Related Analogues Research Articles

Zephycandidine A and Synthetic Analogues—Synthesis and Evaluation of Biological Activity

A convenient total synthesis of the imidazo[1,2-f]phenanthridine-type Amaryllidaceae alkaloid zephycandidine A (3) was developed, which further allowed us to perform modifications of substituents on benzenoid ring A and imidazole ring D. The biological activities of all synthesized compounds were evaluated, and it was reported that activities against cancer cells of the parent alkaloid were poorly reproducible, while the closely related analogue THK-121 (11) showed a strong inhibitory effect on proliferation. Additionally, our novel analogue significantly induced cell death via the intrinsic apoptosis pathway, evident by the loss of mitochondrial membrane potential, increased mitochondrial oxidative stress, and disrupted mitochondrial structure in the same cells. At the same time, healthy cells were less affected by the treatment with THK-121 (11), indicating a potential therapeutic margin.

Quinoxaline-based anti-schistosomal compounds have potent anti-plasmodial activity.

The human pathogens Plasmodium and Schistosoma are each responsible for over 200 million infections annually, especially in low- and middle-income countries. There is a pressing need for new drug targets for these diseases, driven by emergence of drug-resistance in Plasmodium and an overall dearth of drug targets against Schistosoma. Here, we explored the opportunity for pathogen-hopping by evaluating a series of quinoxaline-based anti-schistosomal compounds for their activity against P. falciparum. We identified compounds with low nanomolar potency against 3D7 and multidrug-resistant strains. In vitro resistance selections using wildtype and mutator P. falciparum lines revealed a low propensity for resistance. Only one of the series, compound 22, yielded resistance mutations, including point mutations in a non-essential putative hydrolase pfqrp1, as well as copy-number amplification of a phospholipid-translocating ATPase, pfatp2, a potential target. Notably, independently generated CRISPR-edited mutants in pfqrp1 also showed resistance to compound 22 and a related analogue. Moreover, previous lines with pfatp2 copy number variations were similarly less susceptible to challenge with the new compounds. Finally, we examined whether the predicted hydrolase activity of PfQRP1 underlies its mechanism of resistance, showing that both mutation of the putative catalytic triad and a more severe loss of function mutation elicited resistance. Collectively, we describe a compound series with potent activity against two important pathogens and their potential target in P. falciparum.

Toxicological evaluation, postmortem case descriptions, and pharmacological activity of N,N-dimethylpentylone and related analogues.

Identification of N,N-dimethylpentylone (DMP) in counterfeit "Ecstasy" and "Molly" tablets poses risk to public health due to its adverse effects. Little information is available regarding the pharmacological activity or relevant blood or tissue concentrations of DMP, and even less is known about other structurally related beta-keto methylenedioxyamphetamine analogues on recreational drug markets, such as N-propyl butylone. Here, a novel toxicological assay utilizing liquid chromatography-tandem quadrupole mass spectrometry (LC-QQQ-MS) was developed and validated for the quantitation of DMP and five related synthetic cathinones (eutylone, pentylone, N-ethyl pentylone (NEP), N-propyl butylone, and N-cyclohexyl butylone), with chromatographic resolution from isomeric variants and quantitation performed by standard addition. A forensic series of 125 cases is presented for DMP and related analogs, along with pharmacological activity assessments using monoamine transporter and mouse behavioral assays. The blood concentration range for DMP in postmortem forensic cases was 3.3-4,600 ng/mL (mean: 320±570 ng/mL, median: 150 ng/mL), whereas pentylone, the primary N-desmethyl metabolite of DMP, was identified in 98% of cases with a concentration range 1.3-710 ng/mL (mean±SD: 105±120 ng/mL, median: 71 ng/mL). N-Propyl butylone, a newly identified synthetic cathinone, was quantitated in seven cases (mean±SD: 82±75 ng/mL, median: 50 ng/mL, range: 1.7-200 ng/mL). DMP displayed potent uptake inhibition at the dopamine transporter (IC50=49 nM), with 100-fold weaker potency at the serotonin transporter (IC50=4990 nM). DMP was a locomotor stimulant in mice (ED50=3.5 mg/kg) exhibiting potency relatively similar to eutylone, N-ethyl pentylone, and pentylone. Our results show that DMP is a psychomotor stimulant associated with adverse clinical outcomes leading to death. Forensic laboratories must continue to update testing methods to capture emerging drugs, with specific emphasis on resolution and identification of isomeric species. Following the scheduling of DMP in early-2024, there could be an anticipated market shift towards a new unregulated synthetic stimulant to replace DMP.

