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A series of 2-substituted-4,6-diaminipyrimidine derivatives were synthesized and evaluated for their dihydrofolate reductase (DHFR) inhibitory activity. Saturation transfer difference (STD) (1)H-NMR experiments were used to probe the binding characteristics of the compounds with human DHFR enzyme. The most potent molecules, 12 and 15, in enzyme assay study showed the best results in STD experiments indicating their intimate interaction with the receptor. The docking studies were followed to explain the structural basis for the observed interaction between the ligands and DHFR. All the compounds were also assayed in vitro for their growth inhibitory activity on MCF-7, HepG2, SKHep1, and Hela tumor cell lines. Compounds 16, 17, and 22 demonstrated the most potent in vitro anti-proliferative activity among the others.

Nonalcoholic fatty liver disease (NAFLD) is a clinicopathological term that encompasses a spectrum of abnormalities ranging from simple triglyceride accumulation in the hepatocytes (hepatic steatosis) to hepatic steatosis with inflammation (steatohepatitis, also known as nonalcoholic steatohepatitis or NASH). NASH can also progress to cirrhosis and hepatocellular carcinoma (HCC). Steatohepatitis has been estimated to affect around 5% of the total population and 20% of those who are overweight. The mechanisms leading to NASH and its progression to cirrhosis and HCC remain unclear, but it is a condition typically associated with obesity, insulin resistance, diabetes, and hypertriglyceridemia. This point corroborates the need for animal models and molecular markers that allow us to understand the mechanisms underlying this disease. Nowadays, there are numerous mice models to study abnormal liver function such as steatosis, NASH, and hepatocellular carcinoma. The study of the established animal models has provided many clues in the pathogenesis of steatosis and steatohepatitis, although these remain incompletely understood and no mice model completely fulfills the clinical features observed in humans. In addition, there is a lack of accurate sensitive diagnostic tests that do not involve invasive procedures. Current laboratory tests include some biochemical analysis, but their utility for diagnosing NASH is still poor. For that reason, a great effort is being made toward the identification and validation of novel biomarkers to assess NASH using high-throughput analysis based on genomics, proteomics, and metabolomics. The most recent discoveries and their validation will be discussed.