RESUMO
Achieving high gas selectivity is challenging when dealing with gas pairs of similar size and physiochemical properties. The "molecular trapdoor" mechanism discovered in zeolites holds promise for highly selective gas adsorption separation but faces limitations like constrained pore volume and slow adsorption kinetics. To address these challenges, for the first time, a flexible metal-organic framework (MOF) featuring 1D channels and functioning as a "molecular trapdoor" material is intoduced. Extra-framework anions act as "gate-keeping" groups at the narrowest points of channels, permitting gas admissions via gate opening induced by thermal/pressure stimuli and guest interactions. Different guest molecules induce varied energy barriers for anion movement, enabling gas separation based on distinct threshold temperatures for gas admission. The flexible framework of Pytpy MOFs, featuring swelling structure with rotatable pyridine rings, facilitates faster gas adsorption than zeolite. Analyzing anion properties of Pytpy MOFs reveals a guiding principle for selecting anions to tailor threshold gas admission. This study not only overcomes the kinetic limitations related to gas admission in the "molecular trapdoor" zeolites but also underscores the potential of developing MOFs as molecular trapdoor adsorbents, providing valuable insights for designing ionic MOFs tailored to diverse gas separation applications.
RESUMO
Here we developed the functionalized biochar as low-cost and heavy metal-free photocatalysts via a facile iodine doping method, which exhibit efficient adsorption and visible-light-driven photocatalytic degradation of representative organic pollutants, phenol and tetracycline. On one hand, iodine doping elevates the adsorption via creating extra pores, e.g., the adsorbed amounts of phenol by iodine-doped WSP and OSR biochar are increased by 161.8% and 146.3%, respectively, which in turn facilitates the photocatalytic oxidation of the adsorbed pollutants. On the other hand, iodine doping leads to the strong photo-induced excitation and remarkably reduced charge carrier transfer resistance, boosting the photocatalytic activity of iodine-doped biochar by more than 20 orders towards organic pollutants (e.g., phenol) degradation. The systematic analysis of reactive species reveals the active roles of O2-, H2O2, 1O2, OH, electrons, and holes in photocatalytic process and identifies O2- to be the major contributor. This work affords a facile approach to generating porous and visible-light-driven photocatalyst from biomass for efficient adsorbing and degrading organic pollutants, opening up an avenue to turn biowaste into biomaterials for sustainable environmental remediation.
Assuntos
Dopagem Esportivo , Poluentes Ambientais , Iodo , Adsorção , Catálise , Carvão Vegetal , Peróxido de Hidrogênio , LuzRESUMO
We report herein the design and synthesis of a series of less lipophilic Q203 derivatives containing an alkaline fused ring moiety. Most of them show considerable potency against MTB H37Rv strain (MICâ¯<â¯0.25⯵M). Nine compounds (13, 15, 19, 21, 23, 25, 29, 35, 36) have the same excellent activity against both drug-sensitive and -resistant strains (MICâ¯<â¯0.035⯵M) as Q203 and PBTZ169. Especially, compound 29 also displays acceptable safety, greater absorption in plasma and aqueous solubility than Q203, suggesting its promising potential to be lead compound for future antitubercular drug discovery.
Assuntos
Antituberculosos/farmacologia , Imidazóis/farmacologia , Piridinas/farmacologia , Animais , Antituberculosos/síntese química , Antituberculosos/toxicidade , Chlorocebus aethiops , Desenho de Fármacos , Feminino , Imidazóis/síntese química , Imidazóis/toxicidade , Camundongos Endogâmicos ICR , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Piridinas/síntese química , Piridinas/toxicidade , Relação Estrutura-Atividade , Células VeroRESUMO
We report herein the design, synthesis and antimycobacterial activity of 3,5-dinitrobenzamide derivatives containing fused ring moieties. Results reveal that many of the target compounds have considerable in vitro antitubercular activity. Especially, N-((2-(4-fluorophenyl)/N-((2-(3-fluorobenzyl)-1,2,3,4-tetrahydroisoquilin-6-yl)methyl)-3,5-dinitrobenzamides 18a and 20e exhibit potent MIC values of 0.056-0.078⯵g/mL against both drug-sensitive Mycobacterium tuberculosis (MTB) H37Rv strain and two clinically isolated multidrug-resistant MTB (MDR-MTB) strains, opening a new direction for further SAR studies.
