RESUMO
A series of novel carbazole-containing amides and ureas were synthesized. A structure-activity relationship study of these compounds led to the identification of potent cryptochrome modulators. Based on the desired pharmacokinetic/pharmacodynamic parameters and the results of efficacy studies in db/db mice, compound 50 was selected for further profiling.
Assuntos
Amidas/farmacologia , Carbazóis/farmacologia , Criptocromos/metabolismo , Descoberta de Drogas , Hipoglicemiantes/farmacologia , Ureia/farmacologia , Amidas/síntese química , Amidas/química , Animais , Carbazóis/química , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Relação Dose-Resposta a Droga , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Masculino , Camundongos , Estrutura Molecular , Obesidade/tratamento farmacológico , Relação Estrutura-Atividade , Ureia/análogos & derivados , Ureia/químicaRESUMO
A series of novel carbazole-containing sulfonamides and sulfamides were synthesized. A structure-activity relationship study of these compounds led to the identification of potent cryptochrome modulators. Based on the results of efficacy studies in diet-induced obese (DIO) mice, and the desired pharmacokinetic parameters, compound 41 was selected for further profiling.
Assuntos
Carbazóis/química , Criptocromos/química , Hipoglicemiantes/química , Sulfonamidas/química , Animais , Glicemia/análise , Linhagem Celular Tumoral , Criptocromos/genética , Criptocromos/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/patologia , Dieta Hiperlipídica , Regulação da Expressão Gênica/efeitos dos fármacos , Genes Reporter , Humanos , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Relação Estrutura-Atividade , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêuticoRESUMO
The discovery and development of antimicrobial agents that do not give rise to resistance remains an ongoing challenge. Our efforts in this regard continue to reveal new potential therapeutic agents with differing physicochemical properties while retaining the effective N,N-dichloroamine pharmacophore as the key antimicrobial warhead. In this Letter, we disclose agents containing polyol units as a water solubilizing group. These sulfonyl-polyol agents show broad spectrum bactericidal and virucidal activity. These compounds show 1 h MBC's of 16-512 µg/mL against Escherichia coli and 4-256 µg/mL against Staphylococcus aureus at neutral pH, and 1-h IC50's of 4.5-32 µM against Adenovirus 5 and 0.7-3.0 µM against Herpes simplex virus 1. The lead compounds were tested in a tissue culture irritancy assay and showed only minimal irritation at the highest concentrations tested.
Assuntos
Aminas/química , Anti-Infecciosos/química , Polímeros/química , Adenoviridae/metabolismo , Aminas/síntese química , Aminas/farmacologia , Animais , Anti-Infecciosos/síntese química , Anti-Infecciosos/farmacologia , Linhagem Celular Tumoral , Chlorocebus aethiops , Efeito Citopatogênico Viral/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Herpesvirus Humano 1/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Testes de Sensibilidade Microbiana , Staphylococcus aureus/efeitos dos fármacos , Células VeroRESUMO
Structure stability/activity relationships (SXR) of a new class of N,N-dichloroamine compounds were explored to improve antimicrobial activity against Escherichia coli, Staphylococcus aureus, and Candida albicans while maintaining aqueous solution stability. This study identified a new class of solution-stable and topical antimicrobial agents. These agents are sulfone-stabilized and possess either a quaternary ammonium or sulfonate appendages as a water solubilizing group. Several unique challenges were confronted in the synthesis of these novel compounds which are highlighted in the discussion.
Assuntos
Anti-Infecciosos/síntese química , Cloraminas/síntese química , Sulfonas/síntese química , Água/química , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Anti-Infecciosos/farmacologia , Cloraminas/química , Cloraminas/farmacologia , Estabilidade de Medicamentos , Escherichia coli/efeitos dos fármacos , Estrutura Molecular , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-Atividade , Sulfonas/química , Sulfonas/farmacologiaRESUMO
Antimicrobial resistance against many known therapeutics is on the rise. We examined derivatives of 3-chlorooxazolidin-2-one 1a (X=H) as antibacterial and antifungal agents. The key findings were that the activity and apparent in vitro cytotoxicity could be controlled by the substitution of charged solubilizers at the 4- and 5- positions. These changes both significantly increase the antifungal potency and decrease cytotoxicity. Particularly effective were trialkylammonium groups which led to 400- to 600-fold increases in the antifungal therapeutic index when compared to their unsubstituted counterparts.
Assuntos
Anti-Infecciosos/farmacologia , Bactérias/efeitos dos fármacos , Cloro/química , Fungos/efeitos dos fármacos , Oxazolidinonas/farmacologia , Anti-Infecciosos/síntese química , Anti-Infecciosos/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Oxazolidinonas/síntese química , Oxazolidinonas/químicaRESUMO
Antimicrobial compounds with broad-spectrum activity and minimal potential for antibiotic resistance are urgently needed. Toward this end, we prepared and investigated a novel series of N-chloroheterocycles. Of the compounds examined, the N-chloroamine series were found superior over N-chloroamide series in regards to exhibiting high antimicrobial activity, low cytotoxicity, and long-term aqueous stability.
