ABSTRACT
A novel multifunctional mechanically interlocked switchable [2]rotaxane R4 containing two molecular stations and rotaxane arms terminated with boron-dipyrromethene (BODIPY) fluorophores and its derivatives were synthesized for the first time by CuAAC click reaction. The shuttling motion of macrocycle between the dibenzylammonium and triazolium recognition sites and the distance dependent photoinduced electron transfer process of R4 is demonstrated by utilizing external chemical stimuli (acid/base). Interestingly, the reversible self-assembly process of R4 was recognized by the acid-base molecular switch strategy. Notably, two symmetrical triazolium groups acted as molecular stations, H2PO4(-) receptors, and H-bonded donors. Both [2]rotaxane R4 and thread R2 demonstrated excellent optical responses and high selectivity toward H2PO4(-) ion. The specific motion and guest-host interactions of mechanically interlocked machines (MIMs) were also further explored by quantum mechanical calculations. The thread R2 also demonstrated to enable the detection of H2PO4(-) in RAW 264.7 cells successfully.
Subject(s)
Alkalies/chemistry , Aza Compounds/chemistry , Boron Compounds/chemistry , Optical Phenomena , Phosphoric Acids/chemistry , Rotaxanes/chemistry , Animals , Kinetics , Mice , Molecular Conformation , Molecular Imaging , Proton Magnetic Resonance Spectroscopy , RAW 264.7 Cells , Spectrometry, Fluorescence , Spectrophotometry, UltravioletABSTRACT
A series of dual-targeting, alcohol-containing benzothiazoles has been identified with superior antibacterial activity and drug-like properties. Early lead benzothiazoles containing carboxylic acid moieties showed efficacy in a well-established in vivo model, but inferior drug-like properties demanded modifications of functionality capable of demonstrating superior efficacy. Eliminating the acid group in favor of hydrophilic alcohol moieties at C(5), as well as incorporating solubilizing groups at the C(7) position of the core ring provided potent, broad-spectrum Gram-positive antibacterial activity, lower protein binding, and markedly improved efficacy in vivo.
Subject(s)
Anti-Bacterial Agents/pharmacology , Benzothiazoles/chemistry , Benzothiazoles/pharmacology , DNA, Bacterial/chemistry , DNA, Bacterial/drug effects , DNA, Superhelical/drug effects , Haemophilus influenzae/drug effects , Alcohols/chemistry , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Benzothiazoles/chemical synthesis , Dose-Response Relationship, Drug , Drug Discovery , Microbial Sensitivity Tests , Molecular Structure , Staphylococcus , Structure-Activity RelationshipABSTRACT
The discovery and optimisation of a new class of benzothiazole small molecules that inhibit bacterial DNA gyrase and topoisomerase IV are described. Antibacterial properties have been demonstrated by activity against DNA gyrase ATPase and potent activity against Staphylococcus aureus, Enterococcus faecalis, Streptococcus pyogenes and Haemophilus influenzae. Further refinements to the scaffold designed to enhance drug-likeness included analogues bearing an α-substituent to the carboxylic acid group, resulting in excellent solubility and favourable pharmacokinetic properties.