Retrospective Evaluation of Novel Synthetic Opioids and Xylazine Chronic Intake by Post-Mortem Hair Testing.

Fentanyl and its derivatives (nonpharmaceutical fentanyl, NPFs) represent the largest group among synthetic opioids. Fentanyl-related deaths and fatalities from tampering with pharmaceutical products have been reported. Furthermore, in the United States, adulterants such as xylazine and other substances, including the nitazenes class of opioids, have been found in an increasing number of unintentional overdose deaths, drug seizures, and reports of use by recreational drug users. Monitoring the diffusion of fentanyl, NPFs, nitazenes, and adulterants among the population is a fundamental pursuit in forensic toxicology. The use of hair analysis is perfect for this purpose, providing essential information regarding previous intake or exposure to xenobiotics. The present study focused on the development and validation of a UPLC-MS/MS method for the detection and quantification of fentanyl, NPFs, and xylazine, as well as the semiquantitative detection of nitazenes in hair samples from post-mortem cases collected under the jurisdiction of the Jefferson County Coroner/Medical Examiner's Office (Birmingham, AL, USA). The method was validated according to international guidelines and applied to the analysis of n = 250 post-mortem hair samples. In 52% of the analyzed hair samples, fentanyl, its main metabolites, and related analogs were detected, showing significant exposure to these substances in the population. Moreover, xylazine was detected in n = 48 hair samples (19.2%). The developed UPLC-MS/MS method proved suitable for rapid chromatographic separation and sensitive detection of the studied compounds. In addition, this is the first time that xylazine and protonitazene have been measured in hair samples of subjects exposed to synthetic opioids.

Mechanistic Insights into the Anticancer Potential of Methoxyflavones Analogs: A Review.

2-phenylchromen-4-one, commonly known as flavone, plays multifaceted roles in biological response that can be abundantly present in natural sources. The methoxy group in naturally occurring flavones promotes cytotoxic activity in various cancer cell lines by targeting protein markers, in facilitating ligand-protein binding mechanisms and activating cascading downstream signaling pathways leading to cell death. However, the lipophilic nature of these analogs is a key concern as it impacts drug membrane transfer. While lipophilicity is crucial for drug efficacy, the excessive lipophilic effects in flavonoids can reduce water solubility and hinder drug transport to target sites. Recent in vitro studies suggest that the incorporation of polar hydroxyl groups which can form hydrogen bonds and stabilize free radicals may help overcome the challenges associated with methoxy groups while maintaining their essential lipophilic properties. Naturally coexisting with methoxyflavones, this review explores the synergistic role of hydroxy and methoxy moieties through hydrogen bonding capacity in maximizing cytotoxicity against cancer cell lines. The physicochemical analysis revealed the potential intramolecular interaction and favorable electron delocalization region between both moieties to improve cytotoxicity levels. Together, the analysis provides a useful strategy for the structure-activity relationship (SAR) of flavonoid analogs in distinct protein markers, suggesting optimal functional group positioning to achieve balanced lipophilicity, effective hydrogen bonding, and simultaneously minimized steric hindrance in targeting specific cancer cell types.

Mining Druggable Sites in Influenza A Hemagglutinin: Binding of the Pinanamine-Based Inhibitor M090.

