Design, Synthesis, and Activity Evaluation of Stereoconfigured Tartarate Derivatives as Potential Anti-inflammatory Agents In Vitro and In Vivo.
Priya KumariPalwinder SinghJashanpreet KaurRajbir BhattiPublished in: Journal of medicinal chemistry (2021)
Preclinical and clinical data reveal that inflammation is strongly correlated with the pathogenesis of a number of diseases including those of cancer, Alzheimer, and diabetes. The inflammatory cascade involves a multitude of cytokines ending ultimately with the activation of COX-2/LOX for the production of prostaglandins and leukotrienes. While the available inhibitors for these enzymes suffer from nonoptimal selectivity, in particular for COX-2, we present here the results of purposely designed tartarate derivatives that exhibit favorable selectivity and significant effectiveness against COX-2 and LOX. Integrated approaches of molecular simulation, organic synthesis, and biochemical/physical experiments identified 15 inhibiting COX-2 and LOX with respective IC50 4 and 7 nM. At a dose of 5 mg kg-1 to Swiss albino mice, 15 reversed algesia by 65% and inflammation by 33% in 2-3 h. We find good agreement between experiments and simulations and use the simulations to rationalize our observations.
Keyphrases
- oxidative stress
- anti inflammatory
- molecular dynamics
- type diabetes
- cardiovascular disease
- randomized controlled trial
- systematic review
- papillary thyroid
- low density lipoprotein
- signaling pathway
- monte carlo
- electronic health record
- squamous cell
- stem cells
- cognitive decline
- mental health
- genome wide
- metabolic syndrome
- gene expression
- mild cognitive impairment
- squamous cell carcinoma
- cell therapy
- glycemic control
- dna methylation
- human health
- climate change
- single molecule
- structural basis
- wild type
- skeletal muscle
- high fat diet induced
- insulin resistance