Synthesis Of Fungicides Based On IV ParE Subunit Of Xanthomonas Oryzae Topoisomerase

Bacterial leaf blight(BLB), caused by Xanthomonas oryzae pv. Oryzae(Xoo), is a serious bacterial disease and has caused severe damage to rice production..Topoisomerases are marvelous molecular machines that manage the topological states of DNA by introducing temporary single- or double-strand breaks in the DNA. Two main mechanisms are responsible for the antibacterial activity of drugs targeting bacterial topoisomerases. The first is the inhibition of the catalytic site in Gyr A/ParC subunit, involves stabilisation of the covalent enzyme-DNA complex, while the second is the inhibition of ATP binding site in Gyr B/ParE subunit.Surflex-Dock was applied for the virtual screening based on the receptor-ligand docking, in which compounds from ZINC database were used as ligands, and the ParE-Novobiocin complex was used as the receptor. Based on the results of virtual screening, a series of N-substitution-1-(9H-purin-6-yl)piperidine-4-carboxamides were designed and synthesized.Two different synthetic routes of target compounds were investigated in A-1’s case. With piperidine-4-carboxylic acid as the starting material, target compounds were synthesized via two routes respectively when different amines were used.Antibacterial activities of all title compounds were tested in vitro by the nephelometry method. It was found that the inhibitory activities of compounds A-5(75.0±1.7%, 73.1±6.8%),B-4(97.2±5.6%, 55.8±0.2%) and B-6(75.4±1.0%, 60.6±3.4%) against Xanthomonas axonopodis pv. citri at 200 and 100 μg/mL were higher than those of the positive control Novobiocin(48.5±4.0%, 36.9±4.4%). Yet all the compounds were almost inactive against Xanthomonas oryzae pv. Oryzae, Ralstonia solanacearum and Staphylococcus aureus.Further, curative effects to Tobacco mosaic virus of the target compounds were tested by the half-leaf method. The results showed that A-9 has potential curative effect against TMV. Also anticancer activities of the compounds were tested against A549 cell line by the MTT assay in vitro. It was found that the antiproliferation activities of A-1(81.1±3.2%, 60.8±5.9%), A-3(80.6±1.8%, 89.9±1.1%) and A-6(87.9±2.7%, 85.7±3.3%) at 1 and 10 μM were better than those of the positive control gifitinib(72.0±3.7%, 54.0±4.0%).