Assessing the binding mode of drug-like compounds is key in structure-based drug design. However, this may be challenged by factors such as the structural flexibility of the target protein. In this case, state-of-the-art computational methods can be valuable to explore the linkages between structural and pharmacological data. Following this strategy, extended molecular dynamics simulations and thermodynamic integration calculations are used to examine the binding of the potent antiviral inhibitor M090 and related pinanamine-based analogues, covering a 250-fold difference in inhibitory potency to the influenza A hemagglutinin, which is essential for virus entry and membrane fusion. This analysis has disclosed the hydrophobic shielding effect played by the 3-cyclopropylthiophene moiety in M090. Furthermore, the results support the negative effect of the resistance-induced E742 → D mutation, which should weaken the binding by increasing the structural flexibility of the L2-BS loop. The results pave the way to exploration of the antiviral activity of novel compounds.

Multi-scale approach: Structure–texture relationship of meat and meat analogues

Plant-based meat analogues are considered a sustainable substitute for meat. However, the current attempts to reproduce the visible fibrous structure on a macro scale (1 mm) have not yet achieved the desired texture properties. The role of the meso-scale fiber structure (50–200 μm) in the meat texture remains uncertain. To characterize the texture properties, this study employed Warner–Bratzler shear force tests and texture profile analysis, comparing cuts that were parallel and perpendicular to the fiber direction. Scanning electron microscopy was employed for the purpose of structural characterization. Anisotropy and texture properties were observed to differ between the meat and the meat analogues. The meat exhibited a fibrous structure at both the macro and meso scales, while the meat analogues displayed a porous structure without a clear fiber direction from the meso scale onward. The texture of meat is primarily determined by the connective tissue and muscle fibers, whereas the texture of meat analogues is mainly influenced by the fibers. This study elucidates the structure–texture relationships of meat and meat analogues at macro and meso scales, developing a mechanistic model to explain their differing responses to mechanical stress. These findings are crucial for improving the texture properties of meat analogues, advancing their ability to mimic meat's texture.

Mixed-mode separation of antisense oligonucleotides using a single column with complementary anion-exchange and hydrophobic interaction chromatography approaches

The current study investigates the use of mixed-mode chromatography as a combination of anion-exchange (AEX) and hydrophobic interaction chromatography (HIC) for the analysis and purification of single-stranded antisense oligonucleotides with stereo-controlled phosphorothioate inter- nucleotide linkages.Initially a Scherzo-SS-C18 trimodal stationary phase with reversed-phase/AEX/ cation-exchange (CEX) functionalities is systematically evaluated to reveal the presence of U-shaped retention composed of two retention modes namely AEX and HIC, where the latter was also observed on related trimodal Scherzo SM and SW analogues. For the first time, retention and separation of deprotected oligonucleotides was described on a single mixed-mode column using a combination of AEX and HIC. This methodology was later applied to an alternative reversed-phase/AEX support, Newcrom BH, displaying similar retention trends under dual salt / organic modifier gradients. The merit of the method was assessed on the basis of separations between a phosphodiester (PO) impurity and phosphorothioate (PS) target for an assortment of selected 2’-O-methoxyethyl 18- to 20-mer single-stranded antisense oligonucleotides. Various parameters were evaluated mostly under HIC conditions including organic modifier percentage, type of salt, temperature, pH and type of buffer in the mobile phase. Retention of the oligonucleotides was significantly affected by the acetonitrile composition and the type of salt ((NH4)2SO4, NaBr, NaCl) where the latter NaCl also afforded resolution between the PS target and closely eluting PO impurities. Small changes in pH between 6.5 and 7 using MES and TRIS respectively demonstrated notable differences in retention and resolution. The optimized methods were compared against a range of traditional supports and applied to various mixed-mode analogues, possessing embedded amino acid, complex forming weak cation-exchange and terminal strong cation-exchange functionalities. The mixed-mode supports displayed HIC retention and better resolution between PS target and PO impurity was evident with a more focused 5% acetonitrile gradient over its 10% counterpart. Overall, throughout the study AEX and HIC demonstrated comparable resolution trends.Finally, the optimized HIC method was applied to a selected 18-mer antisense oligonucleotide at semi-preparative scale using the Newcrom BH column, affording purities of 60-80% and recoveries of 52-76%. Although HIC does not provide better separations between PS and PO than AEX, it opens possibilities to operate under non-denaturing conditions and allows purification of samples containing high salt content, as a standalone method or post AEX without a prior desalting step, which can result in 20-30% sample loss.

