Novel Pyrazole Acyl(thio)urea Derivatives Containing a Biphenyl Scaffold as Potential Succinate Dehydrogenase Inhibitors: Design, Synthesis, Fungicidal Activity, and SAR.

As part of a program to discover novel succinate dehydrogenase inhibitor fungicides, a series of new pyrazole acyl(thio)urea compounds containing a diphenyl motif were designed and synthesized. Their structures were confirmed by 1H NMR, HRMS, and single X-ray crystal diffraction analysis. Most of these compounds possessed excellent activity against 10 fungal plant pathogens at 50 µg mL-1, especially against Rhizoctonia solani, Alternaria solani, Sclerotinia sclerotiorum, Botrytis cinerea, and Cercospora arachidicola. Interestingly, compounds 3-(difluoromethyl)-1-methyl-N-((3',4',5'-trifluoro-[1,1'-biphenyl]-2-yl)carbamoyl)-1H-pyrazole-4-carboxamide (9b, EC50 = 0.97 ± 0.18 µg mL-1), 1,3-dimethyl-N-((3',4',5'-trifluoro-[1,1'-biphenyl]-2-yl)carbamoyl)-1H-pyrazole-4-carboxamide (9a, EC50 = 2.63 ± 0.41 µg mL-1), and N-((4'-chloro-[1,1'-biphenyl]-2-yl)carbamoyl)-1,3-dimethyl-1H-pyrazole-4-carboxamide (9g, EC50 = 1.31 ± 0.15 µg mL-1) exhibited activities against S. sclerotiorum that were better than the commercial fungicide bixafen (EC50 = 9.15 ± 0.05 µg mL-1) and similar to the positive control fluxapyroxad (EC50 = 0.71 ± 0.11 µg mL-1). These compounds were not significantly phytotoxic to monocotyledonous and dicotyledonous plants. Structure-activity relationships (SAR) are discussed by substituent effects/molecular docking, and density functional theory analysis indicated that these compounds are succinate dehydrogenase inhibitors.

Discovery of Highly Efficient Novel Antifungal Lead Compounds Targeting Succinate Dehydrogenase: Pyrazole-4-carboxamide Derivatives with an N-Phenyl Substituted Amide Fragment.

Developing environmentally friendly fungicides is crucial to tackle the issue of rising pesticide resistance. In this study, a series of novel pyrazole-4-carboxamide derivatives containing N-phenyl substituted amide fragments were designed and synthesized. The structures of target compounds were confirmed by 1H NMR, 13C NMR, and HRMS, and the crystal structure of the most active compound N-(1-(4-(4-(tert-butyl)benzamido)phenyl)propan-2-yl)-3-(difluoromethyl)-N-methoxy-1-methyl-1H-pyrazole-4-carboxamide (U22) was further determined by X-ray single-crystal diffraction. The bioassay results indicated that the 26 target compounds possessed good in vitro antifungal activity against Sclerotinia sclerotiorum with EC50 values for compounds U12, U13, U15, U16, U18, U22, and U23 being 4.17 ± 0.46, 8.04 ± 0.71, 7.01 ± 0.71, 12.77 ± 1.00, 8.11 ± 0.70, 0.94 ± 0.11, and 9.48 ± 0.83 µg·mL-1, respectively, which were the similar to controls bixafen (6.70 ± 0.47 µg·mL-1), fluxapyroxad (0.71 ± 0.14 µg·mL-1), and pydiflumetofen (0.06 ± 0.01 µg·mL-1). Furthermore, in vivo antifungal activity results against S. sclerotiorum indicated that compounds U12 (80.6%) and U22 (89.9%) possessed excellent preventative efficacy at 200 µg·mL-1, which was the same as the control pydiflumetofen (82.4%). Scanning electron microscopy and transmission electron microscopy studies found that the compound U22 could destroy the hyphal morphology and damage mitochondria, cell membranes, and vacuoles. The results of molecular docking of compound U22 and pydiflumetofen with succinate dehydrogenase (SDH) indicated they interact well with the active site of SDH. This study validated our approach and design strategy to produce compounds with an enhanced biological activity as compared to the parent structure.

Design, Synthesis, Insecticidal Activity, and SAR of Aryl Isoxazoline Derivatives Containing Pyrazole-5-carboxamide Motif.

