Natural Fibre and Hybrid Composite Thin-Walled Structures for Automotive Crashworthiness: A Review.

Natural fibres, valued for their low density, cost-effectiveness, high strength-to-weight ratio, and efficient energy absorption, are increasingly emerging as alternatives to synthetic materials in green composites. Although they cannot fully replace synthetic counterparts, like carbon, in structural applications due to their inferior mechanical performance, combining them through hybridization presents a potential solution. This approach promotes a balance between environmental benefits and mechanical efficiency. Recently, the transportation sector has shifted its focus towards delivering lightweight and crashworthy composite structures to improve vehicle performance, address safety concerns, and minimise environmental impact through the use of eco-friendly materials. The crashworthiness of energy absorbers, typically thin-walled structures, is influenced by several factors, including their material and geometric design. This paper presents a comprehensive overview of recent studies focused on the crashworthiness of fibre-reinforced, thin-walled composites under axial crushing. It explores different aspects, such as their materials, cross-sections, stacking sequences, triggering or filling mechanisms, and the effect of loading rate speed. Emphasis is placed on natural-fibre-based materials, including a comparative analysis of synthetic ones and their hybridization. The primary objective is to review the progress of solutions using green composites as energy absorbers in the automotive industry, considering their lightweight design, crashworthiness, and environmental sustainability.

Use of Bio-Epoxies and Their Effect on the Performance of Polymer Composites: A Critical Review.

This study comprehensively examines recent developments in bio-epoxy resins and their applications in composites. Despite the reliability of traditional epoxy systems, the increasing demand for sustainability has driven researchers and industries to explore new bio-based alternatives. Additionally, natural fibers have the potential to serve as environmentally friendly substitutes for synthetic ones, contributing to the production of lightweight and biodegradable composites. Enhancing the mechanical properties of these bio-composites also involves improving the compatibility between the matrix and fibers. The use of bio-epoxy resins facilitates better adhesion of natural composite constituents, addressing sustainability and environmental concerns. The principles and methods proposed for both available commercial and especially non-commercial bio-epoxy solutions are investigated, with a focus on promising renewable sources like wood, food waste, and vegetable oils. Bio-epoxy systems with a minimum bio-content of 20% are analyzed from a thermomechanical perspective. This review also discusses the effect of incorporating synthetic and natural fibers into bio-epoxy resins both on their own and in hybrid form. A comparative analysis is conducted against traditional epoxy-based references, with the aim of emphasizing viable alternatives. The focus is on addressing their benefits and challenges in applications fields such as aviation and the automotive industry.

Reactive Docking: A Computational Method for High-Throughput Virtual Screenings of Reactive Species.

We describe the formalization of the reactive docking protocol, a method developed to model and predict reactions between small molecules and biological macromolecules. The method has been successfully used in a number of applications already, including recapitulating large proteomics data sets, performing structure-reactivity target optimizations, and prospective virtual screenings. By modeling a near-attack conformation-like state, no QM calculations are required to model the ligand and receptor geometries. Here, we present its generalization using a large data set containing more than 400 ligand-target complexes, 8 nucleophilic modifiable residue types, and more than 30 warheads. The method correctly predicts the modified residue in ∼85% of complexes and shows enrichments comparable to standard focused virtual screenings in ranking ligands. This performance supports this approach for the docking and screening of reactive ligands in virtual chemoproteomics and drug design campaigns.

Diversity oriented clicking delivers ß-substituted alkenyl sulfonyl fluorides as covalent human neutrophil elastase inhibitors.

Diversity Oriented Clicking (DOC) is a discovery method geared toward the rapid synthesis of functional libraries. It combines the best attributes of both classical and modern click chemistries. DOC strategies center upon the chemical diversification of core "SuFExable" hubs-exemplified by 2-Substituted-Alkynyl-1-Sulfonyl Fluorides (SASFs)-enabling the modular assembly of compounds through multiple reaction pathways. We report here a range of stereoselective Michael-type addition pathways from SASF hubs including reactions with secondary amines, carboxylates, 1H-1,2,3-triazole, and halides. These high yielding conjugate addition pathways deliver unprecedented ß-substituted alkenyl sulfonyl fluorides as single isomers with minimal purification, greatly enriching the repertoire of DOC and holding true to the fundamentals of modular click chemistry. Further, we demonstrate the potential for biological function - a key objective of click chemistry - of this family of SASF-derived molecules as covalent inhibitors of human neutrophil elastase.

