Design, Synthesis And Bioactivity Studies Of Novel Triketones As 4-Hydroxyphenylpyruvate Dioxygenase Inhibitors

4-Hydroxyphenylpyruvate dioxygenase (EC 1.13.11.27, HPPD) is an important enzyme in the catabolism of tyrosine, belongs to the large family of 2-his-1-carboxylate facial triad oxidative enzymes, catalyzing the conversion of 4-hydroxyphenyl pyruvic acid (HPPA) into homogentisic acid (HGA). In plants, HGA is an important precursor for biosynthesis of plastoquinone and tocopherols. If HPPD is inhibited, the photosynthesis of plant will be blocked. When exposing to sunlight, the plant will be severely damaged, developing unique bleaching symptoms followed by necrosis and death. Therefore HPPD is an important target for herbicides discovery, HPPD-inhibit ing herbicides have many advantages, such as low toxicity, low application rate, excellent crop selectivity, broad-spectrum of weed control (inclusive these resistant biotypes), benign environment effects.To discover novel HPPD inhibitors with improved herbicidal activity and increased crop selectivity, we have designed and synthesized three series of (total 211) novel triketone-containing quinazoline-2,4-diones, quinolines and aryloxyacetic acids based on the structure of HPPD and its inhibitors. The spectral properties, bioactivity and structure-activity relationships of them were well studied. The results indicated that, most of the synthesized compounds displayed excellent weeds control, good crop selectivity and high AtHPPD-inhibiting activity. Most promisingly, some compounds even displayed higher herbicidal activity than the commercial herbicide mesotrione under filed trial experiments. Furthermore, in this thesis we have reported that the triketone-containing quinazoline-2,4-diones can be used as human neutrophil elastase (HNE) for the first time. The detailed information can be summarized as follows:In this thesis, we have summarized the structures, functions and the recent development of HPPD and its inhibitors thoroughly. Based on these findings, we have designed and synthesized a total amount of 211 compounds by multi-step synthetic procedures. All the synthetic target compounds were characterized by 1H NMR, I3C NMR and HRMS spectrum data, the structure of some representative compounds were further verified by X-ray analysis.The results of herbicidal activity indicated that, most of the synthesized triketone-containing quinazoline-2,4-diones displayed strong and promising herbicidal activity against the tested broadleaf weeds Amaranthus retroflexus, Eclipta prostrate, Abutilon juncea and the monocotyledonous weeds Echinochloa crus-galli, Setariafaberii, Digitaria sanguinalis at the rate of 37.5-150 g ai/ha, some of them displayed increased weed control than mesotrione against the tested monocotyledonous weeds. To our delighted that, several of the synthesized compounds even displayed broader spectrum of weed control than mesotrione at the rate of 37.5 g ai/ha, for example, compounds 2-9A4s 2-9A8,2-23B3,2-36A1-2-36A5. Some of the synthesized quinolines displayed good herbicidal activity against six weeds tested at the rate of 150 g ai/ha, promisingly, compounds 3-10A24 displayed broader spectrum of weed control than mesotrione at the rate of 75 g ai/ha. Several of the synthesized aryloxyacetic acids displayed moderate to good herbicidal activity at the rate of 150 g ai/ha. To our surprise that, compounds 4-2A13 displayed 100% inhibition against the tested broadleaf weeds at the rate of 37.5-150 g ai/ha, which was nearly as potent as mesotrione.The results of crop selectivity experiments showed that, some of the synthesized triketones displayed good crop safety at the rate of 150 g ai/ha by post-emergence application. For example, compounds 2-9A4,2-23A25,2-23A31,2-23C6 were safe for maize and wheat; compounds 2-9A8,2-23A11,3-10A24 and 4-2A13 was safe for maize; compound 2-23A8 was safe for rape; compound 2-23A28 was safe for rice and wheat; compound 3-10A25 was safe for maize, rice and wheat; compound 2-23B3 was safe for cotton, maize and wheat, whereas, the commercial herbicide mesotrione was only safe for maize at the same condition.In order to investigate the commercial development potential, some compounds with excellent herbicidal control and good crop selectivity were chose for further filed trial experiment. The results showed that, compound 2-9A4 displayed 94.5%-99% weed control in the field trial at the rate of 37.5-600 g ai/ha; 2-9A8 exhibited 79.4%-98.2% weed control in the field trial at the rate of 18.8-300 g ai/ha; 2-23A25 showed 45.4%-97.7% weed control in the field trial at the rate of 37.5-600 g ai/ha. Exhilaratingly, all the three compounds displayed enhanced herbicidal activity when compared with mesotrione at the rate of 150 g ai/ha. Moreover, the three compounds at their recommend using dosages (2-9A4,75-150 g ai/ha; 2-9A8,150 g ai/ha; 2-23A25,150-300 g ai/ha) were safe for maize, there were no adverse effects of the on predators and parasitoids in the test fields. The promising results indicated that, compounds 2-9A4,2-9A8 and 2-23A25 can be further developed as novel herbicides for maize field.The results of in vitro experiments showed that, most of the synthesized compounds displayed strong AtHPPD-inhibitory activity in the nano-mole range. Some compounds, for example,2-9A8 (Ki=0.005 ?M),2-23A29 (Ki=0.005 ?M),2-28A2 (Ki=0.009 ?M), 2-36A3 (Ki= 0.010 ?M),2-36A4 (Ki= 0.009 ?M),3-10A13 (Ki= 0.009 ?M),3-10A23 (Ki= 0.011 ?M),3-10A24 (ki=0.009 ?M),3-10A30 (Ki= 0.011 ?M),3-16A1 (Ki= 0.007 ?M),3-16A2 (Ki=0.007 ?M),3-20A1 (Ki=0.007 ?M),3-20A2 (Ki=0.008 ?M) even displayed a slight high activity than mesotrione (Ki=0.013?M).The results of HNE inhibitory experiments indicated that, some of the synthesized triketone-containing quinazoline-2,4-diones displayed good HNE-inhibiting activity. For example, the Ki, values for compounds 2-23A3 and 2-9A7 are 13.85 ?M and 15.76 ?M, respectively. To the best of our knowledge this is the first report about triketones with potential anti-inflammatory activity.