It is important to develop new insecticides with a new mode of action because of increasing pesticide resistance. In this study, a series of novel aryl isoxazoline derivatives containing the pyrazole-5-carboxamide motif were designed and synthesized. Their structures were confirmed by 1H NMR, 13C NMR, and HRMS. Bioassays indicated that the 24 compounds synthesized possessed excellent insecticidal activity against Mythimna separate and no activity against Aphis craccivora and Tetranychus cinnabarinus. Among these aryl isoxazoline derivatives, 3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydrozol-3-yl)-N-(4-fluorophenyl)-1-methyl-1H-pyrazole-5-carboxamide (IA-8) had the best insecticidal activity against M. separate, which is comparable with the positive control fluralaner. The molecular docking results of compound IA-8 and fluralaner with the GABA model demonstrated the same docking mode between compound IA-8 and positive control fluralaner in the active site of GABA. Molecular structure comparisons and ADMET analysis can potentially be used to design more active compounds. The structure-activity relationships are also discussed. This work provided an excellent insecticide for further optimization.

Synthesis, crystal structure, herbicidal activity and mode of action of new cyclopropane-1,1-dicarboxylic acid analogues.

A new series of cyclopropane-1,1-dicarboxylic (CPD) acid analogues were designed and synthesized. CPD is an inhibitor of ketol-acid reductoisomerase (KARI), an enzyme of the branched chain amino acid pathway in plants. The structures of CPD analogues were characterized by 1H NMR and HRMS. The structure of N,N'-bis(4-(tert-butyl)phenyl)cyclopropane-1,1-dicarboxamide was further elucidated by X-ray diffraction. The herbicidal activities of these compounds were tested against lettuce (Lactuca sativa) and bentgrass (Agrostis stolonifera). Most of these compounds exhibited low herbicidal activity against both plant species. Among them, N,N'-bis(2-ethylphenyl)cyclopropane-1,1-dicarboxamide displayed moderate activity against bentgrass. Inhibition of KARI activity by the CPD analogues was also assessed experimentally and by molecular docking simulation with results supporting inhibition of KARI as their mode of action. These results provide the basis for design of more effective KARI inhibitors.

Novel Dioxolane Ring Compounds for the Management of Phytopathogen Diseases as Ergosterol Biosynthesis Inhibitors: Synthesis, Biological Activities, and Molecular Docking.

Thirty novel dioxolane ring compounds were designed and synthesized. Their chemical structures were confirmed by 1H NMR, HRMS, and single crystal X-ray diffraction analysis. Bioassays indicated that these dioxolane ring derivatives exhibited excellent fungicidal activity against Rhizoctonia solani, Pyricularia oryae, Botrytis cinerea, Colletotrichum gloeosporioides, Fusarium oxysporum, Physalospora piricola, Cercospora arachidicola and herbicidal activity against lettuce (Lactuca sativa), bentgrass (Agrostis stolonifera), and duckweed (Lemna pausicostata). Among these compounds, 1-((2-(4-chlorophenyl)-5-methyl-1,3-dioxan-2-yl)methyl)-1H-1,2,4-triazole (D17), 1-(((4R)-2-(4-chlorophenyl)-4-methyl-1,3-dioxolan-2-yl)methyl)-1H-1,2,4-triazole (D20), 1-((5-methyl-2-(4-(trifluoromethyl)phenyl)-1,3-dioxan-2-yl)methyl)-1H-1,2,4-triazole (D22), and 1-((2-(4-fluorophenyl)-1,3-dioxolan-2-yl)methyl)-1H-1,2,4-triazole (D26) had broad spectrum fungicidal and herbicidal activity. The IC50 values against duckweed were 20.5 ± 9.0, 14.2 ± 6.7, 24.0 ± 11.0, 8.7 ± 3.5, and 8.0 ± 3.1 µM for D17, D20, D22, and D26 and the positive control difenoconazole, respectively. The EC50 values were 7.31 ± 0.67, 9.74 ± 0.83, 17.32 ± 1.23, 11.96 ± 0.98, and 8.93 ± 0.91 mg/L for D17, D20, D22, and D26 and the positive control difenoconazole against the plant pathogen R. solani, respectively. Germination experiments with Arabidopsis seeds indicated that the target of these dioxolane ring compounds in plants is brassinosteroid biosynthesis. Molecular simulation docking results of compound D26 and difenoconazole with fungal CYP51 P450 confirmed that they both inhibit this enzyme involved in ergosterol biosynthesis. The structure-activity relationships (SAR) are discussed by substituent effect, molecular docking, and density functional theory analysis, which provided useful information for designing more active compounds.

