ABSTRACT
In this study, we identified three novel compound classes with potent activity against Plasmodium falciparum, the most dangerous human malarial parasite. Resistance of this pathogen to known drugs is increasing, and compounds with different modes of action are urgently needed. One promising drug target is the enzyme 1-deoxy-d-xylulose-5-phosphate synthase (DXPS) of the methylerythritol 4-phosphate (MEP) pathway for which we have previously identified three active compound classes against Mycobacterium tuberculosis. The close structural similarities of the active sites of the DXPS enzymes of P. falciparum and M. tuberculosis prompted investigation of their antiparasitic action, all classes display good cell-based activity. Through structure-activity relationship studies, we increased their antimalarial potency and two classes also show good metabolic stability and low toxicity against human liver cells. The most active compound 1 inhibits the growth of blood-stage P. falciparum with an IC50 of 600 nM. The results from three different methods for target validation of compound 1 suggest no engagement of DXPS. All inhibitor classes are active against chloroquine-resistant strains, confirming a new mode of action that has to be further investigated.
Subject(s)
Antimalarials , Malaria, Falciparum , Thiazoles , Humans , Plasmodium falciparum , Malaria, Falciparum/drug therapy , Malaria, Falciparum/parasitology , Chloroquine , Antimalarials/pharmacology , Antimalarials/chemistrySubject(s)
Calcium/metabolism , Pyrazines/pharmacology , Receptor, Serotonin, 5-HT2C/genetics , Receptor, Serotonin, 5-HT2C/physiology , Digitonin/pharmacology , Humans , Leukocytes, Mononuclear , Lipopolysaccharides/pharmacology , Polymorphism, Single Nucleotide/physiology , Serotonin/analogs & derivatives , Serotonin/pharmacologyABSTRACT
The synthesis and SAR of 3-alkyl-4-aryl-4,5-dihydropyrazole-1-carboxamides 1-23 and 1-alkyl-5-aryl-4,5-dihydropyrazole-3-carboxamides 24-27 as two novel cannabinoid CB(1) receptor agonist classes were described. The target compounds elicited high affinities to the CB(1) as well as the CB(2) receptor and were found to act as CB(1) receptor agonists. The key compound 19 elicited potent CB(1) agonistic and CB(2) inverse agonistic properties in vitro and showed in vivo activity in a rodent model for multiple sclerosis after oral administration.
Subject(s)
Pyrazoles/pharmacology , Receptor, Cannabinoid, CB1/agonists , Pyrazoles/chemistryABSTRACT
The synthesis, structure-activity relationship (SAR) studies and intramolecular hydrogen bonding pattern of 1,3,5-trisubstituted 4,5-dihydropyrazoles are described. The target compounds 6-18 represent a novel class of potent and selective CB(1) receptor antagonists. Based on X-ray diffraction data, the orally active 17 is shown to elicit a different intramolecular H-bonding mode as compared to ibipinabant (3) and SLV330 (4).
Subject(s)
Anti-Obesity Agents/chemical synthesis , Pyrazoles/chemical synthesis , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Sulfonamides/chemical synthesis , Administration, Oral , Animals , Anti-Obesity Agents/chemistry , Anti-Obesity Agents/pharmacology , Binding Sites , Crystallography, X-Ray , Humans , Hydrogen Bonding , Molecular Conformation , Pyrazoles/chemistry , Pyrazoles/pharmacology , Rats , Receptor, Cannabinoid, CB1/metabolism , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacologyABSTRACT
The cannabinoid CB(1)/CB(2) receptor subtype selectivity in the 1,2-diarylimidazole-4-carboxamide series was boosted by fine-tuning its 5-substitution pattern. The presence of the 5-methylsulfonyl group in 11 led to a greater than approximately 840-fold CB(1)/CB(2) subtype selectivity. The compounds 10, 18 and 19 were found more active than rimonabant (1) in a CB(1)-mediated rodent hypotension model after oral administration. Our findings suggest a limited brain exposure of the P-glycoprotein substrates 11, 12 and 21.
Subject(s)
Aminoimidazole Carboxamide/analogs & derivatives , Imidazoles/chemistry , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Receptor, Cannabinoid, CB2/antagonists & inhibitors , Sulfones/chemistry , Administration, Oral , Aminoimidazole Carboxamide/chemical synthesis , Aminoimidazole Carboxamide/chemistry , Aminoimidazole Carboxamide/therapeutic use , Animals , Disease Models, Animal , Drug Inverse Agonism , Hypotension/drug therapy , Imidazoles/chemical synthesis , Imidazoles/therapeutic use , Mice , Rats , Receptor, Cannabinoid, CB1/metabolism , Receptor, Cannabinoid, CB2/metabolism , Structure-Activity Relationship , Sulfones/chemical synthesis , Sulfones/therapeutic useABSTRACT
The synthesis and structure-activity relationship studies of imidazoles are described. The target compounds 6-20 represent a novel chemotype of potent and CB(2)/CB(1) selective cannabinoid CB(2) receptor antagonists/inverse agonists with very high binding efficiencies in combination with favourable logP and calculated polar surface area values. Compound 12 exhibited the highest CB(2) receptor affinity (K(i)=1.03 nM) in this series, as well as the highest CB(2)/CB(1) subtype selectivity (>9708-fold).
