A series of new fused polyhetrocyclic derivatives containing pyrimidopyridopyrazole moiety have been synthesized using ami-no-pyrazolopyridopyrimidine (2), as precursors starting materials. The pyrimidopyridopyrazolopyrimidine derivatives (3a-e) have been synthesized by via nucleophilic and cyclocondensation reaction of amino derivative with diethylmalonates derivatives. Also, dichloro derivatives (5) undergo to nucleophilic cyclocondensation reactions, after its treatment with primary amines such as phenyl hydrazine and/or thiourea, affording the polyherocyclic, trihydropyrimidopyridopyrazolopyrimidopyrrolidine-1,3-dione (6a-d), tetrahydropyrim-idopyridopyrazolopyrimidopyridazine-1,3-dione (7) and trihydropyrimidopyridopyrazolopyrimidothiophene-1,3-dione (8) derivatives respectively. The synthesized compounds were characterized using various spectroscopic techniques such as IR, 1HNMR, 13CNMR, MS and elemental analysis. All new derivatives (3-8) were assessed for their antibacterial activity against four bacterial strains, including escherchia coli, pseudomonas aeruginosa, staphylococcus aureus, and staphlococcus pyogenes, using sub-minimal inhibitory concen-tration. Among the tested compounds 3a, 3c, 4, 6a-d, and 8 exhibited superior antibacterial potency.