Synthesis and Pesticidal Activity of New Niacinamide Derivatives Containing a Flexible, Chiral Chain.

Natural products are a source for pesticide or drug discovery. In order to discover lead compounds with high fungicidal or herbicidal activity, new niacinamide derivatives derived from the natural product niacinamide, containing chiral flexible chains, were designed and synthesized. Their structures were confirmed by 1H NMR, 13C NMR and HRMS analysis. The fungicidal and herbicidal activities of these compounds were tested. The fungicidal activity results demonstrated that the compound (S)-2-(2-chloronicotinamido)propyl-2-methylbenzoate (3i) exhibited good fungicidal activity (92.3% inhibition) against the plant pathogen Botryosphaeria berengriana at 50 µg/mL and with an EC50 of 6.68 ± 0.72 µg/mL, which is the same as the positive control (fluxapyroxad). Compound 3i was not phytotoxic and could therefore be used as a fungicide on crops. Structure-activity relationships (SAR) were studied by molecular docking simulations with the succinate dehydrogenase of the fungal mitochondrial respiratory chain.

Synthesis, Crystal Structure, Herbicidal Activity, and SAR Study of Novel N-(Arylmethoxy)-2-chloronicotinamides Derived from Nicotinic Acid.

Nicotinic acid, also known as niacin, is a natural product, which is widely found in plants and animals. To discover novel natural-product-based herbicides, a series of N-(arylmethoxy)-2-chloronicotinamides were designed and synthesized. Some of the new N-(arylmethoxy)-2-chloronicotinamides exhibited excellent herbicidal activity against Agrostis stolonifera (bentgrass) at 100 µM. Compound 5f (2-chloro-N-((3,4-dichlorobenzyl)oxy)nicotinamide) possessed excellent herbicidal activity against Lemna paucicostata (duckweed), with an IC50 value of 7.8 µM, whereas the commercial herbicides clomazone and propanil had values of 125 and 2 µM, respectively. The structure-activity relationships reported in this paper could be used for the development of new herbicides against monocotyledonous weeds.

Design, Synthesis, and Pesticidal Activities of Pyrimidin-4-amine Derivatives Bearing a 5-(Trifluoromethyl)-1,2,4-oxadiazole Moiety.

It is important to discover new pesticides with new modes of action because of the increasing evolution of pesticide resistance. In this study, a series of novel pyrimidin-4-amine derivatives containing a 5-(trifluoromethyl)-1,2,4-oxadiazole moiety were designed and synthesized. Their structures were confirmed by 1H NMR, 13C NMR, and HRMS. Bioassays indicated that the 29 compounds synthesized possessed excellent insecticidal activity against Mythimna separata, Aphis medicagini, and Tetranychus cinnabarinus and fungicidal activity against Pseudoperonospora cubensis. Among these pyrimidin-4-amine compounds, 5-chloro-N-(2-fluoro-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzyl)-6-(1-fluoroethyl)pyrimidin-4-amine (U7) and 5-bromo-N-(2-fluoro-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzyl)-6-(1-fluoroethyl) pyrimidin-4-amine(U8) had broad-spectrum insecticidal and fungicidal activity. The LC50 values were 3.57 ± 0.42, 4.22 ± 0.47, and 3.14 ± 0.73 mg/L for U7, U8, and flufenerim against M. separata, respectively. The EC50 values were 24.94 ± 2.13, 30.79 ± 2.21, and 3.18 ± 0.21 mg/L for U7, U8, and azoxystrobin against P. cubensis, respectively. The AChE enzymatic activity testing revealed that the enzyme activities of compounds U7, U8, and flufenerim are 0.215, 0.184, and 0.184 U/mg prot, respectively. The molecular docking results of compounds U7, U8, and flufenerim with the AChE model demonstrated the opposite docking mode between compound U7 or U8 and positive control flufenerim in the active site of AChE. The structure-activity relationships are also discussed. This work provided excellent pesticide for further optimization. Density functional theory analysis can potentially be used to design more active compounds.

1,2,4-Oxadiazole-Based Bio-Isosteres of Benzamides: Synthesis, Biological Activity and Toxicity to Zebrafish Embryo.