Assuntos
Antibacterianos/farmacologia , Benzamidas/farmacologia , Desenho de Fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Benzamidas/síntese química , Benzamidas/química , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mycobacterium tuberculosis/isolamento & purificação , Relação Estrutura-AtividadeRESUMO
GYH2-18 is a type II HBV CAM with 6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxamine (DPPC) skeleton discovered by Roche INC. A series of GYH2-18 derivatives were designed, synthesized and evaluated for their anti-HBV activity. Two compounds 2f and 3k exhibited excellent anti-HBV activity, low cytotoxicity and accepted oral PK profiles. Chiral separation of 2f and 3k was conducted successfully, and (6S)-cyclopropyl DPPC isomers 2f-1, 2f-3, 3k-1 and 3k-3 were identified to be much more active than the corresponding (6R)-ones. The preliminary structure-activity relationship, particle gel assay and molecular modeling studies were also discussed, which provide useful indications for guiding the further rational design of new (6S)-cyclopropyl DPPC analogues.
Assuntos
Antivirais/farmacologia , Proteínas do Capsídeo/antagonistas & inibidores , Vírus da Hepatite B/efeitos dos fármacos , Pirazinas/farmacologia , Antivirais/síntese química , Antivirais/química , Proteínas do Capsídeo/metabolismo , Relação Dose-Resposta a Droga , Vírus da Hepatite B/metabolismo , Humanos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Pirazinas/síntese química , Pirazinas/química , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacosRESUMO
A series of bis(l-amino acid) ester prodrugs of tenofovir (TFV) were designed and synthesized as new anti-HBV agents in this work. Four compounds 11, 12a, 12d, and 13b displayed better anti-HBV activity (IC50: 0.71-4.22 µM) than the parent drug TFV. The most active compound 11 (IC50: 0.71 µM), a bis(l-valine) ester prodrug of TFV, was found to have obviously greater AUC0-∞, C max, and F% than tenofovir disoproxil fumarate (TDF), and potent in vivo efficacy which is not inferior to TDF in a duck HBV (DHBV) model and a HBV DNA hydrodynamic mouse model, and it may serve as a promising lead compound for further anti-HBV drug discovery.
RESUMO
A series of benzothiazinones (BTZs) containing an oxime moiety, based on the structure of ZR-10 discovered in our lab, were designed and synthesized. Most of the compounds with alkoxyimino groups attached to the piperazine or cyclohexyl ring of PBTZ169, exhibit excellent in vitro activity against both drug-sensitive and clinically isolated multidrug-resistant Mycobacterium tuberculosis (MTB) strains (MIC: < 0.016-0.037⯵g/mL) and low cell cytotoxicity. Two close PBTZ169-analogues 3a and 3b with proper ADME/T and PK properties show potent in vivo efficacy in an acute mouse model of tuberculosis. Compound 3a is under evaluation as a potential clinical candidate for treatment of tuberculosis.
Assuntos
Antituberculosos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Oximas/farmacologia , Tiazinas/farmacologia , Animais , Antituberculosos/química , Antituberculosos/farmacocinética , Desenho de Fármacos , Feminino , Humanos , Camundongos Endogâmicos ICR , Testes de Sensibilidade Microbiana , Oximas/química , Oximas/farmacocinética , Piperazinas , Tiazinas/química , Tiazinas/farmacocinética , Tuberculose/tratamento farmacológicoRESUMO
A series of reduced lipophilic N-benzylic imidazo[1,2-a]pyridine carboxamides (IPAs) with various side chains were designed and synthesized as new anti-TB agents in this work. Five derivatives A2, A3, A4, B1 and B9 exhibit excellent in vitro activity (MIC: < 0.035 µM) against the drug susceptive Mycobacterium tuberculosis H37Rv strain and two clinically isolated multidrug-resistant strains, and acceptable PK properties. Compound B1 bearing a cyclohexylmethyl piperazine moiety, the same side chain of PBTZ169, was found to have obviously greater AUC0-∞ and Cmax than Q203 and PBTZ169, suggesting its promising potential to be a lead compound for future antitubercular drug discovery.
Assuntos
Antituberculosos/síntese química , Imidazóis/química , Piridinas/química , Antituberculosos/química , Antituberculosos/farmacologia , Área Sob a Curva , Resistência a Múltiplos Medicamentos , Interações Hidrofóbicas e Hidrofílicas , Mycobacterium tuberculosis/efeitos dos fármacos , Piperazina , Piperazinas , Relação Estrutura-Atividade , TiazinasRESUMO
IMB1603, a new benzothiazinone lead discovered by our lab, exhibited potent anti-MTB activity in vitro and in vivo, but significant hERG binding potency (IRâ¯>â¯90% at 10⯵M). Thus, we embarked on a lead optimization program with the goal of identifying alternative leads that could reduce the hERG liability without sacrificing antimycobacterial potency. Compounds 2c and 4c were identified to maintain the anti-MTB activity (MICs <0.035-0.078⯵M), and had lower hERG binding affinity (IRâ¯<â¯50% at 10⯵M). Both of them were also found to have acceptable safety and pharmacokinetic properties. Studies to determine the in vivo efficacy of 2c and 4c are currently underway.
