ABSTRACT
Matrix metalloproteinase (MMP)-2 knockout (KO) mice show impaired neurological recovery after spinal cord injury (SCI), suggesting that this proteinase is critical to recovery processes. However, this finding in the KO has been confounded by a compensatory increase in MMP-9. We synthesized the thiirane mechanism-based inhibitor ND-378 and document that it is a potent (nanomolar) and selective slow-binding inhibitor of MMP-2 that does not inhibit the closely related MMP-9 and MMP-14. ND-378 crosses the blood-spinal cord barrier, achieving therapeutic concentrations in the injured spinal cord. Spinal-cord injured mice treated with ND-378 showed no change in long-term neurological outcomes, suggesting that MMP-2 is not a key determinant of locomotor recovery.
Subject(s)
Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase Inhibitors/pharmacology , Phenyl Ethers/pharmacology , Recovery of Function/physiology , Spinal Cord Injuries/enzymology , Spinal Cord/enzymology , Sulfones/pharmacology , Animals , Disease Models, Animal , Drug Design , Drug Evaluation, Preclinical , Male , Matrix Metalloproteinase 14/metabolism , Matrix Metalloproteinase 2/genetics , Matrix Metalloproteinase 9/metabolism , Matrix Metalloproteinase Inhibitors/chemical synthesis , Matrix Metalloproteinase Inhibitors/pharmacokinetics , Mice , Mice, Knockout , Molecular Docking Simulation , Molecular Structure , Motor Activity/drug effects , Motor Activity/physiology , Phenyl Ethers/chemical synthesis , Phenyl Ethers/pharmacokinetics , Recovery of Function/drug effects , Spinal Cord/drug effects , Spinal Cord Injuries/drug therapy , Sulfones/chemical synthesis , Sulfones/pharmacokineticsABSTRACT
AIM: To investigate the chemical constituents of the endophytic fungus Verticillium sp. isolated from Rehmannia glutinosa. METHODS: The compounds were isolated and purified by repeated column chromatography, and their structures were determined on the basis of physicochemical properties and spectral analysis. Their cytotoxic and antifungal activities were evaluated. RESULTS: Ten compounds were obtained and their structures were identified as 2, 4-dihydroxy-2', 6-diacetoxy-3'-methoxy-5'-methyl-diphenyl ether (1), paecilospirone (2), α-acetylorcinol (3), 2-methoxy-1,8-dimethyl-xanthen-9-one (4), 4-hydroxy-α-lapachone (5), enalin A (6), 2,3,4-trimethyl-5,7-dihydroxy-2,3-dihydrobenzofuran (7), 4-hydroxyethyl-phenol (8), 2,4-dihydroxy-3,5,6-trimethyl- methylbenzoate (9), and 3-isopropenyl-(Z)-monomethyl maleate (10). CONCLUSIONS: Compound 1 is a new diphenyl ether, and showed cytotoxic activity against HL-60 cells (IC50 2.24 µg · mL(-1)), and antifungal activities against Candida albicans (MIC 8 µg · mL(-1)) and Aspergillus fumigatus (MIC 16 µg · mL(-1)).
Subject(s)
Antifungal Agents/isolation & purification , Antineoplastic Agents/isolation & purification , Endophytes/chemistry , Phenyl Ethers/isolation & purification , Rehmannia/microbiology , Verticillium/chemistry , Antifungal Agents/chemistry , Antifungal Agents/metabolism , Antifungal Agents/pharmacokinetics , Antineoplastic Agents/chemistry , Antineoplastic Agents/metabolism , Antineoplastic Agents/pharmacokinetics , Aspergillus fumigatus/drug effects , Candida albicans/drug effects , Cell Line, Tumor , Endophytes/metabolism , Humans , Phenyl Ethers/chemistry , Phenyl Ethers/metabolism , Phenyl Ethers/pharmacokinetics , Verticillium/metabolismABSTRACT
Two novel series of 5-nitro-2-phenoxybenzoic acid derivatives are designed as potent PAI-1 inhibitors using hybridization and conformational restriction strategy in the tiplaxtinin and piperazine chemo types. The lead compounds 5a, 6c, and 6e exhibited potent PAI-1 inhibitory activity and favorable oral bioavailability in the rodents.