To discover new compounds with broad spectrum and high activity, we designed a series of novel benzamides containing 1,2,4-oxadiazole moiety by bioisosterism, and 28 benzamides derivatives with antifungal activity were synthesized. These compounds were evaluated against four fungi: Botrytis cinereal, FusaHum graminearum, Marssonina mali, and Thanatephorus cucumeris. The results indicated that most of the compounds displayed good fungicidal activities, especially against Botrytis cinereal. For example, 10a (84.4%), 10d (83.6%), 10e (83.3%), 10f (83.1%), 10i (83.3%), and 10l (83.6%) were better than pyraclostrobin (81.4%) at 100 mg/L. In addition, the acute toxicity of 10f to zebrafish embryo was 20.58 mg/L, which was classified as a low-toxicity compound.

Synthesis and Biological Activity of Benzamides Substituted with Pyridine-Linked 1,2,4-Oxadiazole.

To find pesticidal lead compounds with high activity, a series of novel benzamides substituted with pyridine-linked 1,2,4-oxadiazole were designed by bioisosterism, and synthesized easily via esterification, cyanation, cyclization and aminolysis reactions. The structures of the target compounds were confirmed by 1H-NMR, 13C-NMR and HRMS. The preliminary bioassay showed that most compounds had good larvicidal activities against mosquito larvae at 10 mg/L, especially compound 7a, with a larvicidal activity as high as 100%, and even at 1 mg/L was still 40%; at 50 mg/L, all the target compounds showed good fungicidal activities against the eight tested fungi. Moreover, compound 7h exhibited better inhibitory activity (90.5%) than fluxapyroxad (63.6%) against Botrytis cinereal. Therefore, this type of compound can be further studied.

Synthesis and Pesticidal Activities of New Quinoxalines.

Natural products are a source of many novel compounds with biological activity for the discovery of new pesticides and pharmaceuticals. Quinoxaline is a fused N-heterocycle in many natural products and synthetic compounds, and seven novel quinoxaline derivatives were designed and synthesized via three steps. Pesticidal activities of title quinoxaline derivatives were bioassayed. Most of these compounds had herbicidal, fungicidal, and insecticidal activities. The compounds 2-(6-methoxy-2-oxo-3-phenylquinoxalin-1(2H)-yl)acetonitrile (3f) and 1-allyl-6-methoxy-3-phenylquinoxalin-2(1H)-one (3g) were the most active herbicides and fungicides. Mode-of-action studies indicated that 3f is a protoprophyrinogen oxidase-inhibiting herbicide. Compound 3f also possessed broad-spectrum fungicidal activity against the plant pathogen Colletotrichum species. Some of these compounds also had insecticidal activity. Molecular docking and DFT analysis can potentially be used to design more active compounds.

Design, synthesis and antifungal activity of threoninamide carbamate derivatives via pharmacophore model.

Thirty-six novel threoninamide carbamate derivatives were designed and synthesised using active fragment-based pharmacophore model. Antifungal activities of these compounds were tested against Oomycete fungi Phytophthora capsici in vitro and in vivo. Interestingly, compound I-1, I-2, I-3, I-6 and I-7 exhibited moderate control effect (>50%) against Pseudoperonospora cubensis in greenhouse at 6.25 µg/mL, which is better than that of control. Meanwhile most of these compounds exhibited significant inhibitory against P. capsici. The other nine fungi were also tested. More importantly, some compounds exhibited remarkably high activities against Sclerotinia sclerotiorum, P. piricola and R. solan in vitro with EC50 values of 3.74-9.76 µg/mL. It is possible that the model is reliabile and this method can be used to discover lead compounds for the development of fungicides.

Synthesis and herbicidal activity of novel pyrazole aromatic ketone analogs as HPPD inhibitor.

BACKGROUND: 4-Hydroxyphenylpyruvate dioxygenase (HPPD, EC 1.13.11.27) has been a good target for herbicide discovery. In order to discover novel HPPD herbicides, a series of pyrazole aromatic ketone analogs were designed and synthesized. RESULTS: The 25 pyrazole aromatic ketone analogs synthesized were tested for herbicidal activity and compounds A1, A3, A4, A17, A20 and A25 displayed excellent herbicidal activity against Chenopodium serotinum, Stellaria media and Brassica juncea at 37.5 g ha-1 . In addition, compounds A1, A5, A9, A10, A16, A17, A20 and A25 exhibited good crop selectivity for wheat, maize and rice at 150 g ha-1 . Inhibition activities against AtHPPD proved the compounds were HPPD inhibitors. The structure-activity relationship of these pyrazole aromatic ketone analogs was studied using molecular docking. CONCLUSION: These pyrazole aromatic ketone derivatives could be used as lead structures for development of HPPD herbicides against dicotyledonous weeds with further structure modification. © 2019 Society of Chemical Industry.

