Synthesis, Molecular Modelling, and Antiproliferative Activity of New Thiadiazole-Pyrazolotriazine and Thiadiazole-Pyrazolopyrimidine Hybrids

New thiadiazole-pyrazolotriazine and thiadiazole-pyrazolopyrimidine hybrids were produced by heterocyclization reactions of aminopyrazole-thiadiazole hybrid with various active methylene compounds and/or unsaturated nitriles. The configuration and energy of the DFT predicted frontier molecular orbitals of the produced hybrids were investigated and hybrids with a low energy gap (& UDelta;EH-L) offered better biological activity. The in vitro anticancer activity of the synthesized compounds was examined against four cancer cell lines (MCF-7, PC3, Hep-2, and HepG2) as well as normal fibroblast cells (WI38). The hybrids 6, 7, 8, and 9 revealed strong cytotoxic efficacy toward MCF-7 cell line, IC50 = 6.54-18.36 & mu;M, in comparison to 5-Fu with IC50 = 5.39 & PLUSMN; 0.52 & mu;M. The structural activity relationship (SAR) and Multiple Linear Regression (MLR) studies have been performed to establish the relationship between anticancer efficiency and chemical structure, as well as the quantum calculated parameters. Furthermore, the in silico docking studies were employed to simulate breast hormone signaling with (PDB:5NQR).