2-Acylpyrrole-based alkaloids from the leaves of Sauropus spatulifolius and their α-glucosidase inhibitory activities.

Pyrrole alkaloids are a class of natural products with intriguing structures and promising biological actives. Within the Sauropus plants, these alkaloids are mainly present in Sauropus spatulifolius. An investigation of the leaves of S. spatulifoliuswas conducted to discover novel and bioactive pyrrole alkaloids. This study led to the identification of 38 alkaloids, including 21 new pyrrole alkaloids (1-5, 13, 16, 19-23, 26-31, 33, 35, and 36), along with 17 related analogues (6-12, 14, 15, 17, 18, 24, 25, 32, 34 37, and 38). The structures of the new compounds were elucidated by NMR, HRESIMS, electronic circular dichroism (ECD), and X-ray diffraction analysis. Notably, compounds 28-31 were identified as pyrrole alkaloids with unprecedented skeletons. Compounds 28 and 29 featured a 2-acylpyrrole alkaloid and a cinnamic acid heterodimers, while 30 and 31 possessed a pyrrolooxazinone scaffold with a 1,2-hexadecanediol moiety. These structures were rare in plants. Three compounds (27, 31, and 38) displayed α-glucosidase inhibitory activity. Particularly, compounds 27 (IC50: 320.3μM) and 31 (IC50: 153.7μM) exhibited stronger activity than that of acarbose (IC50: 545.9μM). Molecular docking studies showed the strong interactions of the three bioactive compounds with the α-glucosidase protein. Additionally, compounds 27, 31, and 38 showed significant effects on enhancing glucose consumption in HepG2 cells.

Breviane Spiroditerpenoids with Anti-inflammatory and Antiviral Activities from Deep-Sea-Derived Fungus Penicillium sp. F59.

Twelve new breviane spiroditerpenoids, namely, chrysobreviones A-L (1-12), together with seven structurally related analogues (13-19) were isolated from the EtOAc extract of the fermented cultures of deep-sea-derived fungus Penicillium sp. F59. These structures including absolute configurations were resolved on the basis of extensive analysis of NMR spectroscopic data and HRESIMS, in association with experimental and calculated ECD data as well as the modified Mosher's method. Compound 1 represented the first breviane derivative containing an unusual octahydrodifuro[2,3-b:2',3'-d]furan moiety, while 7 and 9 were the first breviones featuring an epoxy ring and an 18-hydroxymethyl group, respectively. The anti-inflammatory and antiviral activities of compounds 1-19 were evaluated. Compounds 1, 8, 16, and 17 showed inhibitory effects against NO secretion in LPS-activated Raw264.7 macrophage cells with IC50 values ranging from 1.4 to 12.9 μM, while 1 and 7 exhibited antiviral effects against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) omicron subvariant BA.2 pseudovirus with IC50 values of 8.5 and 10.3 μM, respectively.

UPLC-MS/MS High-Risk Screening for Sphingolipidoses Using Dried Urine Spots

Background: Early detection of sphingolipidoses is crucial to prevent irreversible complications and improve patient outcomes. The use of urine samples dried on filter paper (DUS) is a non-invasive strategy that simplifies the collection, storage, and shipping of samples compared to using liquid urine specimens. Objectives: (1) Develop and validate a multiplex ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS) methodology using DUS to quantify twenty-one lysosphingolipids normalized to creatinine for eight different sphingolipidoses. (2) Establish normal reference values to evaluate the clinical utility of the methodology. Methods: Samples were eluted from a 5 cm filter paper disk (~1 mL of urine) and extracted on Oasis MCX solid-phase extraction cartridges prior to injection in the UPLC-MS/MS system. Results: Urinary lysosphingolipids were stable on DUS at −80 °C and −30 °C for 117 days, at 21.5 °C and 4 °C for at least 26 days, and at 35 °C for 3 days. Globotriaosylsphingosine, glucosylsphingosine, and their analogs were elevated in patients with Fabry disease and Gaucher disease, respectively, compared to controls (p-value < 0.0001). The analysis of related analog profiles suggests a better overall reliability in detecting patients early, especially for Fabry patients. Conclusions: This approach is feasible and might be useful for the early detection, monitoring, and follow-up of patients with sphingolipidoses.

