Abstract: Background/Objectives: Supported by a comparative study between conventional, grinding,
and microwave techniques, a mild and versatile method based on the [1 + 3] cycloaddition
of 2-((3-nitrophenyl)diazenyl)malononitrile to tether pyrazole and pyrimidine derivatives in good
yields was used. Methods: The newly synthesized compounds were analyzed with IR, 13C NMR,
1H NMR, mass, and elemental analysis methods. The products show interesting precursors for their
antiproliferative anti-breast cancer activity. Results: Pyrimidine-containing scaffold compounds 9
and 10 were the most active, achieving IC50 = 26.07 and 4.72 μM against the breast cancer MCF-7 cell
line, and 10.64 and 7.64 μM against breast cancer MDA-MB231-tested cell lines, respectively. Also,
compounds 9 and 10 showed a remarkable inhibitory activity against the Hsp90 protein with IC50
values of 2.44 and 7.30 μM, respectively, in comparison to the reference novobiocin (IC50 = 1.14 μM).
Moreover, there were possible apoptosis and cell cycle arrest in the G1 phase for both tested compounds
(supported by CD1, caspase-3,8, BAX, and Bcl-2 studies). Also, the binding interactions
of compound 9 were confirmed through molecular docking, and simulation studies displayed a
complete overlay into the Hsp90 protein pocket. Conclusions: Compounds 9 and 10 may have
apoptotic antiproliferative action as Hsp90 inhibitors.