Subject(s)
Imidazoles/chemical synthesis , Imidazoles/metabolism , Receptor, Cannabinoid, CB2/antagonists & inhibitors , Receptor, Cannabinoid, CB2/metabolism , Animals , CHO Cells , Cannabinoids/antagonists & inhibitors , Cannabinoids/metabolism , Cricetinae , Cricetulus , Dose-Response Relationship, Drug , Humans , Protein Binding/physiology , Structure-Activity RelationshipABSTRACT
The synthesis and structure-activity relationship studies of 1,4,5,6-tetrahydropyridazines are described. The target compounds 3-5 represent a novel class of potent and selective CB1 receptor antagonists.
Subject(s)
Pyridazines/chemical synthesis , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Animals , CHO Cells , Cricetinae , Cricetulus , Humans , Pyridazines/chemistry , Pyridazines/pharmacology , Receptor, Cannabinoid, CB1/metabolism , Structure-Activity RelationshipABSTRACT
COPD is characterized by persistent airflow limitation, neutrophilia and oxidative stress from endogenous and exogenous insults. Current COPD therapy involving anticholinergics, ß2-adrenoceptor agonists and/or corticosteroids, do not specifically target oxidative stress, nor do they reduce chronic pulmonary inflammation and disease progression in all patients. Here, we explore the effects of Sul-121, a novel compound with anti-oxidative capacity, on hyperresponsiveness (AHR) and inflammation in experimental models of COPD. Using a guinea pig model of lipopolysaccharide (LPS)-induced neutrophilia, we demonstrated that Sul-121 inhalation dose-dependently prevented LPS-induced airway neutrophilia (up to ~60%) and AHR (up to ~90%). Non-cartilaginous airways neutrophilia was inversely correlated with blood H2S, and LPS-induced attenuation of blood H2S (~60%) was prevented by Sul-121. Concomitantly, Sul-121 prevented LPS-induced production of the oxidative stress marker, malondialdehyde by ~80%. In immortalized human airway smooth muscle (ASM) cells, Sul-121 dose-dependently prevented cigarette smoke extract-induced IL-8 release parallel with inhibition of nuclear translocation of the NF-κB subunit, p65 (each ~90%). Sul-121 also diminished cellular reactive oxygen species production in ASM cells, and inhibited nuclear translocation of the anti-oxidative response regulator, Nrf2. Our data show that Sul-121 effectively inhibits airway inflammation and AHR in experimental COPD models, prospectively through inhibition of oxidative stress.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Antioxidants/pharmacology , Chromans/pharmacology , Hypersensitivity/prevention & control , Piperazines/pharmacology , Pulmonary Disease, Chronic Obstructive/drug therapy , Reactive Oxygen Species/antagonists & inhibitors , Animals , Cell Line, Transformed , Chromans/chemistry , Complex Mixtures/antagonists & inhibitors , Complex Mixtures/pharmacology , Disease Models, Animal , Gene Expression Regulation , Guinea Pigs , Humans , Hydrogen Sulfide/agonists , Hydrogen Sulfide/blood , Hypersensitivity/etiology , Hypersensitivity/immunology , Hypersensitivity/metabolism , Inflammation , Interleukin-8/antagonists & inhibitors , Interleukin-8/genetics , Interleukin-8/immunology , Lipopolysaccharides/administration & dosage , Lung , Male , Malondialdehyde/antagonists & inhibitors , Malondialdehyde/metabolism , Myocytes, Smooth Muscle/drug effects , Myocytes, Smooth Muscle/immunology , Myocytes, Smooth Muscle/pathology , NF-E2-Related Factor 2/antagonists & inhibitors , NF-E2-Related Factor 2/genetics , NF-E2-Related Factor 2/immunology , Neutrophils/drug effects , Neutrophils/immunology , Neutrophils/pathology , Oxidative Stress , Piperazines/chemistry , Pulmonary Disease, Chronic Obstructive/immunology , Pulmonary Disease, Chronic Obstructive/metabolism , Pulmonary Disease, Chronic Obstructive/physiopathology , Reactive Oxygen Species/metabolism , Tars/chemistry , Tars/toxicity , Transcription Factor RelA/antagonists & inhibitors , Transcription Factor RelA/genetics , Transcription Factor RelA/immunologyABSTRACT
In the traumatic brain injury (TBI) the initial impact causes both primary injury, and launches secondary injury cascades. One consequence, and a factor that may contribute to these secondary changes and functional outcome, is altered hemodynamics. The relative cerebral blood volume (CBV) changes in rat brain after severe controlled cortical impact injury were characterized to assess their interrelations with motor function impairment. Magnetic resonance imaging (MRI) was performed 1, 2, 4 h, and 1, 2, 3, 4, 7, and 14 days after TBI to quantify CBV and water diffusion. Neuroscore test was conducted before, and 2, 7, and 14 days after the TBI. We found distinct temporal profile of CBV in the perilesional area, hippocampus, and in the primary lesion. In all regions, the first response was drop of CBV. Perifocal CBV was reduced for over 4 days thereafter gradually recovering. After the initial drop, the hippocampal CBV was increased for 2 weeks. Neuroscore demonstrated severely impaired motor functions 2 days after injury (33% decrease), which then slowly recovered in 2 weeks. This recovery parallelled the recovery of perifocal CBV. CBV MRI can detect cerebrovascular pathophysiology after TBI in the vulnerable perilesional area, which seems to potentially associate with time course of sensory-motor deficit.