Stapled Transanal Rectal Resection (Starr) in the Treatment of Obstructed Defecation: A Systematic Review.

Obstructed defecation syndrome (ODS) is a form of constipation that influences the quality of life in most patients and is an important health care issue. In 2004 Longo introduced a minimal invasive trans-anal approach known as Stapled Trans-Anal Rectal Resection (STARR) in order to correct mechanical disorders such as rectocele or rectal intussusception, two conditions present in more than 90% of patients with ODS. Considering the lack of a common view around ODS and STARR procedure. the aim of our study is to review the literature about preoperative assessment, operative features and outcomes of the STARR technique for the treatment of ODS. We performed a systematic search of literature, between January 2008 and December 2020 and 24 studies were included in this review. The total number of patients treated with STARR procedure was 4,464. In conclusion STARR surgical procedure has been proven to be safe and effective in treating symptoms of ODS and improving patients Quality of Life (QoL) and should be taken in consideration in the context of a holistic and multi modal approach to this complex condition. International guidelines are needed in order to optimize the diagnostic and therapeutic process and to improve outcomes.

[The Pacemaker and Implantable Cardioverter-Defibrillator Registry of the Italian Association of Arrhythmology and Cardiac Pacing - Annual report 2019]. / Registro Italiano Pacemaker e Defibrillatori - Bollettino Periodico 2019. Associazione Italiana di Aritmologia e Cardiostimolazione.

BACKGROUND: The pacemaker (PM) and implantable cardioverter-defibrillator (ICD) Registry of the Italian Association of Arrhythmology and Cardiac Pacing (AIAC) monitors the main epidemiological data in real-world practice. The survey for the 2019 activity collects information about demographics, clinical characteristics, main indications for PM/ICD therapy and device types from the Italian collaborating centers. METHODS: The Registry collects prospectively national PM and ICD implantation activity on the basis of European cards. RESULTS: PM Registry: data about 22 889 PM implantations were collected (19 621 first implants and 3268 replacements). The number of collaborating centers was 173. Median age of treated patients was 81 years (75 quartile I; 87 quartile III). ECG indications included atrioventricular conduction disorders in 33.3% of first PM implants, sick sinus syndrome in 16.4%, atrial fibrillation plus bradycardia in 11.6%, other in 38.7%. Among atrioventricular conduction defects, third-degree atrioventricular block was the most common type (18.3% of first implants). Use of single-chamber PMs was reported in 25.5% of first implants, of dual-chamber PMs in 67.1%, of PMs with cardiac resynchronization therapy (CRT) in 1.5%, and of single lead atrial-synchronized ventricular stimulation (VDD/R PMs) in 5.8%. ICD Registry: data about 17 328 ICD implantations were collected (12 129 first implants and 5199 replacements). The number of collaborating centers was 425. Median age of treated patients was 71 years (62 quartile I; 77 quartile III). Primary prevention indication was reported in 83.1% of first implants, secondary prevention in 16.9% (cardiac arrest in 5.9%). A single-chamber ICD was used in 26.1% of first implants, dual-chamber ICD in 28.0% and biventricular ICD in 45.9%. CONCLUSIONS: The PM and ICD Registry appears fundamental for monitoring PM and ICD utilization on a large national scale with rigorous examination of demographics and clinical indications. The PM Registry showed stable electrocardiographic and symptom indications, with an important prevalence of dual-chamber pacing. The use of CRT-PM regards a very limited number of patients. The ICD Registry documented a large use of prophylactic and biventricular ICD, reflecting a favorable adherence to trials and guidelines in clinical practice. In order to increase and optimize the cooperation of Italian implanting centers, online data entry (https://www.aiac.it/riprid) should be adopted at large scale.

Clinical Validation of the Comprehensive Complication Index in Colon Cancer Surgery.

(1) Introduction: To date, the sensitivity of the Comprehensive Complication Index (CCI) in a homogeneous cohort of colonic resections for oncologic purposes has not been reported. The present study aims to compare the CCI with the conventional Clavien-Dindo classification (CDC) in colon cancer patients. (2) Methods: The clinical data of patients submitted to an elective colectomy for adenocarcinoma were retrieved from a prospectively maintained database. Postoperative complications and length of stay were reviewed, and CDC and CCI scores were calculated for each patient. The association of the CCI and the CDC with the length of stay, prolongation of stay and readmission rate were assessed and compared. (3) Results: The overall postoperative morbidity was 26.9%. In particular, 157 (20.4%) patients had more than one complication. A strong correlation between the two scoring systems was observed (r = 99.4%; 95%CI: 99.3-99.5%). In multivariate analysis, CCI had a higher predictive ability for all endpoints. Regarding subgroup analysis, the difference between the CCI and CDC was progressively increased when evaluating outcome measures in complicated and multi-complicated patients. (4) Conclusion: Both scoring systems adequately report the overall burden of postoperative complications. The CCI showed a greater ability than the CDC to predict hospital stay, particularly in patients with multiple postoperative complications.

