Supplemental material for Analysis of monodisperse, sequence-defined, and POSS-functionalized polyester copolymers by MALDI tandem mass spectrometry

Supplemental Material for Analysis of monodisperse, sequence-defined, and POSS-functionalized polyester copolymers by MALDI tandem mass spectrometry by Jialin Mao, Wei Zhang, Stephen ZD Cheng and Chrys Wesdemiotis in European Journal of Mass Spectrometry</p

Adaptive Covalent Networks Enabled by Dual Reactivity: The Evolution of Reversible Covalent Bonds, Their Molecular Assemblies, and Guest Recognition

Adaptive chemistry allows transformation and selection within molecular networks, and adaptive systems composed of different types of dynamic covalent reactions (DCRs) are challenging. Herein, we demonstrate dual reactivity-based covalent networks encompassing the regulation of and switching between C–N- and C–S-based reversible covalent assemblies. The creation and exchange of C–N- or C–S-derived assemblies exhibiting diverse architectures, including linear structures, macrocycles, and cages, were achieved. The shift of reactivity then permitted the interconversion between C–N- and C–S-containing assemblies. Moreover, the adaption of intramolecular and intermolecular scaffolds was feasible via linker design. The latent hemiaminal chirality center offered a pathway for the induction of chirality within assemblies. Finally, switchable structural change and controlled extraction of ions were realized with Hg2+ as a guest for macrocycles. The remarkable complexity of networks described herein could open the door for the utility in sophisticated functional systems

Structure−Activity Relationships for a Series of Quinoline-Based Compounds Active against Replicating and Nonreplicating <i>Mycobacterium tuberculosis</i>

Tuberculosis (TB) remains as a global pandemic that is aggravated by a lack of health care, the spread of HIV, and the emergence of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) strains. New anti-TB drugs are urgently required to shorten the long 6−12 month treatment regimen and to battle drug-resistant Mtb strains. We have identified several potent quinoline-based anti-TB compounds, bearing an isoxazole containing side-chain. The most potent compounds, 7g and 13, exhibited submicromolar activity against the replicating bacteria (R-TB), with minimum inhibitory concentrations (MICs) of 0.77 and 0.95 μM, respectively. In general, these compounds also had micromolar activity against the nonreplicating persistent bacteria (NRP-TB) and did not show toxicity on Vero cells up to 128 μM concentration. Compounds 7g and 13 were shown to retain their anti-TB activity against rifampin, isoniazid, and streptomycin resistant Mtb strains. The results suggest that quinoline−isoxazole-based anti-TB compounds are promising leads for new TB drug development

Structure−Activity Relationships for a Series of Quinoline-Based Compounds Active against Replicating and Nonreplicating <i>Mycobacterium tuberculosis</i>

Tuberculosis (TB) remains as a global pandemic that is aggravated by a lack of health care, the spread of HIV, and the emergence of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) strains. New anti-TB drugs are urgently required to shorten the long 6−12 month treatment regimen and to battle drug-resistant Mtb strains. We have identified several potent quinoline-based anti-TB compounds, bearing an isoxazole containing side-chain. The most potent compounds, 7g and 13, exhibited submicromolar activity against the replicating bacteria (R-TB), with minimum inhibitory concentrations (MICs) of 0.77 and 0.95 μM, respectively. In general, these compounds also had micromolar activity against the nonreplicating persistent bacteria (NRP-TB) and did not show toxicity on Vero cells up to 128 μM concentration. Compounds 7g and 13 were shown to retain their anti-TB activity against rifampin, isoniazid, and streptomycin resistant Mtb strains. The results suggest that quinoline−isoxazole-based anti-TB compounds are promising leads for new TB drug development

Searching for New Cures for Tuberculosis: Design, Synthesis, and Biological Evaluation of 2-Methylbenzothiazoles

The actual development and clinical use of new therapeutics for tuberculosis (TB) have remained stagnant for years because of the complexity of the disease process, the treatment of which at present requires the administration of drug combinations over a 6 month period. There is thus an urgent need for the discovery and development of novel, more active, and less toxic anti-TB agents. In this study, we report on the chemistry and biology of a series of potent 5-(2-methylbenzothiazol-5-yloxymethyl)isoxazole-3-carboxamide derivatives, which proved to be active against replicating Mycobacterium tuberculosis (Mtb) H37Rv. The most potent compounds 7j and 7s were found to inhibit Mtb growth at micromolar concentrations, with MIC values of 1.4 and 1.9 μM, respectively. Impressively, all active compounds were nontoxic toward Vero cells (IC50 > 128 μM). Moreover, the best of these compounds were also tested against protozoan parasites, and some of these compounds were found to show activity, especially against Plasmodium falciparum. These studies thus suggest that certain 2-methylbenzothiazole based compounds may serve as promising lead scaffolds for further elaboration as anti-TB drugs and as possible antimalaria drugs

