Background: Squalene Synthase is one of the cholesterol biosynthetic pathway enzymes,
inhibition of which produces potent lipid lowering action. A variety of chemical classes have been
evaluated for its inhibition to provide alternate antihyperlipidemic agents to statins.
Methods: A series of N-substituted-sulfomoyl-phenyl-amino carboxylic acid derivatives were designed
through pharmacophore modelling as Squalene Synthase inhibitors. We report here the synthesis, characterization
and in vitro pharmacological screening of the designed molecules as Squalene synthase
inhibitors. The target molecules were synthesized by a simple procedure and each molecule was characterized
by IR, Mass, 1HNMR and 13CNMR spectroscopic techniques. As a primary site of action for
cholesterol biosynthesis is liver, each of the molecules were first screened for in vitro cytotoxicity over
human hepatic cell line (HepG2) by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
(MTT) assay method. The enzyme inhibition assay was performed on cell lysates prepared from HepG2
cells by Human Squalene Synthase ELISA kit, where test compounds were added in the nontoxic concentrations
Results: Compound 5f was found to be most potent with the IC50 value of 11.91 µM. The CTC50 value
for 5f on human hepatic cell line was > 1000 µM so it was considered that the compound was relatively
safe and might be free of hepatotoxicity.
Conclusion: From the results of our studies, it was observed that compounds with poly nuclear aromatic
or hetero aromatic substituent on a side chain were more potent enzyme inhibitors and a distance of 4-5
atoms is optimum between amide nitrogen and hydroxyl group of carboxylic acid.