Abstract
Some new pyrimidine derivatives comprising arylsulfonylhydrazino, ethoxycarbonylhydrazino, thiocarbamoylhydrazino and substituted hydrazone and thiosemicarbazide functionalities were prepared from Biginelli-derived pyrimidine precursors. Heterocyclic ring systems such as pyrazole, pyrazolidinedione, thiazoline and thiazolidinone ring systems were also incorporated into the designed pyrimidine core. Furthermore, fused triazolopyrimidine and pyrimidotriazine ring systems were prepared. The synthesized compounds were evaluated for their calcium channel blocking activity as potential hypotensive agents. Compounds
,
,
,
,
and
showed the highest ex vivo calcium channel blocking activities compared with the reference drug nifedipine. Compounds
and
were selected for further biological evaluation. They revealed good hypotensive activities following intravenous administration in dogs. Furthermore,
and
displayed drug-like
ADME parameters. A ligand-based pharmacophore model was developed to provide adequate information about the binding mode of the newly synthesized active compounds
,
,
,
,
and
. This may also serve as a reliable basis for designing new active pyrimidine-based calcium channel blockers.