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Escaping from Flatland: Substituted Bridged Pyrrolidine Fragments with Inherent Three-Dimensional Character.

ABSTRACT: The pressure to deliver new medicines to the patient continues to grow along with increases in compound failure rate, thus putting the current R&D model at risk. Analysis has shown that increasing the three-dimensionality of potential drug candidates decreases the risk of failure and improves binding selectivity and frequency. For this reason many workers have taken a new look at the power of photochemistry as a means to generate novel sp³ rich scaffolds for use in drug discovery programs. Here we report the design, synthesis, and computational structural analysis of a series of 2,4-methanoprolines having inherent 3D character (PMI and PBF scores) significantly higher than that of the broader AbbVie Rule of 3 (Ro3) collection.

SUBMITTER: Cox B

PROVIDER: S-EPMC7294729 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Escaping from Flatland: Antimalarial Activity of sp<sup>3</sup>-Rich Bridged Pyrrolidine Derivatives.

Project description:We utilized synthetic photochemistry to generate novel sp3-rich scaffolds and report the design, synthesis, and biological testing of a diverse series of amides based on the 1-(amino-methyl)-2-benzyl-2-aza-bicyclo[2.1.1]hexane scaffold. Preliminary antimalarial screening of the library provided promising compounds with activity in the 1-5 μM range with an enhanced hit rate. Further evaluation (solubility, drug metabolism and pharmacokinetics (DMPK), and toxicity) of a selected compound (9) suggested that this series represents an excellent opportunity for further optimization with the framework offering multiple opportunities for the addition of uniquely vectorally positioned extra functionality.

| S-EPMC7734793 | biostudies-literature

Design and Synthesis of Pyrrolidine-based Fragments That Sample Three-dimensional Molecular Space.

Project description:Fragment-based drug discovery (FBDD) is a well-established technology for lead compound generation in drug discovery. As this technology has evolved, the design of fragments for screening has also evolved to engender not just an understanding of the role of modulating the physicochemical properties of fragments (Rule of Three, Ro3) but also the importance and implications of incorporating shape and, in particular, 3D characteristics into fragments. Herein, we describe the design and synthesis of pyrrolidine-based fragments with good fragment-like (Ro3) physicochemical properties that effectively sample three-dimensional molecular space.

| S-EPMC6511948 | biostudies-literature

Three-dimensional character of the deformation twin in magnesium.

Project description:Deformation twins are three-dimensional domains, traditionally viewed as ellipsoids because of their two-dimensional lenticular sections. In this work, we performed statistical analysis of twin shapes viewing along three orthogonal directions: the 'dark side' (DS) view along the twin shear direction (η1), the twinning plane normal (TPN) view (k1) and the 'bright side' (BS) view along the direction λ(=k1 × η1). Our electron back-scatter diffraction results show that twins in the DS and BS views normally exhibit a lenticular shape, whereas they show an irregular shape in the TPN view. Moreover, the findings in the TPN view revealed that twins grow faster along λ the lateral direction than along η1 the forward propagation direction at the initial stages of twin growth. These twin sections are irregular, indicating that growth is locally controlled and the overall shape is not perfectly ellipsoidal. We explain these findings using atomistic models, and ascribe them to differences in the mobility of the edge and screw components of the twinning dislocations.

| S-EPMC6658514 | biostudies-literature

Substituted nitrogen-bridged diazocines.

Project description:Novel nitrogen-bridged diazocines (triazocines) were synthesized that carry a formyl or an acetyl group at the CH2NR-bridge and bromo- or iodo-substituents at the distant phenyl ring. The photophysical properties were investigated in acetonitrile and water. As compared to previous approaches the yields of the intramolecular azo cyclizations were increased (from ≈40 to 60%) using an oxidative approach starting from the corresponding aniline precursors. The Z→E photoconversion yields in acetonitrile are 80-85% and the thermal half-lives of the metastable E configurations are 31-74 min. Particularly, the high photoconversion yields (≈70%) of the water-soluble diazocines are noteworthy, which makes them promising candidates for applications in photopharmacology. The halogen substituents allow further functionalization via cross-coupling reactions.

| S-EPMC8239257 | biostudies-literature

Route to three-dimensional fragments using diversity-oriented synthesis.