Exploring Mycolactone-The Unique Causative Toxin of Buruli Ulcer: Biosynthetic, Synthetic Pathways, Biomarker for Diagnosis, and Therapeutic Potential.

Mycolactone is a complex macrolide toxin produced by Mycobacterium ulcerans, the causative agent of Buruli ulcer. The aim of this paper is to review the chemistry, biosynthetic, and synthetic pathways of mycolactone A/B to help develop an understanding of the mode of action of these polyketides as well as their therapeutic potential. The synthetic work has largely been driven by the desire to afford researchers enough (≥100 mg) of the pure toxins for systematic biological studies toward understanding their very high biological activities. The review focuses on pioneering studies of Kishi which elaborate first-, second-, and third-generation approaches to the synthesis of mycolactones A/B. The three generations focused on the construction of the key intermediates required for the mycolactone synthesis. Synthesis of the first generation involves assignment of the relative and absolute stereochemistry of the mycolactones A and B. This was accomplished by employing a linear series of 17 chemical steps (1.3% overall yield) using the mycolactone core. The second generation significantly improved the first generation in three ways: (1) by optimizing the selection of protecting groups; (2) by removing needless protecting group adjustments; and (3) by enhancing the stereoselectivity and overall synthetic efficiency. Though the synthetic route to the mycolactone core was longer than the first generation, the overall yield was significantly higher (8.8%). The third-generation total synthesis was specifically aimed at an efficient, scalable, stereoselective, and shorter synthesis of mycolactone. The synthesis of the mycolactone core was achieved in 14 linear chemical steps with 19% overall yield. Furthermore, a modular synthetic approach where diverse analogues of mycolactone A/B were synthesized via a cascade of catalytic and/or asymmetric reactions as well as several Pd-catalyzed key steps coupled with hydroboration reactions were reviewed. In addition, the review discusses how mycolactone is employed in the diagnosis of Buruli ulcer with emphasis on detection methods of mass spectrometry, immunological assays, RNA aptamer techniques, and fluorescent-thin layer chromatography (f-TLC) methods as diagnostic tools. We examined studies of the structure-activity relationship (SAR) of various analogues of mycolactone. The paper highlights the multiple biological consequences associated with mycolactone such as skin ulceration, host immunomodulation, and analgesia. These effects are attributed to various proposed mechanisms of actions including Wiskott-Aldrich Syndrome protein (WASP)/neural Wiskott-Aldrich Syndrome protein (N-WASP) inhibition, Sec61 translocon inhibition, angiotensin II type 2 receptor (AT2R) inhibition, and inhibition of mTOR. The possible application of novel mycolactone analogues produced based on SAR investigations as therapeutic agents for the treatment of inflammatory disorders and inflammatory pain are discussed. Additionally, their therapeutic potential as anti-viral and anti-cancer agents have also been addressed.

An Insight into Common and Advanced Synthesis Methodologies of Acyl Urea Analogs Targeting the CNS

: The acyl urea functionality and related analogs are increasingly used in medicinal chemistry and drug design to prove well-defined pharmacological actions and optimal physicochemical properties. This review paper aimed to summarize information related to synthesis methods of acyl urea derivatives, marketed products, and patents to explore their applications in counteracting CNS-related diseases by multiple targeting. Comprehensive data related to acyl urea and related compounds of the last 15 years is collected from various resources to provide enormous information to the readers. The content of the study uniformly includes considerable evidence linked to the common and unique synthesis techniques of acyl urea from starting materials like benzamide, isocyanates, substituted iodoglycals, 2 chloro nicotinic acid, and methyl hydrazines, as well as patents related to the same. This work describes the reactions of several substrates that can be used to manufacture various acyl urea derivatives. An understanding of patents related to acyl urea analogs with specific targets for CNS action may also help researchers working on additional synthesis of acyl urea derivatives with potential CNS action.

