The adenosine cyclic 3', 5' -monophosphate (c-AMP) phosphodiesterase (PDE) inhibitory activity of a series of mesoionic 1, 3, 4- thiadiazolopyrimidines and of a group of benz-fused mesoionic xanthine analogs are found to be significantly correlated with the van der Waals volume (V_w) of the substituents or the first order valence connectivity index (¹X^v) of the molecule. From the correlating equations it is observed that the size of the substituents at certain positions, of pyrimidine ring particularly, in the molecule are determinatitve to the activity. Further based on these equations it may be suggested that PDE inhibition by this class of drugs involves either hydrophobic interaction or van der Waals type of interaction. In certain cases steric and electronic factors are also indicated to affect the inhibition.