Synthesis, antimicrobial and antiproliferative activities, molecular docking, and computational studies of novel heterocycles

We studied the reaction of enaminone 3 with some nitrogen nucleophiles to afford the corresponding pyrazole 4 , isoxazole 5 , and pyrimidine 6 derivatives, and the reactivity of enaminone 3 with heterocyclic amines to afford the corresponding fused pyrrolo[1,2- a ]pyrimidine 9a , imidazo[1,2- a ]pyrimidine 9b , phenylpyrrolo[1,2- a ]pyrimidine 9c , and benzo[4,5]imidazo[1,2- a ]pyrimidine 11 derivatives. Additionally, the electrophilic azo-coupling reaction of enaminone 3 with aromatic diazonium salts in pyridine afforded the corresponding intermediate hydrazines 13a – d , which cyclized to pyrazolo[5,1- c ][1,2,4]triazine derivatives 14a – d . Moreover, addition of ( E )-3-(dimethylamino)-1-(2-hydroxyphenyl)prop-2-en-1-one ( 3 ) with hydrazonoyl chloride derivatives 15a , b gave novel pyrazole derivatives 17a , b . Almost all of the synthesized heterocyclic compounds exhibited antimicrobial and in vitro anticancer activity (HepG2 and MCF-7 cell lines). Furthermore, the molecular docking of the most effective compound, i.e., 7-(4-fluorophenyl)pyrazolo[5,1- c ][1,2,4]triazin-3-yl)(2-hydroxyphenyl)methanone ( 14c ), was studied against (PDB ID: 3t88), (PDB ID: 2wje), (PDB ID: 4ynt), and (PDB ID: 1tgh) to investigate its antimicrobial activity when attached to different proteins with short bond length. Compound 14a docked with (PDB ID: 4hdq) and (PDB ID: 3pxe) with energy affinity of −9.946 and −10.55 kcal/mol, with the pyrazolo[5,1- c ][1,2,4]triazine derivative involved in the pockets of the proteins. Moreover; the theoretical and investigational studies of compounds 14a , c were compatible with spectral data obtained at HF/6-31G(d) and DFT/B3LYP/6-31G(d) level.