Design,Synthesis And Bioactivity Of Novel 1,2,4-triazole Derivatives

1,2,4-Triazoles are a class of nitrogen-containing aromatic heterocyclic scaffolds of paramount importance.They contain three nitrogens and ?-? conjugated system,which makes themselves have strong coordinating and hydrogen-bond-forming capabilities.Because of the unique structural nature,1,2,4-triazoles exhibit a broad spectrum of biological activities and some other special properties.Thus,they are not only widely used in medicine and agriculture,but also have high potentials in supramolecular chemistry,material science,life science and so on.Many of their derivatives have application in industry.And in medicine,they show good antiviral,antimicrobial,antineoplastic,fungicidal activities and inhibition of tyrosinase.Therefore,in recent years,considerable attentions have been paid to azoles.Developing novel triazole derivatives becomes one of important fields in medicinal chemistry.In order to obtain novel 1,2,4-triazole derivatives with high activities,two series of,totally twenty-nine strobilurin derivatives were designed according to the bioisosterism and the connecting principle of actively biological groups,and synthesized in good to excellent yields.The structures of the target molecules are shown in Scheme 1.Scheme 1.Structures of target molecules ? and ?The synthetic methods,bioactivities,structure-activity relationship and spectral properties of the target compounds ? and ? were studied.As a result,many of them were found to show excellent antibacterial or antitumor activities.This dissertation is summarized as follows:1.The research progress of 1,2,4-triazole derivatives were reviewed.Their main regularities of the structure-activity relationship,fungicidal or antitumor activity,and biochemical mode of action are described in detail.2.Twenty-nine 1,2,4-triazole derivatives were designed and synthesized by a multiple step synthetic procedures.Their structures were characterized by 1H NMR and MS spectra.These compounds are summarized as follows:?a-o:Fifteen 3-substituted thio-4-(1,3-dione isoindoline)-5-substituted phenyl-4H-1,2,4-triazoles?a-n:Fourteen(E)-N-substituted benzylidene-3-(substituted thio)-5-(3,4,5-trimethoxyphenyl)-4H-1,2,4-triazol-4-amine3.In order to further confirm the structures of the desired compcounds ?n,one single crystals ?n were generated.The results showed that the double bonds C = N were present as a trans(E)geometric configuration mode.The crystal belongs to the monoclinic system,space group P21/n and the configuration of double bond of C = N is trans.The bond length of N1-C9 is 1.281 A,which is significantly shorter than the two double bonds C = N(N3-C11 = 1.3177 A,N4-C10 = 1.3079 A)in 1,2,4-triazole ring.This indicates significant electron delocalization in the triazole system.Additionally,the intramolecular C(9)-H(9)…S(1),C(17)-H(17)…N(1),C(19)-H(19A)…O(5)and C(23)-H(23A)…O(6)as well as intermolecular C(3)-H(3)…O(6),C(18)-H(18A)…N(4),C(19)-H(19C)…O(4),C(20)-H(20B)…0(1)and C(21)-H(21B)…O(3)hydrogen bonds found compound ?n play a major role in stabilizing the molecule.4.Bioactivity assay indicated that all the target compounds displayed no or low antibacterial activity against Fusarium oxysporum f.sp.cubense,Pestalotiopsis palmarum,Corynespora cmssiicola(Berk&Curt.)Wei),Colletotrichum gloeosporioides PenZ,Rhizoctonia solani,at the concentration of 150 mg/L by the mycelial growth rate method.By the MTT assay,we screened the antitumor activity of most of synthesized compounds on A549,HepG2,PC-3M,MNK-45 tumor cells and found several lead compounds with excellent activity.Especially,compound ?o showed pretty high potency against A549,HepG2,PC-3M and MNK-45 cell lines with IC50 values of 6.76,9.44,11.71 and 9.62 ?M,respectively.Compound ?n showed pretty high potency against A549,HepG2,PC-3M and MNK-45 cell lines with IC50 values of 9.03,22.03,20.69 and 26.64 ?M,respectively,which was much higher antitumor activity than 5-Fluorouracil.These encouraging results indicated that the isoindoline-1,3-dione derivatives bearing 1,2,4-triazole moiety could be identified as a novel antitumor lead structure.