UbiD domain dynamics underpins aromatic decarboxylation

The widespread UbiD enzyme family utilises the prFMN cofactor to achieve reversible decarboxylation of acrylic and (hetero)aromatic compounds. The reaction with acrylic compounds based on reversible 1,3-dipolar cycloaddition between substrate and prFMN occurs within the confines of the active site. In contrast, during aromatic acid decarboxylation, substantial rearrangement of the substrate aromatic moiety associated with covalent catalysis presents a molecular dynamic challenge. Here we determine the crystal structures of the multi-subunit vanillic acid decarboxylase VdcCD. We demonstrate that the small VdcD subunit acts as an allosteric activator of the UbiD-like VdcC. Comparison of distinct VdcCD structures reveals domain motion of the prFMN-binding domain directly affects active site architecture. Docking of substrate and prFMN-adduct species reveals active site reorganisation coupled to domain motion supports rearrangement of the substrate aromatic moiety. Together with kinetic solvent viscosity effects, this establishes prFMN covalent catalysis of aromatic (de)carboxylation is afforded by UbiD dynamics.

Synthesis of Enantiopure ω-(4-Fluorophenyl) 6,11-Methylene Lipoxin B4 Methyl Ester

The synthesis of Lipoxin B4 analogs (LXB4) to gain access to stabilized inflammation resolving compounds is an active field of research. Focusing on variation and stabilization of the conjugated E,Z,E,E C6–C13 tetraene moiety of natural LXB4, a methylene bridge introduced between C6 and C11 suppresses any Z/E isomerization of the C8–C9 olefin. Furthermore, rapid ω-oxidation (C20) should be avoided by replacing the C18-C20 segment by an aromatic moiety. Optically active C1–C12 building blocks were accessed from cycloheptatriene 1-carbonester (C6–C11, C21) and glutaryl chloride (C1–C5) as described earlier. The ω-segment had been generated via a five-step sequence starting from 4-arylbutanoic acid. Horner key olefination enabled assembly of the carbon backbone. A final five step sequence including a chelate Cram reduction of the unsaturated ketone moiety afforded the target ω-aryl 6,11-methylene-LXB4 methyl ester.

Synthesis and conversion of primary and secondary 2-aminoestradiols into A-ring-integrated benzoxazolone hybrids and their in vitro anticancer activity

Estradiol–benzoxazolone hybrids with a common aromatic moiety were efficiently synthesized via primary and secondary aminophenol intermediates, and their anticancer activities were investigated.

Synthesis and Biological Evaluation of Iodinated Fidaxomicin Antibiotics

<div><div><div><p>Fidaxomicin (1, tiacumicin B, lipiarmycin A3) is a marketed antibiotic that is used in the treatment of C. difficile infections. Based on the analysis of a cryo- EM structure of fidaxomicin binding to its target enzyme (RNA-polymerase), a cation-p interaction of the aromatic moiety with an arginine residue was identified. Therefore, the variation of the substituents and concurrently changing the electronic properties of the aryl moiety represents an interesting strategy in search for new fidaxomicin analogs. Herein, we report the first semisynthetic access to new fidaxomicin analogs with varying halogen substituents via a Pd-catalyzed hydrodechlorination reaction. Subsequent iodination gave access to the first iodo-fidaxomicin derivatives, which matched or improved antibacterial properties compared to fidaxomicin against Mycobacterium tuberculosis and Staphylococcus aureus ATCC 29213.</p></div></div></div>

Synthesis and Biological Evaluation of Iodinated Fidaxomicin Antibiotics

<div><div><div><p>Fidaxomicin (1, tiacumicin B, lipiarmycin A3) is a marketed antibiotic that is used in the treatment of C. difficile infections. Based on the analysis of a cryo- EM structure of fidaxomicin binding to its target enzyme (RNA-polymerase), a cation-p interaction of the aromatic moiety with an arginine residue was identified. Therefore, the variation of the substituents and concurrently changing the electronic properties of the aryl moiety represents an interesting strategy in search for new fidaxomicin analogs. Herein, we report the first semisynthetic access to new fidaxomicin analogs with varying halogen substituents via a Pd-catalyzed hydrodechlorination reaction. Subsequent iodination gave access to the first iodo-fidaxomicin derivatives, which matched or improved antibacterial properties compared to fidaxomicin against Mycobacterium tuberculosis and Staphylococcus aureus ATCC 29213.</p></div></div></div>

Synthesis and Biological Evaluation of Iodinated Fidaxomicin Antibiotics

<div><div><div><p>Fidaxomicin (1, tiacumicin B, lipiarmycin A3) is a marketed antibiotic that is used in the treatment of C. difficile infections. Based on the analysis of a cryo- EM structure of fidaxomicin binding to its target enzyme (RNA-polymerase), a cation-p interaction of the aromatic moiety with an arginine residue was identified. Therefore, the variation of the substituents and concurrently changing the electronic properties of the aryl moiety represents an interesting strategy in search for new fidaxomicin analogs. Herein, we report the first semisynthetic access to new fidaxomicin analogs with varying halogen substitutents via a Pd-catalyzed hydrodechlorination reaction. Subsequent iodination gave access to the first iodo-fidaxomicin derivatives, which matched or improved antibacterial properties compared to fidaxomicin against Mycobacterium tuberculosis and Staphylococcus aureus ATCC 29213.</p></div></div></div>

Synthesis, Antitubercular Activity, Molecular Modeling and Docking Studies of Novel Thiazolidin-4-One Linked Dinitrobenzamide Derivatives

Background: Tuberculosis is a catastrophe sprawled across the world. The World Health Organization Global Tuberculosis Report 2017 inferred that there were an estimated 10.4 million people suffered from tuberculosis including 490000 Multidrug-Resistant TB (MDR-TB) cases. Several new lead molecules like dinitrobenzamide derivatives were found to be highly active against multidrugresistant strains of M. tuberculosis. To further explore the pharmacophoric space around the dinitobenzamide moiety, a series of compounds have been synthesized by linking it with the thiazolidin- 4-one. The presented work is an effort to study the biological effect of thiazolidin-4-one scaffold on dinitrobenzamide derivatives as antitubercular agents. A molecular modeling study was also performed on the synthesized molecules to reveal the requirements for further lead optimization. Methods: The thiazolidin-4-one linked 3,5-dinitrobenzamide derivatives have been synthesized by onepot three-component condensation reaction of an amine, substituted aldehydes and thioglycolic acid in presence of N, N'-Dicyclohexylcarbodiimide (DCC). These compounds were evaluated against Mycobacterium tuberculosis H37Ra. A pharmacophore modeling approach has been used in order to explore the collection of possible pharmacophore queries of thiazolidin-4-one linked 3, 5-dinitrobenzamide derivatives against M. tuberculosis. The synthesized compounds were docked on to the M. tuberculosis DprE1 enzyme to identify the structural features requirement of these analogs against this potential target of M. tuberculosis. Results: The synthesized compounds showed the antitubercular activity in the range of 6.25-50 μg/ml. The pharmacophore modeling suggests that the presence of aromatic moiety, thiazolidin-4-one ring and one of the nitro groups are significant for inhibiting the enzymatic activity. While docking studies showed that hydrophobic and hydrogen bond interactions of the aromatic moiety and nitro group crucial to inactivate the DprE1 enzyme. Conclusion: The study showed that the linking of thiazolidin-4-one with dinitrobenzamide leads to compounds active against M. tuberculosis. These findings also suggested that further lead optimization would be carried out by focusing on the aromatic system along with electron-rich substituents placed on the thiazolidin-4-one for making better hydrophobic and hydrogen bond interactions with the DprE1 target.