Synthesis And Biological Activity Of 6-chloro-4-N(S)-quinazoline Derivatives

The 4-N substituted quinazoline compounds show ed a wide range of biological activity, including antibacterial, antiviral and anticancer activity. In this paper, the quinazoline as matrix, introducing chlorine atom into the 6 positon of quinazoline, and introducing piperazine which containing amide linkage into the 4 positon of quinazoline then obtaining a series 4-N substituted quinazoline compounds.The starting material 2-amino-5-chlorobenzoic acid is commercially available. After cyclization reaction, chlorination with phosphoryl chloride, treated with 1-boc-piperazine, then deprotection of N-Boc to acquire the key intermediate 6-chloro-4-piperazine quinazoline. Finally, 6-chloro-4-piperazine quinazoline reaction with substituted benzoic acid or substituted benzyl chlor ide then obtained the target compounds. The physical characteristics of all the compounds were confirmed with 1H NMR, 13 C NMR, MS and IR.Nephelometry was used to text the in vitro growth inhibitory activity against plant pathogenic bacteria(Ralstonia solanacearum, Xanthomonas oryzae, Xanthomonas citri). The activity test results of anti-Ralstonia solanacearum showed that the inhibition rates of the compounds 5a, 5b, 5c, 5d, 5e, 5f, 5g, 5h, 5i, 5j, 5l, 5m, 5n, 5o, 5p, 5q, 5u, 5x were above 70% at 100 ?g/mL which were btter than thiediazole copper(54.8%), the highest inhibition rate was 92.4%. The EC50 values' testing results of the target compounds to the growth inhibitory activity of Ralstonia solanacearum showed that the EC50 values of the compounds 5b, 5d, 5e, 5f, 5g, 5o, 5p, 5q, 6b were between 1 ?g/m L and 10 ?g/mL. Three-dimensional quantitative structure–activity relationship(3D-QSAR) model was analysed by Co MF A, Topomer CoMFA and CoMSIA on the basis of the median effect concentration(EC50) against Ralstonia solanacearum and exhibited good predictive power. The activity test results of anti-Xanthomonas oryzae showed that the inhibition rates of the compounds 5d, 5h, 5n, 5s, 5v, 6b, 6e were above 60% at 100 ?g/mL which were btter than bismerthiazol(49.9%). The EC50 values' testing results of the target compounds to the growth inhibitory activity of Xanthomonas oryzae showed that the EC50 values of the compounds 6b and 6f were 8.46 ?g/mL and 10.04 ?g/m L respectively. The activity test results of anti-Xanthomonas citri showed that the inhibition rates of the compounds 5i, 5o were above 70% at 100 ?g/m L which were btter than bismerthiazol(67.3%).The in vitro antifungal activities were screened and evaluated against three pathogenic fungi, namely, Thanatephorus cucumeris, Gibberella zeae and Sclerotinia sclerotiorum, by the mycelial growth rate method. The results showed that the compounds possessed weak inhibition activities at 50 ?g/mL, none of them had better activity than the control drug carbendazim.The anti-TMV activity was tested by the half-leaf method. The result showed that the tested compounds showed weak curative activities at 500 ?g/mL.The curative activit ies of compounds 5b, 5d, 5g, 5i, 5l, 5q, 5t, 5v were under 20% which were much lower than the control drug ningnanmycin(51.5%).