Insights on Regioselective Synthesis of Fused Thiazoles: Density Functional Theory Calculations, Local Reactivity Indices, and Molecular Electrostatic Potential Analysis

A regioselective protocol is developed and validated for the synthesis of pyrazolo[3,4-d]thiazoles and polycyclic-fused thiazoles through the reactions of 2-[((E)-benzylidene)hydrazono]-5-[(Z)-4-methoxybenzylidene]thiazolidin-4-one with hydrazine derivatives or heterocyclic amines, respectively. The products are confirmed by spectral and elemental analyses. Density functional theory studies, including frontier molecular orbital analysis, local reactivity indices, and molecular electrostatic potential mapping, explain the observed regioselectivity and support a proposed reaction mechanism. Molecular docking shows that several derivatives (e.g., 6c, 6d) have strong binding to S. aureus, E. coli, and topoisomerase IIα, with energies comparable to standard drugs. Absorption, distribution, metabolism, excretion, and toxicity predictions indicate good oral bioavailability, low blood-brain barrier permeability, and acceptable safety, suggesting these compounds as promising antibacterial and anticancer candidates.