Subject(s)
Benzoates/chemistry , Benzoates/pharmacology , Drug Design , Drug Discovery , Phenyl Ethers/chemistry , Plasminogen Activator Inhibitor 1/metabolism , Administration, Oral , Animals , Benzoates/pharmacokinetics , Biological Availability , Disease Models, Animal , Drug Evaluation, Preclinical , Indoleacetic Acids/chemistry , Indoleacetic Acids/pharmacology , Male , Molecular Structure , Phenyl Ethers/pharmacokinetics , Phenyl Ethers/pharmacology , Piperazine , Piperazines/chemistry , Rats , Rats, Wistar , Structure-Activity Relationship , Thrombosis/chemically induced , Thrombosis/drug therapyABSTRACT
OBJECTIVES: The National Institute of Allergy and Infectious Disease classifies Francisella tularensis as a Category A priority pathogen. Despite the availability of drugs for treating tularaemia, the mortality in naturally acquired cases can still approach 30%. In addition, the usefulness of existing drugs for treatment in response to exposure or for prophylaxis is limited because of toxicity and delivery concerns. The aim of this study was to assess the efficacy of the lead alkyl-substituted diphenyl ether, SBPT04, in the F. tularensis murine model of infection. METHODS: SBPT04 was delivered by intraperitoneal (ip) and oral (po) routes, and mice were monitored for morbidity, mortality and relapse of disease. Pharmacokinetic studies were performed to evaluate bioavailability. Phase I and Phase II metabolism of SBPT04 was assessed in mouse and human microsomes. RESULTS: SBPT04, a potent inhibitor of the enoyl-ACP reductase enzyme ftuFabI, has efficacy against F. tularensis in the murine model of infection when delivered by both ip and po routes. SBPT04 delivered ip cleared infection by day 4 of treatment, and SBPT04 delivered po resulted in delayed dissemination. Importantly, SBPT04 delivered ip or po demonstrated efficacy with no signs of relapse of disease. Pharmacokinetic studies show increased serum concentrations following ip delivery compared with po delivery, which correlates with the observed survival rate of 100%. CONCLUSIONS: In addition to being a potent lead, this work substantiates substituted diphenyl ethers as a platform for the development of novel broad-spectrum chemotherapeutics to other bacterial agents in addition to F. tularensis.
Subject(s)
Anti-Bacterial Agents/therapeutic use , Francisella tularensis/drug effects , Phenyl Ethers/therapeutic use , Tularemia/drug therapy , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacokinetics , Anti-Bacterial Agents/pharmacology , Colony Count, Microbial , Disease Models, Animal , Female , Humans , Inhibitory Concentration 50 , Lung/microbiology , Metabolic Networks and Pathways , Mice , Mice, Inbred ICR , Microbial Sensitivity Tests , Microsomes/metabolism , Models, Molecular , Molecular Structure , Phenyl Ethers/chemistry , Phenyl Ethers/pharmacokinetics , Phenyl Ethers/pharmacology , Plasma/chemistry , Spleen/microbiology , Survival Analysis , Tularemia/pathology , Tularemia/physiopathologyABSTRACT
Diphenyl ether (DPE) was investigated to determine the dermal absorption parameters and subchronic toxicity of this fragrance ingredient. For the absorption, distribution and elimination study, Sprague-Dawley rats received a dermal application of [14C]DPE under a semi-occlusive dressing for 6 h. DPE was diluted in diethyl phthalate (DEP) to administer a total application volume of 2 ml/kg and concentrations of 0.5, 5 and 50% (approximately equal to 10, 100 and 1000 mg DPE/kg body weight). Approximately 17.7% of the administered dose was eliminated in the urine, with small amounts also found in the feces (1.18-3.79%). At 72 h post-dosing, approximately 0.2% of the applied dose was retained in the body with low levels also measured in the liver, kidney and gastrointestinal tract (approximately equal to 0.04, 0.02 and 0.3%, respectively). The 13-week subchronic toxicity study was performed with groups of 12 Sprague-Dawley rats/sex/dose that received semi-occluded daily dermal applications of DPE for 6 h/day. All groups were dosed at a constant 2 ml/kg body weight volume of DPE in the DEP vehicle at concentrations to administer 0, 100, 300 or 1000 mg DPE/kg body weight/day. At the high dose level, there was a slight reduction in body weight gain in males (13%), increase in albumin (5-6%) and phosphate (10-15%) levels in both sexes, a reduction of cholesterol in females (14%), an increase in kidney (17%) and brain (8%) weights in males, and an increase in liver weight (18-19%) in both sexes. No histopathological lesions were seen in any organ examined. At 300 mg/kg body weight/day, the only notable findings were an increase in liver weight (10%) in both sexes and a slight increase in albumin (5%) in females. In addition, skin irritation reactions at the site of application were observed in all DPE dose groups. The systemic no-observed-effect level (NOEL) in this study is 100 mg/kg body weight/day. Owing to mitigating factors, the systemic findings were judged to lack biological significance and the no-observed-adverse-effect level (NOAEL) was determined to be 1000 mg/kg body weight/day.