New derivatives of thieno[3,2-d]pyrimidine and thieno[2,3-b]pyrrole 5a,b and 6a,b, respectively, were obtained from the corresponding thiophene-2-carboxamides 4a,b. On the basis of compounds 5b, 6a and 6b, two novel series of tricyclic- and tetracyclic-condensed pyrimidines 8-15 and 16-19, respectively, were synthesized by the application of the cyclization reactions of 5b and 6a,b with a variety of commercially available reactants. Geometry optimization of selected structures, using the AM1 semiemperical method, revealed a smaller ionization potential and a lower degree of conformational freedom for the tetracyclic pyrimidine derivatives relative to their tricyclic counterparts. Interestingly, computation of the solvation free energies of the lowest energy conformers at physiological conditions indicated that the series is highly soluble under these conditions. The trend in solubility as implied by the relative magnitudes of the solvation free energies is suggestive of a greater contribution of higher moments of charge distribution in modulating the interaction of the structures with the biological environment which could be detrimental for the binding modes of these structures to their putative receptor sites.