From Serendipity to Rational Antituberculosis Drug Discovery of Mefloquine-Isoxazole Carboxylic Acid Esters

Both in vitro and in vivo metabolism studies suggested that 5-(2,8-bis(trifluoromethyl)quinolin-4-yloxymethyl)isoxazole-3-carboxylic acid ethyl ester (compound 3) with previously reported antituberculosis activity is rapidly converted to two metabolites 3a and 3b. In order to improve the metabolic stability of this series, chemistry efforts were focused on the modification of the oxymethylene linker of compound 3 in the present study. Compound 9d with an alkene linker was found to be both more metabolically stable and more potent than compound 3, with a minimum inhibitory concentration (MIC) of 0.2 μM and 2.6 μM against replicating and nonreplicating Mycobaterium tuberculosis, respectively. These attributes make 9d an interesting lead compound. A number of modifications were made to the structure of 9d, and a series of active compounds were discovered. Although some neurotoxicity was observed at a high dosage, this new series was endowed with both improved in vitro anti-TB activity and metabolic stability in comparison to compound 3

Multilevel Manipulation of Supramolecular Structures of Giant Molecules via Macromolecular Composition and Sequence

We have successfully synthesized a series of monodispersed chain-like giant molecules with precisely controlled macromolecular composition and sequence based on polyhedral oligomeric silsesquioxane (POSS) nanoparticles using an orthogonal “click” strategy. Their nonspherical supramolecular structures, such as lamellae, double gyroids, and hexagonal packed cylinders, are mainly determined by the composition (namely, the number of incorporated amphiphilic nanoparticles). In addition, by precisely alternating the sequence of arranged nanoparticles in the giant molecules with identical chemical compositions, the domain sizes of their supramolecular structures could be fine-tuned. This is attributed to the macromolecular conformational differences caused by collective hydrogen bonding interactions in each set of sequence isomeric giant molecules. This work has demonstrated multilevel manipulation of supramolecular structures of giant molecules: coarse tuning by composition and fine-tuning by sequence

Modularly Constructed Polyhedral Oligomeric Silsesquioxane-Based Giant Molecules for Unconventional Nanostructure Fabrication

Controlled assembly of nanoscale building blocks is a promising approach to obtain functional materials with unique properties. Here, we report a way to manipulate the supramolecular structures of giant molecules based on discotic triangle cores and isobutyl polyhedral oligomeric silsesquioxanes (BPOSS) nanoparticles (NPs). It is found that depending upon the number of BPOSS at the periphery of the discotic cores, the packing of these nanoscale components (discotic core and POSS) could be manipulated into either cylindrical or Frank–Kasper (F–K) A15 (Pm3̅n) phases. The formation of these supramolecular nanostructures is mandated by the balance between the stacking of the discotic cores and the steric hindrance effect of the BPOSS NPs. This strategy to manipulate the packing of nanoscale building blocks for different supramolecular nanostructures including the fabrication of cylindrical structures and A15 (Pm3̅n) phases may be extended to other nanoscale building blocks for future development of materials with complex structures as well as tailored functionalities and properties

Continuous Curvature Change into Controllable and Responsive Onion-like Vesicles by Rigid Sphere–Rod Amphiphiles

We observe the formation of highly controllable and responsive onion-like vesicles by using rigid sphere–rod amphiphilic hybrid macromolecules, composed of charged, hydrophilic Keggin-type clusters (spheres) and hydrophobic rod-like oligofluorenes (OFs). Unlike the commonly used approach, which mainly relies on chain bending of flexible molecules to satisfy different curvatures in onion-like vesicles, the rigid hybrids form flexible interdigitations by tuning the angles between OFs, leading to the formation of bilayers with different sizes. The self-assembled vesicles possess complete onion-like structures from most inner to outer layers, and their size (layer number) can be accurately manipulated by different solution conditions including solvent polarity, ionic strength, temperature, and hybrid concentration, with fixed interbilayer distance under all conditions. Moreover, the vesicle size (layer number) shows excellent reversibility to the change of temperature. The charged feature of spheres, rod length, and overall hybrid architecture shows significant effects on the formation of such onion-like vesicles