Impact of a Research Integrity Assessment (RIA) of Randomized Controlled Trials Included in Interventional COVID‐19 Systematic Reviews: A Meta‐Epidemiological Study

ABSTRACT Objective This study aimed to evaluate the feasibility, reliability, and impact of the Research Integrity Assessment (RIA) tool when applied to randomized controlled trials (RCTs) included in systematic reviews. RIA is a structured tool designed to assess retractions, trial registration, ethical approval, authorship, and plausibility of methods and results, thereby identifying RCTs that may not meet basic standards of research integrity. Design Meta‐epidemiological study. Methods We systematically identified Cochrane reviews and non‐Cochrane systematic reviews of RCTs investigating interventions for COVID‐19 and extracted all RCTs. Each RCT was independently assessed by two reviewers (with different expertise in evidence synthesis) using the RIA tool, with disagreements resolved by a senior reviewer. Reliability and feasibility were recorded, and sensitivity analyses examined the impact of excluding studies failing the RIA on meta‐analytic results. Results Two hundred six RCTs from 23 Cochrane reviews and non‐Cochrane systematic reviews were assessed with RIA. Fifty‐nine RCTs (29%) were excluded due to integrity concerns, 79 (38%) classified as “awaiting classification”, and 11 (5%) identified as non‐randomized studies, leaving 57 RCTs (28%) rated as “no concern.” The most common reason for exclusion was absent or retrospective trial registration, while uncertainties around ethics approval were the main reason for “awaiting classification”. Interrater reliability was moderate overall (κ = 0.5), with higher agreement in objective domains and lower in domains requiring interpretive judgment, necessitating senior adjudication in a substantial proportion of assessments. On average, application of RIA required 21–27 min per RCT; however, the time required for senior assessor reassessment, conflict resolution, and author correspondence was not systematically recorded and substantially exceeded that of the initial assessments. We received 35 author responses to 165 individual queries. Sensitivity analyses restricted to RCTs passing RIA reduced the median number of eligible RCTs per meta‐analysis by 60%. This frequently widened confidence intervals and decreased the certainty of conclusions, although the direction of effect estimates changed only rarely. Conclusions These results demonstrate that integrity checks can be feasibly applied and reveal widespread concerns in COVID‐19 RCTs, but require expertise, adjudication mechanisms, and adequate resources. Incorporating such assessments into review methodology can strengthen the trustworthiness of clinical evidence and safeguard patient safety. Registration A protocol to this meta‐epidemiological study has been registered ( https://doi.org/10.17605/OSF.IO/NBRHX ).

Tezepelumab Improves Small Airways Dysfunction in Severe Asthma: A 52‐Week Real‐World Study

Optimization of 4‐Amino‐2‐Pyridone Inhibitors of Proprotein Convertase Subtilisin/Kexin Type 9: Integrating Structure–Activity and Structure–Metabolism Relationships

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key drug target for the treatment of different hypercholesterolemia‐related diseases. A new class of small‐molecule inhibitors of PCSK9 transcription, characterized by a 4‐amino‐2‐pyridone scaffold, has been recently identified by our research group. Among them, the early lead compound 5c shows high in vitro potency and favorable in vivo tolerability. However, given the suboptimal in vitro metabolic stability of 5c , its optimization is reported herein by modification of the predicted metabolic soft spots through chemistry‐driven late‐stage functionalization (LSF) strategies. Microsomal stability on the newly synthesized derivatives allows drawing structure–metabolism relationships (SMRs) that, coupled with a thorough pharmacological investigation on HepG2 cells, leads to the identification of novel C3‐ and dual C3/NHC4‐functionalized pyridones with improved stability and superior pharmacological profiles. Notably, compounds 6b , 7 , and 18a emerge as the best candidates, demonstrating markedly improved metabolic stability/PCSK9 IC 50 ratio and comparable or lower cytotoxicity with respect to the parent compound 5c . These findings underscore the value of LSF strategies in generating optimized analogs of 5c with strong potential for further preclinical development.

