Studies On Rational Design And Screening Of Herbicidal Active Molecules Based On The Herbicide Action Target Transketolase

Herbicides are important agricultural production materials to ensure the yields and quality of crops while excessive use of herbicides causes serious weed resistance.Therefore,the development of a new mode of action herbicide is greatly needed to solve the problem of weed resistance.In this thesis,based on an herbicide target transketolase,using virtual screening,and combining with the herbicide leads ZINC 12007063 and 4u,the optimization of the herbicide lead compounds and their screening studies were carried out.The specific research is as follows:1.In this study,the protein sequence of Arabidopsis transketolase AtTKL1 was obtained from Uniprot,and SWISS-MODEL was used to perform homology modeling to obtain its protein 3D-structure model.Based on the target AtTKL1,the pyrimidine pyrazolamide skeleton was employed as the lead compound,and sixteen compounds were predicted with good activities by using the molecular docking.The docking results revealed that the target molecules could form van der waals force interactions with the key catalytic amino acids His103 and His340 respectively,which suggested their potential herbicidal activity.Finally,sixteen pyrimidine pyrazole amide derivatives were synthesized,chartered by 1H NMR,13C NMR and HRMS and evaluation for their herbicidal activities.2.The herbicidal activities of the target compounds were evaluated by using the small cup method at 200 mg/L and the post-emergence spray treatments respectively.The results showed that compounds 6a,6d,6f,6h,6i.6k and 6o exhibited 66%.80%,74%,62%,54%,65%and 52%growth inhibition against the roots of Digitaria sanguinalis is at 200 mg/L respectively.Among them,6d showed the highest activity,which was significantly better than that of the positive control Atrazine.Compounds 6d and 6g exhibited high activity against the roots of Brassica campestris,with 77%and 82%growth inhibition,respectively,which was better than that of 4u and similar to that of Atrazine.Besides,6d also showed excellent efficacy with the same growth inhibition 64%against Amaranthus retroflexus roots and stems,which were better than those of Atrazine.However,the compounds with good inhibition in the small cup method didn't have obviously good performance in the post-emergence spray treatments.Maybe a waxy layer in the plant leaf surface inhibit the compounds to reach the target site.In summary,6d showed good herbicidal activity in the small cup method and deserved for further study.3.In order to further expand the diversity of the herbicide lead structures targeting at transketolase.the SPECS database was virtual screened based on AtTKL1,and the molecules with great target-ligand interactions were purchased to verify their herbicidal activities at 250 mg/L by the small cup method.The data showed that 1n showed excellent efficacy against A.retroflexus roots and stems,with 64%and 63%growth inhibition,respectively.In also exhibited high activity against D.sanguinalis roots and stems with 58%and 55%growth inhibition,respectively,which were better than those of mesotrione.Besides,compound 1c displayed 55%and 42%growth inhibition against the roots and stems of D.sanguinalis,respectively.In addition,the B.campestris leaves become yellowing,chlorosis,and weak seedling after being treated with compound 1b for 3 d.The compounds 1b and 1c had a dike tone structure,which may be a potential herbicide pharmacophore structure.The two parts of the compound In amide linkage is easy for derivatization studies.In summary,compounds 1b,1c,and 1n may be the ideal structure of the new herbicide leads for transketolase,deserved for potential research and development value.