Preconception exposure to bisphenol A and its alternatives: Effects on female fecundity mediated by oxidative stress and ovarian reserve.

Various 'Bisphenol A (BPA)-free' alternatives have emerged in numerous personal products in recent years. However, it remains unclear whether BPA analogs affect female fecundity and possible biological mechanisms. We aimed to evaluate the relationships of bisphenol analogs with female fecundability and infertility and whether oxidative stress, inflammation, and ovarian reserve may play a mediation role in such associations. This prospective preconception cohort study included 957 couples who attempted pregnancy. BPA and six alternatives were measured in women's urine samples. Bisphenol analogs-outcome associations were estimated using discrete-time Cox hazards and logistic regression models. A quantile g-computation (QGC) methodology was further applied to assess the joint effects of co-exposure to bisphenol analogs on fecundity. We also quantified three biomarkers, including malondialdehyde (MDA), C-reactive protein and Anti-Müllerian hormone (AMH), to explore possible biological pathways. Using an integrated analytical approach consisting of both single-pollutant and mixture models, we found that BPA and bisphenol AP (BPAP) were significantly associated with decreased fecundability (adjusted fecundability ratio (aFR)=0.87, 95%CI: 0.81, 0.94 for BPA; aFR=0.64, 95%CI: 0.48, 0.84 for BPAP) and increased risk of infertility (adjusted odd ratio (aOR)=1.23, 95%CI: 1.06, 1.44 for BPA; aOR=2.27, 95%CI: 1.29, 3.99 for BPAP) after controlling for other bisphenol analogs. The link between BPA and prolonged time to pregnancy was more prominent in overweight or obese women and those who had regular menstrual cycles. Bisphenol AF was associated with impaired fecundity in women aged 35years or older. The mixed effects of bisphenol analogs on fecundity were statistically non-significant. Mediation analysis revealed a significant indirect effect of urinary MDA and serum AMH in bisphenol analogs-induced impaired fecundity, with all average causal mediation effects (ACME) showing statistical significance (PACME<0.05). Our prospective preconception cohort study suggests that BPA and BPAP may be associated with impaired female fecundity. Increased oxidative stress and decreased ovarian reserve may be the underlying pathways.

Examining structure-activity relationships of ManNAc analogs used in the metabolic glycoengineering of human neural stem cells

Examining structure-activity relationships of ManNAc analogs used in the metabolic glycoengineering of human neural stem cells

Discovery of New Antifungal Polyketides Cladrioides A-N against Phytopathogenic Fungi from Cladosporium cladosporioides LD-8.

During the search for natural fungicides, 14 new australifungin analogues cladrioides A-S (1-14) and two known ones (15 and 16) were obtained from Cladosporium cladosporioides LD-8. Their structures were elucidated by comprehensive analysis of NMR and HRESIMS data, as well as ECD calculations. Compounds 1 and 2 possess a novel 6/6/5-fused tricyclic scaffold. Most of the compounds exhibited remarkable antifungal activities against the tested phytopathogenic fungi. Among them, compounds 7, 10, and 16 showed excellent activities with IC50 values ranging from 1.71 to 16.63 μg/mL. Their inhibitory activities against A. brassicicola and A. alternata were higher than that of the commercial fungicide hymexazol. Compound 16 displayed potent in vivo antifungal activity against A. solani at 100 μg/mL with an inhibitory rate of 96.82%. The structure-activity relationship of antifungal australifungin analogues was analyzed for the first time. Therefore, our study provides promising candidates for the development of new fungicides for plant protection.

Classification of psychedelics and psychoactive drugs based on brain-wide imaging of cellular c-Fos expression.

