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Three new dihydroflavonols, gloverinols A-C ( 1 - 3 ), a new flavon-3-ol, gloverinol D ( 4 ), two new isoflavans, gloveriflavan A ( 5 ) and B ( 6 ), and seven known compounds were isolated from the root bark of Dalbergia gloveri . The structures of the isolates were elucidated by using NMR, ECD, and HRESIMS data analyses. Among the isolated compounds, gloverinol B ( 2 ), gloveriflavan B ( 6 ), and 1-(2,4-dihydroxyphenyl)-3-hydroxy-3-(4-hydroxyphenyl)-1-propanone ( 10 ) were the most active against Staphylococcus aureus , with MIC values of 9.2, 18.4, and 14.2 μM, respectively.

Cyclisation of peptides by forming thioether (lanthionine), disulfide (cystine) or methylene thioacetal bridges between side chains is established as an important tool to stabilise a given structure, enhance metabolic stability and optimise both potency and selectivity. However, a systematic comparative study of the effects of differing bridging modalities on peptide conformation has not previously been carried out. In this paper, we have used the NMR deconvolution algorithm, NAMFIS, to determine the conformational ensembles, in aqueous solution, of three cyclic analogues of angiotensin(1-7), incorporating either disulfide, or non-reducible thioether or methylene thioacetal bridges. We demonstrate that the major solution conformations are conserved between the different bridged peptides, but the distribution of conformations differs appreciably. This suggests that subtle differences in ring size and bridging structure can be exploited to fine-tune the conformational properties of cyclic peptides, which may modulate their bioactivities., (© 2024 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

It was recognized only recently that the sister norcembranoids scabrolides A and B have notably different carbotricyclic scaffolds. Therefore, our synthesis route leading to scabrolide A could not be extended to its sibling. Rather, a conceptually new approach had to be devised that relied on a challenging intramolecular alkenylation of a ketone to forge the congested central cycloheptene ring at the bridgehead enone site; the required cyclization precursor was attained by a lanthanide-catalyzed Mukaiyama-Michael addition. The dissonant 1,4-oxygenation pattern was then installed by allylic rearrangement/oxidation of the enone, followed by suprafacial 1,3-transposition. Synthetic scabrolide B was transformed into sinuscalide C by dehydration and into ineleganolide by base-mediated isomerization/oxa-Michael addition, which has potential biosynthetic implications; under basic conditions, the latter compound converts into horiolide by an intricate biomimetic cascade.

Higher-order foldamers represent a unique class of supramolecules at the forefront of molecular design. Herein we control quaternary folding using a novel approach that combines halogen bonding (XBing) and hydrogen bonding (HBing). We present the first anion-templated double helices induced by halogen bonds (XBs) and stabilized by "hydrogen bond enhanced halogen bonds" (HBeXBs). Our findings demonstrate that the number and orientation of hydrogen bond (HB) and XB donors significantly affect the quaternary structure and guest selectivity of two similar oligomers. This research offers new design elements to engineer foldamers and tailor their quaternary structure for specific guest binding.

Paritaprevir is an orally bioavailable, macrocyclic drug used for treating chronic Hepatitis C virus (HCV) infection. Its structures have been elusive to the public until recently when one of the crystal forms is solved by microcrystal electron diffraction (MicroED). In this work, the MicroED structures of two distinct polymorphic crystal forms of paritaprevir are reported from the same experiment. The different polymorphs show conformational changes in the macrocyclic core, as well as the cyclopropyl sulfonamide and methyl pyrazinamide substituents. Molecular docking shows that one of the conformations fits well into the active site pocket of the HCV non-structural 3/4A (NS3/4A) serine protease target, and can interact with the pocket and catalytic triad via hydrophobic interactions and hydrogen bonds. These results can provide further insight for optimization of the binding of acyl sulfonamide inhibitors to the HCV NS3/4A serine protease. In addition, this also demonstrates the opportunity to derive different polymorphs and distinct macrocycle conformations from the same experiments using MicroED., (© 2024 The Authors. Advanced Biology published by Wiley‐VCH GmbH.)