Project description:Fragment-based drug discovery (FBDD) has proven to be an effective means of producing high-quality chemical ligands as starting points for drug-discovery pursuits. The increasing number of clinical candidate drugs developed using FBDD approaches is a testament of the efficacy of this approach. The success of fragment-based methods is highly dependent on the identity of the fragment library used for screening. The vast majority of FBDD has centered on the use of sp(2)-rich aromatic compounds. An expanded set of fragments that possess more 3D character would provide access to a larger chemical space of fragments than those currently used. Diversity-oriented synthesis (DOS) aims to efficiently generate a set of molecules diverse in skeletal and stereochemical properties. Molecules derived from DOS have also displayed significant success in the modulation of function of various "difficult" targets. Herein, we describe the application of DOS toward the construction of a unique set of fragments containing highly sp(3)-rich skeletons for fragment-based screening. Using cheminformatic analysis, we quantified the shapes and physical properties of the new 3D fragments and compared them with a database containing known fragment-like molecules.

| S-EPMC3084099 | biostudies-literature

A BODIPY-Bridged Bisphenoxyl Diradicaloid: Solvent-Dependent Diradical Character and Physical Properties.

Project description:We report a new boron dipyrromethene (BODIPY)-bridged bisphenoxyl diradicaloid (2), which showed closed-shell diamagnetic character in less polar solvents such as dichloromethane but open-shell diradical character with paramagnetic activity in the very polar solvent N,N-dimethylformamide. X-ray crystallographic analysis of 2 revealed an anti-parallel stacked dimer structure via intermolecular dipole-dipole interaction, and the observed solvent-dependent diradical character can be explained by the different dihedral angles between the phenoxyl units and the BODIPY bridge, and structural flexibility of the molecule in different solvents. Compound 2 also exhibited solvent-dependent optical and electrochemical properties.

| S-EPMC6514698 | biostudies-literature

Discovery of novel Cyclophilin D inhibitors starting from three dimensional fragments with millimolar potencies.

Project description:Fragment-based screening by SPR enabled the discovery of chemical diverse fragment hits with millimolar binding affinities to the peptidyl-prolyl isomerase Cyclophilin D (CypD). The CypD protein crystal structures of 6 fragment hits provided the basis for subsequent medicinal chemistry optimization by fragment merging and linking yielding three different chemical series with either urea, oxalyl or amide linkers connecting millimolar fragments in the S1' and S2 pockets. We successfully improved the in vitro CypD potencies in the biochemical FP and PPIase assays and in the biophysical SPR binding assay from millimolar towards the low micromolar and submicromolar range by >1000-fold for some fragment derivatives. The initial SAR together with the protein crystal structures of our novel CypD inhibitors provide a suitable basis for further hit-to-lead optimization.

| S-EPMC7195332 | biostudies-literature

Cationic Pyrrolidine/Pyrroline-Substituted Porphyrins as Efficient Photosensitizers against E. coli.

Project description:New porphyrin-pyrrolidine/pyrroline conjugates were prepared by revisiting 1,3-dipolar cycloaddition reactions between a porphyrinic azomethine ylide and a series of dipolarophiles. Cationic conjugates obtained by alkylation of the pyrrolidine/pyrroline cycloadducts showed ability to generate singlet oxygen and to produce iodine in presence of KI when irradiated with visible light. Some of the cationic derivatives showed photobactericidal properties towards a Gram-negative bioluminescent E. coli. In all cases, these features were significantly improved using KI as coadjutant, allowing, under the tested conditions, the photoinactivation of the bacterium until the detection limit of the method with a drastic reduction of the required photosensitizer concentration and irradiation time. The obtained results showed a high correlation between the ability of the cationic porphyrin derivative to produce singlet oxygen and iodine and its E. coli photoinactivation profile.

| S-EPMC7829939 | biostudies-literature

Zwitterionic Character and Lipid Composition Determine the Behaviour of Glycosylphosphatidylinositol Fragments in Monolayers.

Project description:Glycosylphosphatidylinositols (GPIs) are complex glycolipids found in free form or anchoring proteins to the outer leaflet of the cell membrane in eukaryotes. GPIs have been associated with the formation of lipid rafts and protein sorting on membranes. The presence of a conserved glycan core with cell-specific modifications together with lipid remodelling during biosynthesis suggest that the properties of the glycolipids are being fine-tuned. We synthesized a series of GPI fragments and evaluated the interactions and arrangement of these glycolipids in monolayers as a 2-D membrane model. GIXD and IRRAS analyses showed the need of N-acetylglucosamine deacetylation for the formation of hydrogen bonds to obtain highly structured domains in the monolayers and an effect of the unsaturated lipids in formation and localization of the glycolipids within or between membrane microdomains. These results contribute to understand the role of these glycolipids and their modifications in the organization of membranes.

| S-EPMC8251720 | biostudies-literature

The multiradical character of one- and two-dimensional graphene nanoribbons.

Project description:When is an acene stable? The pronounced multiradical character of graphene nanoribbons of different size and shape was investigated with high-level multireference methods. Quantitative information based on the number of effectively unpaired electrons leads to specific estimates of the chemical stability of graphene nanostructures.

| S-EPMC3648980 | biostudies-literature

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