Assuntos
Antituberculosos/farmacologia , Benzotiazóis/farmacologia , Descoberta de Drogas , Mycobacterium tuberculosis/efeitos dos fármacos , Antituberculosos/síntese química , Antituberculosos/química , Benzotiazóis/síntese química , Benzotiazóis/química , Relação Dose-Resposta a Droga , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
A series of N-(2-phenoxy)ethyl imidazo[1,2-a]pyridine-3-carboxamides (IPAs), based on the structure of WZY02 discovered in our lab, were designed and synthesized as new anti-TB agents. Results reveal that many of them exhibit excellent in vitro inhibitory activity with low nanomolar MIC values against both drug-sensitive MTB strain H37Rv and drug-resistant clinical isolates. Compounds 15b and 15d display good safety and pharmacokinetic profiles, suggesting their promising potential to be lead compounds for future antitubercular drug discovery.
Assuntos
Antituberculosos/farmacologia , Desenho de Fármacos , Imidazóis/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Piridinas/farmacologia , Animais , Antituberculosos/administração & dosagem , Antituberculosos/química , Relação Dose-Resposta a Droga , Feminino , Imidazóis/administração & dosagem , Imidazóis/química , Camundongos , Camundongos Endogâmicos ICR , Testes de Sensibilidade Microbiana , Estrutura Molecular , Piridinas/administração & dosagem , Piridinas/química , Relação Estrutura-AtividadeRESUMO
A series of benzamide scaffolds were designed and synthesized by the thiazinone ring opening of PBTZ169, and N-benzyl 3,5-dinitrobenzamides were finally identified as anti-TB agents in this work. 3,5-Dinitrobenzamides D5, 6, 7, and 12 exhibit excellent in vitro activity against the drug susceptive Mycobacterium tuberculosis H37Rv strain (MIC: 0.0625 µg/mL) and two clinically isolated multidrug-resistant strains (MIC < 0.016-0.125 µg/mL). Compound D6 displays acceptable safety and better pharmacokinetic profiles than PBTZ169, suggesting its promising potential to be a lead compound for future antitubercular drug discovery.
RESUMO
We herein report the design and synthesis of benzothiazinones containing a piperidine moiety as new antitubercular agents based on the structure feature of IMB-ZR-1 discovered in our lab. Some of them were found to have good in vitro activity (MICâ¯<â¯1⯵g/mL) against drug-susceptible Mycobacterium tuberculosis H37RV strain. After two set of modifications, compound 2i were found to display comparable in vitro anti-TB activity (MICâ¯<â¯0.016⯵g/mL) to PBTZ169 against drug-sensitive and resistant mycobacterium tuberculosis strains. Compound 2i also showed acceptable PK profiles. Studies to determine PK profiles in lung and in vivo efficacy of 2i are currently under way.
Assuntos
Antituberculosos/química , Antituberculosos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Piperidinas/química , Piperidinas/farmacologia , Tiazinas/química , Tiazinas/farmacologia , Animais , Antituberculosos/síntese química , Antituberculosos/farmacocinética , Desenho de Fármacos , Feminino , Humanos , Camundongos Endogâmicos ICR , Testes de Sensibilidade Microbiana , Piperidinas/síntese química , Piperidinas/farmacocinética , Tiazinas/síntese química , Tiazinas/farmacocinética , Tuberculose/tratamento farmacológicoRESUMO
We report herein the design and synthesis of a series of novel Sinefungin (SIN) derivatives, based on the structures of SIN and its analogue EPZ004777. Our results reveal that target compounds 1ad-af, 1ba-bb and 1bf-bh show better activity (IC50â¯=â¯4.56-20.16⯵M) than EPZ004777 (IC50â¯=â¯35.19⯵M). Surprisingly, SIN was founded to be not as active (IC50â¯>â¯50⯵M) as we and other research groups predicted. Interestingly, the intermediates 9a-b and 11b display potent anti-ZIKV potency (IC50â¯=â¯6.33-29.98⯵M), and compound 9a also exhibits acceptable cytotoxicity (CC50â¯>â¯200⯵M), suggesting their promising potential to be leads for further development.