Structure-based design and optimization of pyrimidine- and 1,2,4-triazolo[4,3-a]pyrimidine-based matrix metalloproteinase-10/13 inhibitors via Dimroth rearrangement towards targeted polypharmacology.

•Novel hydrazones 6–10 were cyclized to isomeric triazolo[4,3-a]pyrimidines 12–19.•5-Oxo-1,2,4-triazolo[4,3-a]pyrimidines exhibited higher MMP-10/13 inhibition than their regioisomers.•Inactive triazolopyrimidines were rearranged to the potent Dimroth products.•The most active MMP-10 inhibitor 16 (IC50 = 24 nM) was selective over MMP-13,-9 and-7.•MMP-10/13 inhibitors 16 and 18 exhibited anticancer activities superior to quercetin.