Three new ( 1 - 3 ) and six known rotenoids ( 5 - 10 ), along with three known isoflavones ( 11 - 13 ), were isolated from the leaves of Millettia oblata ssp. teitensis . A new glycosylated isoflavone ( 4 ), four known isoflavones ( 14 - 18 ), and one known chalcone ( 19 ) were isolated from the root wood extract of the same plant. The structures were elucidated by NMR and mass spectrometric analyses. The absolute configuration of the chiral compounds was established by a comparison of experimental ECD and VCD data with those calculated for the possible stereoisomers. This is the first report on the use of VCD to assign the absolute configuration of rotenoids. The crude leaves and root wood extracts displayed anti-RSV (human respiratory syncytial virus) activity with IC 50 values of 0.7 and 3.4 μg/mL, respectively. Compounds 6 , 8 , 10 , 11 , and 14 showed anti-RSV activity with IC 50 values of 0.4-10 μM, while compound 3 exhibited anti-HRV-2 (human rhinovirus 2) activity with an IC 50 of 4.2 μM. Most of the compounds showed low cytotoxicity for laryngeal carcinoma (HEp-2) cells; however compounds 3 , 11 , and 14 exhibited low cytotoxicity also in primary lung fibroblasts. This is the first report on rotenoids showing antiviral activity against RSV and HRV viruses.

Cystobactamids are aromatic oligoamides that exert their natural antibacterial properties by inhibition of bacterial gyrases. Such aromatic oligoamides were proposed to inhibit α-helix-mediated protein-protein interactions and may serve for specific recognition of DNA. Based on this suggestion, we designed new derivatives that have duplicated cystobactamid triarene units as model systems to decipher the specific binding mode of cystobactamids to double stranded DNA. Solution NMR analyses revealed that natural cystobactamids as well as their elongated analogues show an overall bent shape at their central aliphatic unit, with an average CX-CY-CZ angle of ~110 degrees. Our finding is corroborated by the target-bound structure of close analogues, as established by cryo-EM very recently. Cystobactamid CN-861-2 binds directly to the bacterial gyrase with an affinity of 9 μM, and also exhibits DNA-binding properties with specificity for AT-rich DNA. Elongation/dimerization of the triarene subunit of native cystobactamids is demonstrated to lead to an increase in DNA binding affinity. This implies that cystobactamids' gyrase inhibitory activity necessitates not just interaction with the gyrase itself, but also with DNA via their triarene unit., (© 2024 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Halenium ions, X + , are particularly strong halogen-bond donors that interact with two Lewis bases simultaneously to form linear [D···X···D] + -type halonium complexes. Their three-center, four-electron halogen bond is both fundamentally interesting and technologically valuable as it tames the reactivity of halogen(I) ions, opening up new horizons in a variety of fields including synthetic organic and supramolecular chemistry. Understanding this bonding situation enables the development of improved halogen(I) transfer reactions and of advanced functional materials. Following a decade of investigations of basic principles, the range of applications is now rapidly widening. In this Perspective, we assess the status of the field and identify its key advances and the main bottlenecks. Clearing common misunderstandings that may hinder future progress, we aim to inspire and direct future research efforts.

Molecular chameleons possess a flexibility that allows them to dynamically shield or expose polar functionalities in response to the properties of the environment. Although the concept of molecular chameleons was introduced already in 1970, interest in them has grown considerably since the 2010s, when drug discovery has focused to an increased extent on new chemical modalities. Such modalities include cyclic peptides, macrocycles and proteolysis-targeting chimeras, all of which reside in a chemical space far from that of traditional small-molecule drugs. Both cell permeability and aqueous solubility are required for the oral absorption of drugs. Engineering these properties, and potent target binding, into the larger new modalities is a more daunting task than for traditional small-molecule drugs. The ability of chameleons to adapt to different environments may be essential for success. In this Review, we provide both general and theoretical insights into the realm of molecular chameleons. We discuss why chameleons have come into fashion and provide a do-it-yourself toolbox for their design; we then provide a glimpse of how advanced in silico methods can support molecular chameleon design., (© 2023. Springer Nature Limited.)