Novel 4-pyrazole carboxamide derivatives containing flexible chain motif: design, synthesis and antifungal activity.

BACKGROUND: In recent years, carboxamide fungicides, targeting succinate dehydrogenase (SDH), have shown highly efficient and broad spectrum fungicidal activity. Structure-activity relationship (SAR) results for these commercial fungicides show that the carboxamide group was a key active group. This is useful information for the discovery of new pyrazole carboxamide derivatives with fungicidal activity. RESULTS: Twenty-seven novel pyrazole carboxamides were designed and synthesized. Their fungicidal activities against Gibberella zeae, Phytophthora infestans, Phytophthora capsici, Rhizoctonia solani, Alternaria solani, Botrytis cinerea, Fusarium oxysporum, Cercospora arachidicola, Sclerotinia sclerotiorum and Physalospora piricola were tested; derivatives possessed excellent inhibitory at 50 mg L-1 in particular. Furthermore, some pyrazole carboxamides exhibited remarkably high activities against Sclerotinia sclerotiorum in vitro with EC50 values of 2.04 to 15.2 µg mL-1 . In addition, some compounds also exhibited high activities against Physalospora piricola, Cercospora arachidicola and Phytophthora capsici. Inhibition activities against SDH proved that the designed analogues were effective at the enzyme level. The SAR of these pyrazole carboxamides was studied by using the docking method. CONCLUSION: It is possible that pyrazole carboxamides, which exhibit good activity against Sclerotinia sclerotiorum, can be further optimized as a lead compounds of carboxamide fungicides. © 2019 Society of Chemical Industry.

Synthesis, biological activities and SAR studies of new 3-substitutedphenyl-4-substitutedbenzylideneamino-1,2,4-triazole Mannich bases and bis-Mannich bases as ketol-acid reductoisomerase inhibitors.

A series of new 3-substitutedphenyl-4-substitutedbenzylideneamino-1,2,4-triazole Mannich bases and bis-Mannich bases were synthesized through Mannich reaction with high yields. Their structures were confirmed by means of IR, 1H NMR, 13C NMR and elemental analysis. The preliminary bioassay indicated that compounds 7g, 7h and 7l exhibited potent in vitro inhibitory activities against ketol-acid reductoisomerase (KARI) with Ki value of (0.38 ±â€¯0.25), (6.59 ±â€¯2.75) and (8.46 ±â€¯3.99) µmol/L, respectively, and were comparable with IpOHA. They could be new KARI inhibitors for follow-up research. Some of the title compounds also exhibited obvious herbicidal activities against Echinochloa crusgalli and remarkable in vitro fungicidal activities against Physalospora piricola and Rhizoctonia cerealis. The SAR of the compounds were analyzed, in which the molecular docking revealed the binding mode of 7g with the KARI, and the 3D-QSAR results provided useful information for guiding further optimization of this kind of structures to discover new fungicidal agents towards Rhizoctonia cerealis.

Synthesis and in vivo fungicidal activity of some new quinoline derivatives against rice blast.

BACKGROUND: Quinoline derivatives possess excellent fungicidal activity against rice blast, but quinoline derivatives have not been thoroughly explored as fungicides. In the process of designing new fungicides, the 1,1,1,2,3,3,3-heptafluoropropan-2-yl group was introduced in order to find new structure quinoline derivatives. RESULTS: Seventeen new quinoline derivatives containing 1,1,1,2,3,3,3-heptafluoropropan-2-yl moiety were designed and synthesised. In vivo fungicidal activities of these compounds were tested against rice blast. Some of the compounds provided effective control at 100 mg L-1 , and a few compounds were effective at 10 mg L-1 . Furthermore, a density functional theory study established the structure-activity relationships of the synthesised compounds. CONCLUSION: Quinoline derivatives, especially benzyl (2,3,8-trimethyl-6-(perfluoropropan-2-yl)quinolin-4-yl) carbonate, which possess good control effective against rice blast and cucumber powdery mildew, may become new lead compounds for the development of fungicides with further structure modification. © 2017 Society of Chemical Industry.

Synthesis, nematocidal activity and SAR study of novel difluoromethylpyrazole carboxamide derivatives containing flexible alkyl chain moieties.