Selective and Effective: Current Progress in Computational Structure-Based Drug Discovery of Targeted Covalent Inhibitors.

Targeted covalent inhibitors are currently showing great promise for systems that are normally difficult to target with small molecule therapies. This renewed interest has spurred the refinement of existing computational methods as well as the designof new ones, expanding the toolbox for discovery and optimization of selectiveand effective covalent inhibitors. Commonly applied approaches are covalentdocking methods that predict the conformation of the covalent complex with known residues. More recently, a new predictive method, reactive docking, was developed, building on the growing corpus of data generated by large proteomics experiments. This method was successfully used in several 'inverse drug discovery' programs that use high-throughput techniques to isolate effective compounds based on screening of entire compound libraries based on desired phenotypes.

An Activity-Guided Map of Electrophile-Cysteine Interactions in Primary Human T Cells.

Electrophilic compounds originating from nature or chemical synthesis have profound effects on immune cells. These compounds are thought to act by cysteine modification to alter the functions of immune-relevant proteins; however, our understanding of electrophile-sensitive cysteines in the human immune proteome remains limited. Here, we present a global map of cysteines in primary human T cells that are susceptible to covalent modification by electrophilic small molecules. More than 3,000 covalently liganded cysteines were found on functionally and structurally diverse proteins, including many that play fundamental roles in immunology. We further show that electrophilic compounds can impair T cell activation by distinct mechanisms involving the direct functional perturbation and/or degradation of proteins. Our findings reveal a rich content of ligandable cysteines in human T cells and point to electrophilic small molecules as a fertile source for chemical probes and ultimately therapeutics that modulate immunological processes and their associated disorders.

[The Pacemaker and Implantable Cardioverter-Defibrillator Registry of the Italian Association of Arrhythmology and Cardiac Pacing - Annual report 2018]. / Registro Italiano Pacemaker e Defibrillatori - Bollettino Periodico 2018. Associazione Italiana di Aritmologia e Cardiostimolazione.

BACKGROUND: The pacemaker (PM) and implantable cardioverter-defibrillator (ICD) Registry of the Italian Association of Arrhythmology and Cardiac Pacing (AIAC) monitors the main epidemiological data in real-world practice. The survey for the 2018 activity collects information about demographics, clinical characteristics, main indications for PM/ICD therapy and device types from the Italian collaborating centers. METHODS: The Registry collects prospectively national PM and ICD implantation activity on the basis of European cards. RESULTS: PM Registry: data about 23 912 PM implantations were collected (20 084 first implants and 3828 replacements). The number of collaborating centers was 180. Median age of treated patients was 81 years (75 quartile I; 86 quartile III). ECG indications included atrioventricular conduction disorders in 34.5% of first PM implants, sick sinus syndrome in 18.3%, atrial fibrillation plus bradycardia in 13.0%, other in 34.2%. Among atrioventricular conduction defects, third-degree atrioventricular block was the most common type (19.2% of first implants). Use of single-chamber PMs was reported in 24.9% of first implants, of dual-chamber PMs in 67.6%, of PMs with cardiac resynchronization therapy (CRT) in 1.6%, and of single lead atrial-synchronized ventricular stimulation (VDD/R PMs) in 5.9%. ICD Registry: data about 18 353 ICD implantations were collected (13 944 first implants and 4359 replacements). The number of collaborating centers was 433. Median age of treated patients was 71 years (63 quartile I; 78 quartile III). Primary prevention indication was reported in 84.3% of first implants, secondary prevention in 15.7% (cardiac arrest in 5.3%). A single-chamber ICD was used in 27.9% of first implants, dual-chamber ICD in 31.9% and biventricular ICD in 40.2%. CONCLUSIONS: The PM and ICD Registry appears fundamental for monitoring PM and ICD utilization on a large national scale with rigorous examination of demographics and clinical indications. The PM Registry showed stable electrocardiographic and symptom indications, with an important prevalence of dual-chamber pacing. The use of CRT-PM regards a very limited number of patients. The ICD Registry documented a large use of prophylactic and biventricular ICD, reflecting a favorable adherence to trials and guidelines in clinical practice. In order to increase and optimize the cooperation of Italian implanting centers, online data entry (http://www.aiac.it/riprid) should be adopted at large scale.