Macrocycles are important drug leads with many advantages including the ability to target flat and featureless binding sites as well as to act as molecular chameleons and thereby reach intracellular targets. However, due to their complex structures and inherent flexibility, macrocycles are difficult to study structurally, and there are limited structural data available. Herein, we use the cryo-EM method MicroED to determine the novel atomic structures of several macrocycles that have previously resisted structural determination. We show that structures of similar complexity can now be obtained rapidly from nanograms of material and that different conformations of flexible compounds can be derived from the same experiment. These results will have an impact on contemporary drug discovery as well as natural product exploration.

Nuclear magnetic resonance (NMR) is the spectroscopic technique of choice for determining molecular conformations in solution at atomic resolution. As solution NMR spectra are rich in structural and dynamic information, the way in which the data should be acquired and handled to deliver accurate ensembles is not trivial. This Review provides a guide to the NMR experiment selection and parametrization process, the generation of viable theoretical conformer pools and the deconvolution of time-averaged NMR data into a conformer ensemble that accurately represents a flexible molecule in solution. In addition to reviewing the key elements of solution ensemble determination of flexible mid-sized molecules, the feasibility and pitfalls of data deconvolution are discussed with a comparison of the performance of representative algorithms., (© 2023. Springer Nature Limited.)

Six new crotofolane diterpenoids ( 1 - 6 ) and 13 known compounds ( 7 - 19 ) were isolated from the MeOH-CH 2 Cl 2 (1:1, v/v) extracts of the leaves and stem bark of Croton kilwae . The structures of the new compounds were elucidated by extensive analysis of spectroscopic and mass spectrometric data. The structure of crotokilwaepoxide A ( 1 ) was confirmed by single-crystal X-ray diffraction, allowing for the determination of its absolute configuration. The crude extracts and the isolated compounds were investigated for antiviral activity against respiratory syncytial virus (RSV) and human rhinovirus type-2 (HRV-2) in HEp-2 and HeLa cells, respectively, for antibacterial activity against the Gram-positive Bacillus subtilis and the Gram-negative Escherichia coli , and for antimalarial activity against the Plasmodium falciparum Dd2 strain. ent -3β,19-Dihydroxykaur-16-ene ( 7 ) and ayanin ( 16 ) displayed anti-RSV activities with IC 50 values of 10.2 and 6.1 μM, respectively, while exhibiting only modest cytotoxic effects on HEp-2 cells that resulted in selectivity indices of 4.9 and 16.4. Compounds 2 and 5 exhibited modest anti-HRV-2 activity (IC 50 of 44.6 μM for both compounds), while compound 16 inhibited HRV-2 with an IC 50 value of 1.8 μM. Compounds 1 - 3 showed promising antiplasmodial activities (80-100% inhibition) at a 50 μM concentration.

The ability to adjust conformations in response to the polarity of the environment, i.e. molecular chameleonicity, is considered to be important for conferring both high aqueous solubility and high cell permeability to drugs in chemical space beyond Lipinski's rule of 5. We determined the conformational ensembles populated by the antiviral drugs asunaprevir, simeprevir, atazanavir and daclatasvir in polar (DMSO-d 6 ) and non-polar (chloroform) environments with NMR spectroscopy. Daclatasvir was fairly rigid, whereas the first three showed large flexibility in both environments, that translated into major differences in solvent accessible 3D polar surface area within each conformational ensemble. No significant differences in size and polar surface area were observed between the DMSO-d 6 and chloroform ensembles of these three drugs. We propose that such flexible compounds are characterized as "partial molecular chameleons" and hypothesize that their ability to adopt conformations with low polar surface area contributes to their membrane permeability and oral absorption., (© 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

The nuclear magnetic resonance extracted data (NMReDATA) format has been proposed as a way to store, exchange, and disseminate nuclear magnetic resonance (NMR) data and physical and chemical metadata of chemical compounds. In this paper, we report on analytical workflows that take advantage of the uniform and standardized NMReDATA format. We also give access to a repository of sample data, which can serve for validating software packages that encode or decode files in NMReDATA format., (© 2021 The Authors. Magnetic Resonance in Chemistry published by John Wiley & Sons Ltd.)

