a mainstream process and a notable trend among emerging technologies for drug synthesis. It is routinely used in academic and industrial laboratories to generate a wide variety of molecules and building blocks. The advantages it provides, in terms of safety, speed, cost efficiency and small-equipment footprint compared to analog batch processes, have been known for some time. What has become even more important in recent years is its compliance with the quality objectives that are required by drug-development protocols that integrate inline analysis and purification tools. There can be no doubt that worldwide government agencies have strongly encouraged the study and implementation of this innovative, sustainable and environmentally friendly technology. In this brief review, we list and evaluate the development and applications of continuous-flow processes for antibiotic synthesis. This work spans the period of 2012–2022 and highlights the main cases in which either active ingredients or their intermediates were produced under continuous flow. We hope that this manuscript will provide an overview of the field and a starting point for a deeper understanding of the impact of flow chemistry on the broad panorama of antibiotic synthesis

Efficient pilot-scale synthesis of the key cefonicid intermediate at room temperature

Abstract Cefonicid is a common second-generation cephalosporin, and the 7-amino-3-[sulphomethyl-1-H-tetrazol-5-yl-thiomethyl]-3-cephem-4-carboxylate monosodium salt is a key synthetic intermediate in its preparation. Despite the considerable international demand for this antibiotic, its preparation is hampered by low synthetic yield, long reaction time, and time-consuming industrial filtration over charcoal after the purification step. In the context of the industrial production of pharmaceutical intermediates, in which the balance between streamlining and enhancing productivity is necessary in order to compete in the global active pharmaceutical ingredients (API) market, we have investigated an efficient and practical procedure for the synthesis of a key cefonicid intermediate that features a telescopic route whose synthetic steps are all performed at room temperature; from the displacement of the acetoxy group with boron trifluoride to crystallization without treatment with charcoal. In other words, a simpler, scalable, cost-effective and energy-saving protocol is herein reported as a means of moving towards commercial manufacturing. The optimization of the process parameters and the industrial-scale impact assessment should pave the way for industrialization

Microbial translocation and T cell activation are modified by direct-acting antiviral therapy in HCV-infected patients

BACKGROUND: Microbial translocation from the gut lumen has been involved in the pathogenesis of liver damage in hepatitis C virus (HCV) infection. AIM: To investigate the impact of direct-acting antiviral treatment on microbial translocation and T-cell activation, in patients with hepatitis C-related liver disease. METHODS: We enrolled two groups of HCV-infected patients undergoing direct-acting antiviral treatment: patients with fibrosis ≥F3 according to Metavir (Group ≥F3); patients with hepatitis C recurrence after liver transplantation and Metavir ≥F2 (Group Liver Transplantation + ≥F2). All patients were treated with direct-acting antivirals based on ongoing guidelines. Surrogate biomarkers of microbial translocation (plasma concentrations of soluble-CD14, lipopolysaccharide-binding protein and intestinal fatty acid-binding protein) were evaluated at baseline, at first month, at the end of treatment and 3 months later. T-cell activation was measured by expression of CD38+ HLA-DR at the same time points, only in Group ≥F3. RESULTS: There were 32 patients in Group ≥F3 and 13 in Group LT + ≥F2. At baseline, levels of soluble-CD14 and lipopolysaccharide-binding protein were significantly higher in both groups vs healthy controls. Baseline soluble-CD14 correlated with glutamic-oxalacetic transaminase (r = 0.384, P = 0.009) and glutamic-pyruvic transaminase (r = 0.293, P = 0.05). A significant decrease in plasma levels of surrogate microbial translocation biomarkers was observed during and after treatment in the two groups although values were not normalised. In Group ≥F3, CD38+ HLADR+ T-cell expression was significantly decreased by direct-acting antiviral treatment. Relapsers (9%) showed higher soluble-CD14 levels at baseline. CONCLUSION: Surrogate microbial translocation markers and T cell activation are increased in HCV-infected patients with liver fibrosis and decrease during direct-acting antiviral treatment