D3R Grand Challenge 4: prospective pose prediction of BACE1 ligands with AutoDock-GPU.

In this paper we describe our approaches to predict the binding mode of twenty BACE1 ligands as part of Grand Challenge 4 (GC4), organized by the Drug Design Data Resource. Calculations for all submissions (except for one, which used AutoDock4.2) were performed using AutoDock-GPU, the new GPU-accelerated version of AutoDock4 implemented in OpenCL, which features a gradient-based local search. The pose prediction challenge was organized in two stages. In Stage 1a, the protein conformations associated with each of the ligands were undisclosed, so we docked each ligand to a set of eleven receptor conformations, chosen to maximize the diversity of binding pocket topography. Protein conformations were made available in Stage 1b, making it a re-docking task. For all calculations, macrocyclic conformations were sampled on the fly during docking, taking the target structure into account. To leverage information from existing structures containing BACE1 bound to ligands available in the PDB, we tested biased docking and pose filter protocols to facilitate poses resembling those experimentally determined. Both pose filters and biased docking resulted in more accurate docked poses, enabling us to predict for both Stages 1a and 1b ligand poses within 2 Å RMSD from the crystallographic pose. Nevertheless, many of the ligands could be correctly docked without using existing structural information, demonstrating the usefulness of physics-based scoring functions, such as the one used in AutoDock4, for structure based drug design.

Comparison of affinity ranking using AutoDock-GPU and MM-GBSA scores for BACE-1 inhibitors in the D3R Grand Challenge 4.

Molecular docking has been successfully used in computer-aided molecular design projects for the identification of ligand poses within protein binding sites. However, relying on docking scores to rank different ligands with respect to their experimental affinities might not be sufficient. It is believed that the binding scores calculated using molecular mechanics combined with the Poisson-Boltzman surface area (MM-PBSA) or generalized Born surface area (MM-GBSA) can predict binding affinities more accurately. In this perspective, we decided to take part in Stage 2 of the Drug Design Data Resource (D3R) Grand Challenge 4 (GC4) to compare the performance of a quick scoring function, AutoDock4, to that of MM-GBSA in predicting the binding affinities of a set of [Formula: see text]-Amyloid Cleaving Enzyme 1 (BACE-1) ligands. Our results show that re-scoring docking poses using MM-GBSA did not improve the correlation with experimental affinities. We further did a retrospective analysis of the results and found that our MM-GBSA protocol is sensitive to details in the protein-ligand system: (i) neutral ligands are more adapted to MM-GBSA calculations than charged ligands, (ii) predicted binding affinities depend on the initial conformation of the BACE-1 receptor, (iii) protonating the aspartyl dyad of BACE-1 correctly results in more accurate binding affinity predictions.

Expedited mapping of the ligandable proteome using fully functionalized enantiomeric probe pairs.

A fundamental challenge in chemical biology and medicine is to understand and expand the fraction of the human proteome that can be targeted by small molecules. We recently described a strategy that integrates fragment-based ligand discovery with chemical proteomics to furnish global portraits of reversible small-molecule/protein interactions in human cells. Excavating clear structure-activity relationships from these 'ligandability' maps, however, was confounded by the distinct physicochemical properties and corresponding overall protein-binding potential of individual fragments. Here, we describe a compelling solution to this problem by introducing a next-generation set of fully functionalized fragments differing only in absolute stereochemistry. Using these enantiomeric probe pairs, or 'enantioprobes', we identify numerous stereoselective protein-fragment interactions in cells and show that these interactions occur at functional sites on proteins from diverse classes. Our findings thus indicate that incorporating chirality into fully functionalized fragment libraries provides a robust and streamlined method to discover ligandable proteins in cells.

[The Pacemaker and Implantable Cardioverter-Defibrillator Registry of the Italian Association of Arrhythmology and Cardiac Pacing - Annual report 2017]. / Registro Italiano Pacemaker e Defibrillatori Bollettino Periodico 2017 Associazione Italiana di Aritmologia e Cardiostimolazione.