Rare‐Earth Salicylate Phenanthroline Complexes Cause Cell Death in Human Tumor Cells

Rare‐earth (RE) salicylate phenanthroline complexes [RE(sal) 3 (phen)] (RE = Y, Eu, Dy, Yb; sal = salicylate; Phen = 1,10‐phenanthroline) are conveniently prepared starting from RE homoleptic carbamate precursors and salicylic aldehyde in the presence of phenanthroline. The yttrium derivative is structurally characterized by single‐crystal X‐ray diffraction, IR, and NMR spectroscopy, showing the mononuclear nature of the complex, while the structure of the other paramagnetic complexes are assigned on comparative IR spectra bases and elemental analyses. The antiproliferative effect of the complexes are studied in vitro on a panel of human tumor cell lines (A2780, ovarian carcinoma sensitive to cisplatin; A2780cis, ovarian carcinoma resistant to cisplatin and LN229, glioblastoma), and on nontumorigenic mesothelial cells (MeT‐5A). The reactive oxygen species production is determined to investigate the intracellular mechanism of action. For the most interesting complex [Dy(sal) 3 (phen)] ( 3 ), the effects on mitochondrial transmembrane potential and on cell cycle are also analyzed. Finally, epifluorescence images allow to demonstrate the uptake of the complex and to observe relevant morphological changes in cells, suggesting the occurrence of mitotic catastrophe.

Synthesis and In Vitro Activity of Hypofuran B and Analogs Against Plasmodium Falciparum and Trypanosoma Cruzi

Herein, the synthesis and biological evaluation of hypofuran B and a series of analogs against Trypanosoma cruzi and Plasmodium falciparum is described. The compounds are obtained through crossed aldol condensation between phenylacetaldehyde and furfural derivatives, using reaction conditions optimized according to the aromatic substituents. Yields ranged from 20% to 83%, with E / Z ratios between 89:11 and 98:2. Three compounds are isolated as single crystals suitable for X‐ray diffraction, and their crystal structures are determined. The most active analogs showed IC 50 values of 5.35–10.35 µg mL −1 and are further evaluated for cytotoxicity in L929 cells. For P. falciparum , a clear structure–activity–toxicity relationship is observed. The most promising compound displayed a CC 50 value above 400 µg mL −1 , indicating lower cytotoxicity than chloroquine. In silico predictions also supported favorable drug‐like profiles. Overall, the moderate antiparasitic activity, low cytotoxicity, and consistent structure–activity trends highlight hypofuran B and related drynaran derivatives as promising antimalarial leads.

Functional Proteomics of Quinazolin‐4‐One Derivatives Targeting the Proteasome

Quinazolinones have been recently recognized as valuable scaffolds for developing novel therapeutic opportunities. They indeed exhibit structural versatility and a wide range of biological activities, including antifungal, antitubercular, antihypertensive, anticancer, and antiviral ones. In this work, a focused library of new bioactive 4‐(3‐H)‐quinazolinones has been synthesized, their cytotoxic action against DU‐145 prostate cancer cells has been detailed, and compound 4k has been revealed as the most active one. Consequently, its interactome has been characterized by a label‐free functional proteomics‐based platform coupling drug affinity responsive target stability (DARTS) and targeted limited proteolysis‐multiple reaction monitoring‐mass spectrometry (t‐LiP‐MRM‐MS). This multifaced strategy has been employed to reveal few subunits of the 26S proteasome machinery as the most reliable compound 4k biological targets. This paved the way for the deepening of the protein–ligand interaction using in vitro and in silico bio‐orthogonal techniques. Finally, the analysis of its function in living DU‐145 cells prompted compound 4k as a novel quinazolinone‐bearing inhibitor of the chymotrypsin‐like activity of the proteasomal β −5 subunit, stirring this framework for the development of new anticancer drugs.