A series of novel difluoromethylpyrazole carboxamides derivatives were synthesized by introduction of flexible alkyl chain. Nematicidal bioassay results showed that some of them exhibited good control efficacy against M. incognita, which indicated that these difluoromethylpyrazole carboxamides derivatives might be potential novel lead compounds for discovery new nematicides. The nematicidal activity was affected by the substituted position in the molecule, especially the substitution group on the alkyl chain. It was found that the compound 6-9 and 6-23 possess about 50% inhibition effect against M. incognita even at 5.0 and 1.0 mg L-1. Meanwhile, greenhouse field trial showed the nematicidal activity of compound 6-9 is a litter weaker than that of Abamectin. The mammalian toxicology results indicated that compound 6-9 was a low-toxicity and low-sensitive compound. In conclusion compound 6-9 is a potential candidate for further development. In addition, the molecular docking simulations revealed that compounds 6 with a flexible NHCOO show its binding affinities for the acetylcholine receptor (AChR), which may provide useful information for further design novel nematicides.

Synthesis and insecticidal activity of novel pyrimidine derivatives containing urea pharmacophore against Aedes aegypti.

BACKGROUND: Aedes aegypti is a major mosquito vector for the transmission of serious diseases, especially dengue and yellow fever. More than 1 billion people in developing countries are at risk. The widespread and continual use of pesticides can lead to resistant mosquitoes. In order to maintain mosquito control gains, it is critical to develop and evaluate novel bioactive molecules that differ in mode of action from currently used products. RESULTS: A series of novel pyrimidine derivatives were designed and synthesized. Their structures were elucidated by proton nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry. The biological activities of these compounds were tested against Ae. aegypti. Many of them exhibited insecticidal activity against adult and larval mosquitoes. Compound 4d displayed relatively good activity to reach 70% mortality at 2 µg mL-1 . Furthermore, density functional theory calculations were established to study the structure-activity relationship of these novel compounds. CONCLUSION: A practical synthetic route for pyrimidine derivatives is presented. This study suggests that these pyrimidine derivatives exhibit some activity against the yellow fever mosquito and, with further structure modification, could be novel lead compounds for the development of insecticides against mosquitoes. © 2016 Society of Chemical Industry.

Microwave assisted synthesis, antifungal activity, DFT and SAR study of 1,2,4-triazolo[4,3-a]pyridine derivatives containing hydrazone moieties.

BACKGROUND: The increasing prevalence of multi-drug resistant fungal infections has encouraged the search for new antifungal agents. Hydrazone derivatives always exhibited diversity activities, including antifungal, anti-inflammatory, anti-oxidation, anti-cancer activity. Regarding the heterocyclic moiety, 1,2,4-triazolo[4,3-a]pyridine derivatives also display broad activities, such as antifungal activity, anticonvulsant activity, herbicidal activity, antimicrobial activity and anticancer activity. RESULTS: A series of novel 1,2,4-triazolo[4,3-a]pyridine derivatives containing hydrazone moiety were designed and synthesized from 2,3-dichloropyridine, hydrazine hydrate by multi-step reactions under microwave irradiation condition, and their structures were characterized by FT IR, (1)H NMR, (13)C NMR, (19)F NMR, MS and elemental analysis. The antifungal activities of title compounds were determined. The results indicated that some of the title compounds exhibited good antifungal activity. Furthermore, DFT calculation was carried out for studying the structure-activity relationship (SAR). CONCLUSION: A practical synthetic route to obtain 1,2,4-triazolo[4,3-a]pyridine derivatives is presented. This study suggests that the 1,2,4-triazolo[4,3-a]pyridine derivatives exhibited good antifungal activity.

Synthesis and biological activities of novel 5-substituted-1,3,4-oxadiazole Mannich bases and bis-Mannich bases as ketol-acid reductoisomerase inhibitors.

A series of novel 5-substituted-1,3,4-oxadiazole Mannich bases and bis-Mannich bases have been conveniently synthesized in good yields. Their structures were characterized by IR, (1)H NMR, (13)C NMR and elemental analysis. The preliminary bioassay results indicated that some of the compounds showed promising in vitro fungicidal activities towards several test plant fungi; some of them exhibited significant herbicidal activities against Brassica campestris and excellent in vitro inhibitory activities against rice ketol-acid reductoisomerase (KARI). Among 14 novel compounds, 8c, 8d and 8m showed potent KARI inhibitory activities with Ki value of (0.96±0.42), (3.86±0.49) and (3.10±0.71) µmol/L, respectively, and were comparable with IpOHA. These compounds could be novel KARI inhibitors for further investigation. The density functional theory (DFT) calculations and molecular docking were carried out to study the structure-activity relationship (SAR) of the active inhibitors in this Letter.