BACKGROUND: The pacemaker (PM) and implantable cardioverter-defibrillator (ICD) Registry of the Italian Association of Arrhythmology and Cardiac Pacing (AIAC) monitors the main epidemiological data in real-world practice. The survey for the 2017 activity collects information about demographics, clinical characteristics, main indications for PM/ICD therapy and device types from the Italian collaborating centers. METHODS: The Registry collects prospectively national PM and ICD implantation activity on the basis of European cards. RESULTS: PM Registry: data about 23 457 PM implantations were collected (19 378 first implant and 4079 replacements). The number of collaborating centers was 185. Median age of treated patients was 81 years (75 quartile I; 86 quartile III). ECG indications included atrioventricular conduction disorders in 37.1% of first PM implants, sick sinus syndrome in 19.5%, atrial fibrillation plus bradycardia in 13.2%, other in 30.2%. Among atrioventricular conduction defects, third-degree atrioventricular block was the most common type (21.0% of first implants). Use of single-chamber PMs was reported in 25.6% of first implants, of dual-chamber PMs in 66.7%, of PMs with cardiac resynchronization therapy (CRT) in 1.4%, and of single lead atrial-synchronized ventricular stimulation (VDD/R PMs) in 6.3%. ICD Registry: data about 19 023 ICD implantations were collected (13 898 first implants and 5125 replacements). The number of collaborating centers was 437. Median age of treated patients was 71 years (63 quartile I; 78 quartile III). Primary prevention indication was reported in 81.8% of first implants, secondary prevention in 18.2% (cardiac arrest in 6.4%). A single-chamber ICD was used in 27.0% of first implants, dual-chamber in 33.6% and biventricular in 39.3%. CONCLUSIONS: The PM and ICD Registry appears fundamental for monitoring PM and ICD utilization on a large national scale with rigorous examination of demographics and clinical indications. The PM Registry showed stable electrocardiographic and symptom indications, with an important prevalence of dual-chamber pacing. The use of CRT-PM regards a very limited number of patients. The ICD Registry documented a large use of prophylactic and biventricular ICD, reflecting a favorable adherence to trials and guidelines in clinical practice. In order to increase and optimize the cooperation of Italian implanting centers, online data entry (http://www.aiac.it/riprid) should be adopted at large scale.

The clinical and therapeutic approach to anal stenosis.

Anal stenosis is a fibrous narrowing of the anal channel. It develops, in most cases, in the aftermath of proctologic surgical procedures with extensive anoderm excision or in the presence of chronic anal inflammation in patients with Crohn Disease. However rare, this condition is thoroughly debilitating for the patients. Symptoms include constipation, pain and bleeding with defecation and a reduction of the caliber of stools. Diagnosis is essentially clinical. Prevention of postsurgical stenosis is based on a scrupulous surgical technique and on an extensive and carefully- planned follow up. Treatment is based on an initially conservative approach with regularization of stool transit through hydration, dietary fibers and bulk-forming laxatives. The role of mechanical dilatation in the treatment of AS is still debated. For severe cases and cases that are not responsive to conservative treatment we must resort to surgery. Surgical approach is tailored on the severity, position and extension. The most severe cases require anoplasty procedures with mucosal or anal flaps. KEY WORDS: Anal stenosis, Anal stricture,Proctology.

"All In One Mesh Hernioplasty" device for inguinal hernia repair. Results of 400 cases.

BACKGROUND: Our intention in this study was to evaluate the effectiveness of a new open mesh hernia repair procedure, the "All in One Mesh Hernioplasty", for the treatment of primary inguinal hernias in adults. METHODS: Between February 2014 and February 2016, we performed the All In One Mesh Hernioplasty procedure on 400 patient suffering from primary unilateral inguinal hernia at our Institution. The prosthesis was placed on the floor of the inguinal canal, as described in the original technique, and later covered by the fibrocremasteric sheath. Followup visits with the evaluation of postoperative pain using Numerical Rating Scale, and of short and long-term complications were performed after 1, 6, and 24 months. RESULTS: All patients were discharged within three hours after surgery. The majority of patients reported only slight pain at discharge and 31,7% of them were completely painless . One week after surgery 83% of patients reported no pain and no other symptoms. 91 % of patients returned to their normal daily activities within 2-3 days after surgery. We didn't record any case of postoperative neuralgia or recurrence after a 24 months follow up. KEY WORDS: All In One Mesh Hernioplasty, Neuralgia post-hernioplasty, Tension free hernia repair.

Identification of Myricetin as an Ebola Virus VP35-Double-Stranded RNA Interaction Inhibitor through a Novel Fluorescence-Based Assay.