Psilocybin, ketamine, and MDMA are psychoactive compounds that exert behavioral effects with distinguishable but also overlapping features. The growing interest in using these compounds as therapeutics necessitates preclinical assays that can accurately screen psychedelics and related analogs. We posit that a promising approach may be to measure drug action on markers of neural plasticity in native brain tissues. We therefore developed a pipeline for drug classification using light sheet fluorescence microscopy of immediate early gene expression at cellular resolution followed by machine learning. We tested male and female mice with a panel of drugs, including psilocybin, ketamine, 5-MeO-DMT, 6-fluoro-DET, MDMA, acute fluoxetine, chronic fluoxetine, and vehicle. In one-versus-rest classification, the exact drug was identified with 67% accuracy, significantly above the chance level of 12.5%. In one-versus-one classifications, psilocybin was discriminated from 5-MeO-DMT, ketamine, MDMA, or acute fluoxetine with >95% accuracy. We used Shapley additive explanation to pinpoint the brain regions driving the machine learning predictions. Our results support a novel approach for characterizing and validating psychoactive drugs with psychedelic properties.

Synthesis and Structure-Activity Relationship of Covalent Inhibitors of SARS-CoV-2 Papain-Like Protease with Antiviral Potency

The papain-like protease (PLpro) is a highly conserved domain encoded by the coronavirus (CoV) genome and it plays an essential role in the replication and maturation of the virus in addition to weakening host immune response. Due to the virus’s reliance on PLpro for survival and propagation, small-molecule inhibitors of PLpro serve as an attractive model for direct-acting antiviral therapeutic agents against SARS-CoV-2. Building upon existing work aimed at designing covalent inhibitors against PLpro, we report the synthesis and structure–activity relationship of analogs based on the known covalent inhibitor 1 (Sanders, et al.2023). To evaluate the efficacy of synthesized derivatives, we conducted enzymatic inhibition assays, SARS-CoV-2/HeLa-ACE2 cellular potency and toxicity assays, and profiled the most promising analogs via in vitro ADME and in vivo pharmacokinetic studies. Additionally, we describe computational docking of profiled compounds bound to PLpro to elucidate the structure–activity relationship of compounds based on 1 and offer suggestions for optimizing the potency and selectivity of the electrophilic warhead and improving ADME and PK properties for this chemotype. Relative to the parent compound, new designs demonstrate comparable potency and target selectivity for PLpro. The accomplished SAR campaign provides novel insight for future development of antivirals against SARS-CoV-2.

Analogy and Image in E. L. Mascall

AbstractE. L. Mascall devoted much of his early scholarly career to developing accounts of analogy and natural theology grounded in the study both of Thomas Aquinas and in his Thomist successors. This essay examines Mascall’s account of analogy in relation to other views on analogy in his day, finding that in the 1950s, ‘image’ becomes at least as important a category for Mascall as ‘analogy’. Even while beginning from Thomist metaphysical standpoints and motivated by Thomist considerations, Mascall develops an account of thinking and speaking about God that diverges from his Thomist contemporaries, resembling more the thought of his ‘para-Thomist’ friend and colleague, Austin Farrer.

Concentric dual π delocalisation and conflicting aromaticity in bowl-like B56 cluster: an all-boron analogue of circumbiphenyl C38H16

We present computational evidence for concentric dual π delocalisation and conflicting aromaticity in an elongated quasi-planar bowl-like B56 (C 2v, 1A1) cluster, using the canonical molecular orbital (CMO) and the adaptive natural density partitioning (AdNDP) analyses at the density functional theory (DFT) level. The first B12 and second B18 rings constitute an inner BDR ribbon, and the second B18 and third B24 rings form an outer BDR ribbon. Chemical bonding analyses indicate that the 19 delocalised π bonds can be divided into two separate π subsystems, with inner 14π and outer 24π delocalised electrons. The bonding pattern is consistent with conflicting π aromaticity, which leads to an elongated geometry. A refined bonding model is also proposed for circumbiphenyl molecule C38H16, of which the B56 cluster is an inorganic analogue. The updated bonding pictures differ from that reported in prior studies on the system. It is further unravelled the mechanism as to why the two hexagonal holes prefer to be located at the centre. This research enriches the analogous relationship between quasi-planar boron clusters and their polycyclic hydrocarbons counterparts.