To date, most nuclear magnetic resonance (NMR)-based 3-D structure determinations of both small molecules and of biopolymers utilize the nuclear Overhauser effect (NOE) via NOESY spectra. The acquisition of high-quality NOESY spectra is a prerequisite for quantitative analysis providing accurate interatomic distances. As the acquisition of NOE build-ups is time-consuming, acceleration of the process by the use of non-uniform sampling (NUS) may seem beneficial; however, the quantitativity of NOESY spectra acquired with NUS has not yet been validated. Herein, NOESY spectra with various extents of NUS have been recorded, artificial NUS spectra with two different sampling schemes created, and by using two different NUS reconstruction algorithms the influence of NUS on the data quality was evaluated. Using statistical analyses, NUS is demonstrated to influence the accuracy of quantitative NOE experiments. The NOE-based distances show an increased error as the sampling density decreases. Weak NOE signals are affected more severely by NUS than more intense ones. The application of NUS with NOESY comes at two major costs: the interatomic distances are determined with lower accuracy and long-range correlations are lost., (© 2021 The Authors. Magnetic Resonance in Chemistry published by John Wiley & Sons Ltd.)

Macrocycles constitute superior ligands for targets that have flat binding sites but often require long synthetic routes, emphasizing the need for property prediction prior to synthesis. We have investigated the scope and limitations of machine learning classification models and of regression models for predicting the cell permeability of a set of denovo-designed, drug-like macrocycles. 2D-Based classification models, which are fast to calculate, discriminated between macrocycles that had low-medium and high permeability and may be used as virtual filters in early drug discovery projects. Importantly, stereo- and regioisomer were correctly classified. QSPR studies of two small sets of comparator drugs suggested that use of 3D descriptors, calculated from biologically relevant conformations, would allow development of more precise regression models for late phase drug projects. However, a 3D permeability model could only be developed for a rigid series of macrocycles. Comparison of NMR based conformational analysis with in silico conformational sampling indicated that this shortcoming originates from the inability of the molecular mechanics force field to identify the relevant conformations for flexible macrocycles. We speculate that a Kier flexibility index of ≤10 constitutes a current upper limit for reasonably accurate 3D prediction of macrocycle cell permeability., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

It has been hypothesised that drugs in the chemical space "beyond the rule of 5" (bRo5) must behave as molecular chameleons to combine otherwise conflicting properties, including aqueous solubility, cell permeability and target binding. Evidence for this has, however, been limited to the cyclic peptide cyclosporine A. Herein, we show that the non-peptidic and macrocyclic drugs roxithromycin, telithromycin and spiramycin behave as molecular chameleons, with rifampicin showing a less pronounced behaviour. In particular roxithromycin, telithromycin and spiramycin display a marked, yet limited flexibility and populate significantly less polar and more compact conformational ensembles in an apolar than in a polar environment. In addition to balancing of membrane permeability and aqueous solubility, this flexibility also allows binding to targets that vary in structure between species. The drugs' passive cell permeability correlates to their 3D polar surface area and corroborate two theoretical models for permeability, developed for cyclic peptides. We conclude that molecular chameleonicity should be incorporated in the design of orally administered drugs in the bRo5 space., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Chemical probes that label proteins of interest in the context of complex biological samples are useful research tools. The reactive group that forms the covalent bond with the target protein has a large effect on the selectivity and selecting the appropriate group determines the success of a probe. We here report the development of a combinatorial methodology based on imine chemistry that enables straightforward in situ synthesis and screening of different reactive groups and thereby simplifies identification of probe leads. Using our methodology, we found chemical probes targeting BirA and chloramphenicol acetyl transferase, two proteins associated with antibacterial activity and resistance.