Ebola virus (EBOV) is a filovirus that causes a severe and rapidly progressing hemorrhagic syndrome; a recent epidemic illustrated the urgent need for novel therapeutic agents because no drugs have been approved for treatment of Ebola virus. A key contribution to the high lethality observed during EBOV outbreaks comes from viral evasion of the host antiviral innate immune response in which viral protein VP35 plays a crucial role, blocking interferon type I production, first by masking the viral double-stranded RNA (dsRNA) and preventing its detection by the pattern recognition receptor RIG-I. Aiming to identify inhibitors of the interaction of VP35 with the viral dsRNA, counteracting the VP35 viral innate immune evasion, we established a new methodology for high-yield recombinant VP35 (rVP35) expression and purification and a novel and robust fluorescence-based rVP35-RNA interaction assay ( Z' factor of 0.69). Taking advantage of such newly established methods, we screened a small library of Sardinian natural extracts, identifying Limonium morisianum as the most potent inhibitor extract. A bioguided fractionation led to the identification of myricetin as the component that can inhibit rVP35-dsRNA interaction with an IC50 value of 2.7 µM. Molecular docking studies showed that myricetin interacts with the highly conserved region of the VP35 RNA binding domain, laying the basis for further structural optimization of potent inhibitors of VP35-dsRNA interaction.

15 years experience in proctological day-surgery.

INTRODUCTION: The actual high hospitalization costs have encouraged a growing attention towards reducing hospital stay. Nowadays, many simple surgical procedures are carried out in a one-day surgery regimen . A shorter hospital stay brings many advantages for the patients: lesser inconvenience, a lower risk of hospital infection and an earlier return to work. In proctology, day surgery polices are still uncommon because surgeons fear possible complications. In this paper we sum up our 15 years experience, stressing the possibility to perform even complex procedures in local-regional anesthesia and in a day-surgery context. MATERIALS AND METHODS: In our experience, to be candidate to one-day surgery proctological procdures, patients should be classed as ASA I or II. RESULTS: Between 2005 and 2015 our operative unit executed a total of 2688 proctological procedures in a one-day surgery. 1062 procedures have been completed under local anesthesia exclusively and all patients have been discharged between two and three hours after the procedure without significant complications. In the other 1626 patients perineal posterior block was performed in 932 cases (57.3%) and provided an optimal pain control in 51,6% of cases (301 patients) while in 5,7% of cases there was the need for an intravenous administration of Fentanil. DISCUSSION AND CONCLUSION: Day-surgery is nowadays a concrete reality, made possible by an attentive selection of patients, an accurate surgical technique, an attentive patient monitoring in the postoperative period and a continuous monitoring of the effectiveness of pain medications. Over the last decades our surgical team has developed modified techniques of loco-regional anesthesia that allow us to perform even complex procedures and discharge the patient within 24 hours. KEY WORDS: Day-surgery, Haemorrhoids, Proctological procedures.

Tuning the Dual Inhibition of Carbonic Anhydrase and Cyclooxygenase by Dihydrothiazole Benzensulfonamides.

A novel series of of 4-[(3-phenyl-4-aryl-2,3-dihydro-1,3-thiazol-2-ylidene)amino]benzene-1-sulfonamides (EMAC10111a-g) was synthesized and assayed toward both human carbonic anhydrase isozymes I, II, IX, and XII and cyclooxygenase isoforms. The majority of these derivatives preferentially inhibit hCA isoforms II and XII and hCOX-2 isozyme, indicating that 2,3,4-trisubstituted 2,3-dihydrothiazoles are a promising scaffold for the inhibition of hCA isozymes and of hCOX-2 enzyme. The nature of the substituent at the dihydrothiazole ring position 4 influenced the activity and selectivity toward both enzyme families. EMAC10111g resulted as the best performing compound toward both enzyme families and exhibited preferential activity toward hCA XII and hCOX-2 isozymes.

Targeting Tumor Associated Carbonic Anhydrases IX and XII: Highly Isozyme Selective Coumarin and Psoralen Inhibitors.

A small library of psoralen carboxylic acids and their corresponding benzenesulfonamide derivatives were designed and synthesized to evaluate their activity and selectivity toward tumor associated human carbonic anhydrase (hCA) isoforms IX and XII. Both psoralen acids and sulfonamides exhibited potent inhibition of IX and XII isozymes in the nanomolar concentration range. However, psoralen acids resulted as the most selective in comparison with the corresponding benzenesulfonamide derivatives. Our data indicate that the psoralen scaffold is a promising starting point for the design of highly selective tumor associated hCA inhibitors.