Synthesis of Benzopyrans and Quinolines with Nitrogenated Chain and Their Cytotoxicity Against Human Cancer Cell Lines

Cancer caused 9.9 million deaths in 2020, and natural products and/or their structural analogs represent the greatest number of approved small‐molecules antitumor agents. Benzopyran and quinoline heterocycles have demonstrated cytotoxic activity against different cancer cell lines. Due to its high therapeutic potential, we report the synthesis of 2‐propanamide‐ and 2‐propanamine‐dihydrobenzopyrans bearing different amine moieties in the side chain, as well as the 7‐carbon prenylated derivatives (analogous to natural polyalthidin). Next, we synthesized the 2‐substituted and 2,3‐disubstituted quinolines as benzopyran analogs. We evaluated the cytotoxic activity of all nitrogenated derivatives against human cancer cell lines, including A549 (lung cancer), A2058 (melanoma), HepG2 (hepatocellular carcinoma), MCF‐7 (breast cancer), and Mia PaCa‐2 (pancreas cancer) by the MTT assay. Structure–activity relationship analysis revealed: (i) the benzopyran core was twofold more cytotoxic than quinoline analogs and reached ED 50 values in the low micromolar range (ED 50  < 10 μM) against A2058, HepG2, and MCF‐7; (ii) benzopyran amides showed higher cytotoxicity than benzopyran amines against MCF‐7, and afforded better results for studied lines except for Mia PaCa‐2; and (iii) the amine moiety introduced at 2‐position played a key role for activity; (iv) benzyl and p ‐fluorobenzyl substituents protecting phenol group at 6‐position afforded a similar cytotoxicity.

Front Cover: Functional Proteomics of Quinazolin‐4‐One Derivatives Targeting the Proteasome (ChemMedChem 2/2026)

This cover shows the quinazolinone 4k approaching 26S proteasome, as discovered by limited proteolysis‐based functional proteomics. Its interacting partners, the 20S β2 and β5 subunits, are depicted in white and light blue, respectively. The resulting inhibition of β5 chymotrypsin‐like activity results in 4k cytotoxicity, represented by the green living cells turning into red, dying ones. More details can be found in the Research Article by Carmen Festa, Maria Chiara Monti, and co‐workers (DOI: 10.1002/cmdc.202500728 ).

Fluorescent Dyes for Probing Intracellular and Subcellular Polarity

Herein, the use of solvatochromic fluorescent probes for detecting polarity in cellular microenvironments, a complex physicochemical parameter that influences various biological processes, is reviewed. The nature of polarity itself is related to the physicochemical properties of the environment that affect the spectroscopic properties of luminophores. The mechanisms of solute–solvent interactions and photophysical processes, such as intramolecular charge transfer and photoinduced electron transfer, which are fundamental to understanding the response of the probes to polarity changes are discussed. In the intracellular context, solvatochromic probes have been used to determine polarity in different organelles and subcellular structures. The review puts emphasis on the various targeting strategies and the most commonly utilized photophysical parameters for estimating polarity are focused here. A special attention is paid to those approaches capable of providing absolute quantification of intracellular polarity, for instance, through ratiometric measurements or the use of fluorescence lifetime imaging to improve the accuracy of measurements. Reliable intracellular polarity measurements may provide invaluable information to understand physiological and pathological processes, including neurodegenerative diseases or cancer.

Front Cover: Fluorescent Dyes for Probing Intracellular and Subcellular Polarity (Chem. Methods 1/2026)

The Front Cover shows fluorescence probes that report on subcellular polarity; they are exquisitely tailored by combining environment‐sensitive dyes with organelle‐targeting groups: the “keys” for specific delivery. Such probes have allowed polarity scales within organelles to be established—from the most hydrophobic regions in lipid droplets and membranes to the most polar cellular structures like mitochondria—thus providing invaluable tools for studying polarity changes related to physiological processes and disease. More information can be found in the Review by M. C. Gonzalez‐Garcia, A. Orte and co‐workers (DOI: 10.1002/cmtd.202500072 ). Artwork by Letpub Accdon Ltd.