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Optimization of macrocyclic inhibitors of FXIa is described which focused on modifications to both the macrocyclic linker and the P1 group. Increases in potency were discovered through interactions with a key hydrophobic region near the S1 prime pocket by substitution of the macrocyclic linker with small alkyl groups. Both the position of substitution and the absolute stereochemistry of the alkyl groups on the macrocyclic linker which led to improved potency varied depending on the ring size of the macrocycle. Replacement of the chlorophenyltetrazole cinnamide P1 in these optimized macrocycles reduced the polar surface area and improved the oral bioavailability for the series, albeit at the cost of a decrease in potency.
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http://dx.doi.org/10.1016/j.bmcl.2017.06.058 | DOI Listing |
Chemistry
December 2024
Hiroshima University, Chemistry, 1-3-1 Kagamiyama, 739-8526, Higashi-Hiroshima, JAPAN.
The intermolecular host-guest complexation of head-to-tail monomers consisting of cleft-shaped bisporphyrin and trinitrofluorenone units connected by a chiral binaphthyl linker was employed to construct helically twisted supramolecular polymers. Results from 1H NMR, diffusion-ordered NMR spectroscopy, and viscometry experiments revealed that the supramolecular polymerization of these monomers follows a ring-chain competition mechanism. The introduction of bulky substituents at the linker significantly suppressed the formation of macrocyclic oligomers, whereas smaller alkyl chains facilitated the formation of the cyclic form.
View Article and Find Full Text PDFJ Chem Inf Model
December 2024
Shanghai Engineering Research Center of Molecular Therapeutics & New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China.
Macrocyclization is a critical strategy in rational drug design that can offer several advantages, such as enhancing binding affinity, increasing selectivity, and improving cellular permeability. Herein, we introduce MacGen, a web tool devised for structure-based macrocycle design. MacGen identifies exit vector pairs within a ligand that are suitable for cyclization and finds 3D linkers that can align with the geometric arrangement of these pairs to form macrocycles.
View Article and Find Full Text PDFSmall
December 2024
School of Chemical and Environmental Engineering, Shanghai Institute of Technology, 100 Haiquan Road, Shanghai, 201418, China.
How to improve the stability and activity of metal-organic frameworks is an attractive but challenging task in energy conversion and pollutant degradation of metal-organic frameworks materials. In this paper, we developed a facile method by fabricating TiO nanoparticles (NPs) layer on 2D copper tetracarboxylphenyl-metalloporphyrin metal-organic frameworks (MOFs) with Zn2+ as the linkers (ZnTCuMT-X, "Zn" represented Zn2+ as the linkers, the first "T" represented tetracarboxylphenyl-metalloporphyrin (TCPP), "Cu" represented the Cu2+ coordinated into the porphyrin macrocycle, "M" represented MOFs, the second "T" represented TiO NPs layer, and "X" represented the added volume of n-tetrabutyl titanate (X = 100, 200, 300 or 400)). It was found that the optimized ZnTCuMT-200 showed greatly and stably enhanced H2 generation, which was about 28.
View Article and Find Full Text PDFAngew Chem Int Ed Engl
November 2024
Key Laboratory of Photochemical Conversion and Optoelectronic Materials, CAS-HKU Joint Laboratory on New Materials, Technical Institute of Physics and Chemistry, School of Future Technology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, 100190, China.
The bottom-up synthesis of discrete tubular molecules that mimic the structural features of carbon nanotubes has been a long-standing pursuit for synthetic chemists. As the shortest segments of armchair-type carbon nanotubes, cycloparaphenylenes are regarded as ideal macrocyclic building blocks for achieving this goal. Here we report the synthesis of a helical tubular molecule featuring three diyne linkers between two site-specifically functionalized [9]cycloparaphenylenes.
View Article and Find Full Text PDFACS Appl Bio Mater
November 2024
College of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, Zhejiang 310018, PR. China.
The increasing number of infections caused by pathogenic bacteria has severely affected human society. More and more deaths were originated from Gram-positive methicillin-resistant (MRSA) infection each year. The potential and excellent bacteriostatic activity and resistance to biofilm formation of pillar[5]arene with different functional groups attract important attention to further study the relationship between antimicrobial activity and cytotoxicity by varying the length of the hydrophobic chain, the number of positive charges, and the hydrophobic/hydrophilic balance of the molecule.
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