Recent advances and perspectives in the synthesis of bioactive coumarins

The impressive pharmacological properties shown by a number of coumarins have led to extraordinarily large emphasis being placed on the design of more efficient and greener synthetic procedures to produce them.</p

Reduced Plasma Levels of sCD14 and I-FABP in HIV-infected Patients with Mesalazine-treated Ulcerative Colitis

BACKGROUND: Microbial translocation (MT) is a shared feature of HIV infection and inflammatory bowel disease (IBD). AIMS: This study was conducted to assess the impact of IBD (and particularly ulcerative colitis, UC) on plasma markers of MT and immune activation in HIV+ subjects. METHODS: A cross-sectional study was conducted in 3 groups of patients: HIV+/UC+(group HIV/UC); HIV+/UC- (group HIV); HIV-/UC+(group UC). Plasma levels of soluble CD14 (sCD14), intestinal fatty acid-binding protein (I-FABP), and endotoxin core antibodies (endoCAB) were measured as plasma markers of MT. Inflammation and immune activation were evaluated by measuring plasma levels of IL-6, IL-21, TNF-alpha, and high-sensitivity C-reactive protein (hs-CRP). T- and B-cells subpopulations were characterized by FACS analysis. RESULTS: Seven patients were enrolled in group HIV/UC, 9 in HIV, and 10 in UC. All HIV-positive patients had plasma values of HIV-1 RNA < 37 copies/mL for at least 12 months and good immunological recovery. All patients with UC were treated with oral mesalazine. Markers of MT, immune activation, and inflammation were not increased in subjects with HIV/UC. In fact, they had lower levels of I-FABP (p = 0.001) and sCD14 (p = 0.007) when compared to other patients groups. Positive correlations were found between I-FABP and sCD14 (r = .355, p = 0.076). Frequency of T- and B-cell subsets did not differ among groups. CONCLUSIONS: Our results suggest that UC does not worsen MT, inflammation, or immune activation in HIV-infected subjects. The anti-inflammatory activity of chronic mesalazine administration on intestinal mucosa may contribute to this finding

Indications for upper gastrointestinal endoscopy before bariatric surgery: a multicenter study

The role of preoperative upper gastrointestinal endoscopy before bariatric surgery is still debated, and a consensus among the international scientific community is lacking. The aims of this study, conducted in three different geographic areas, were to analyze data regarding the pathological endoscopic findings and report their impact on the decision-making process and surgical management, in terms of delay in surgical operation, modification of the intended bariatric procedure, or contraindication to surgery

Pre-operative body shape concerns moderate excess weight loss trajectory in bariatric surgery patients: a 2-year longitudinal study

Purpose: The main research aim was to inspect whether pre-operative body shape concerns and discomfort as Body Shape Questionnaire (BSQ) scores moderate post-operative weight loss trajectory in bariatric patients. Methods: Two studies were conducted. Study 1 analyzed cross-sectional data and verified the structural validity of the 34-item BSQ questionnaire on a sample of 327 candidates for bariatric surgery. Study 2 examined longitudinal data, with objective Body Mass Index (BMI) recorded every 6 months, from surgery intervention on, with 5 measurement occasions, from 111 patients who initially completed BSQ as bariatric surgery candidates and then underwent periodic medical post-operative follow-ups, over 2 years. Results: In Study 1, confirmatory factor analysis of a single-dimension model yielded acceptable fit indices and high internal consistency levels. Study 2 showed that post-operative excess BMI reduction trend was not linear and pre-operative BSQ scores moderated it, with a higher risk of weight regain in patients who initially were less concerned with their body shape. Conclusions: The present findings support the structural validity of the BSQ questionnaire in bariatric candidates and call attention on the role of pre-operative body shape concerns on post-operative weight loss trajectories over 2 years, in accordance with a pathoplasty model. They suggest the need for systematic attention on perceived body image and psychological paths aimed to help bariatric patients regain positive attitudes towards their own body. Level of evidence III, well-designed cohort