Synthesis,Bioactivity And Structure-Activity Relationship Of Carboxamide And Carbohydrazide Derivatives Containing Imidazole,Thiazole Or Pyrazole Group

Nitrogen-containing heterocycles are the key structural units of many bioactive compounds.They exist widely in natural products and bear important applications in many disciplines such as chemistry,physics,pharmaceuticals,materials and so on.Benzimidazole,benzothiazole,thiazole and pyrazole,as important aromatic nitrogen-containing heterocycles,are widely used in the research and development of new green pesticides due to their diverse structures and broad-spectrum activities.Carboxamide,hydrazide and ether groups are common bridging structures in pesticide molecules,they are used to bridge other active structural units.It is one of the important factors to be considered in the novel pesticide molecular design.Five new carboxamides,hydrazides and ether derivatives were designed and synthesized using nitrogen-containing heterocycles such as benzimidazole,benzothiazole,thiazole or pyrazole as active structural units in order to develop green pesticides with novel structures.Their fungicidal or insecticidal activities were evaluated and then the 3D-QSAR and preliminary mechanism for part series of the target compounds were also explored.The main contents of this paper include the following five aspects:1.Synthesis,fungicidal activity and 3D-QSAR of carboxamide derivatives containing the benzimidazole and phenylpyrazole groups.Benzimidazole and phenylpyrazole are important active fragments in the structures of fungicides,and amide bonds are common bridging structures in the pesticide molecules.Thirty carboxamide derivatives containing benzimidazole and phenylpyrazole groups were designed and synthesized by introducing benzimidazole and phenylpyrazole into the same molecular skeletons through amide bonds.Their structures were confirmed by 1H NMR,13C NMR,19F NMR,IR and HRMS.The structure of compound 11c was analyzed by X-ray single crystal diffraction.The inhibitory activities of the target compounds against Rhizoctonia solani,Botrytis cinerea,Fusarium graminearum and Alternaria solani were determined by mycelial growth inhibition method.At the concentration of 100 ?g/mL,the target compounds showed certain inhibitory activity against tested four fungi.The inhibition rates of the target compounds were 29.22%-90.64%against B.cinerea,27.43%-56.11%against R.solani,12.89%-52.63%against F.graminearum,and 25.71%-60.00%against A.solani.The inhibitory activity of the target compounds against B.cinerea was significantly higher than that of the other three fungi.The EC50 values of the target compounds against B.cinerea were determined.The EC50 values of compounds 11d and llh were 19.16 ?g/mL and 18.27 ?g/mL,respectively.The molecular model of CoMSIA was constructed,and the 3D-QSAR between the molecular structures of the targrt compounds and their inhibitory activities against B.cinerea was analyzed.When the amide bond on the benzene ring is located at the Meta-position,it is advantageous to improve the fungicidal activity.The introduction of electron-withdrawing groups such as halogens at the 4-position of benzene ring of phenylpyrazole plays an important role in improving the activity.2.Synthesis,fungicidal activity and 3D-QSAR of pyrazole carboxamide and nicotinamide derivatives containing a benzimidazole group.Twenty pyrazole carboxamide and nicotinamide derivatives containing a benzimidazole group were designed and synthesized by splicing benzimidazole group with substituted pyrazole or pyridine through amide bridge group.The structures of the compounds were confirmed by 1H NMR,13C NMR,1R and HRMS.The crystal structure of compound T1 was analyzed by X-ray single crystal diffraction.The inhibitory activities of the compounds against B.cinerea,R.solani,F.graminearum and A.solani were determined.At the concentration of 100 ?g/mL,the inhibitory rates of the target compounds against above four fungi were 31.74%-88.13%,22.69%-69.82%,14.73%-52.37%and 21.42%-68.28%,respectively.The inhibitory activity of the compounds against B.cinerea was significantly higher than that of the other three pathogenic fungi.The EC50 values of compounds T5 and T6 against B.cinerea were 18.24 ?g/mL and 10.16 ?g/mL,respectively.The antifungal activity of T6 was slightly better than that of the control agent,hymexazol(EC50 was 14.22?g/mL).At the concentration of 100 ?g/mL,the protective effect in vivo of compound T6 against B.cinerea was 49.52%,which was higher than that of the control hymexazol(30.83%).The molecular model of CoMFA was constructed,and the 3D-QSAR between the molecular structures of the target compounds and their inhibitory activities against B.cinerea was analyzed.The positions of amide bonds on pyrazole rings,the types of substituents on pyrazole rings and the properties of substituents on benzimidazole rings all affect the fungicidal activity.In the pyrazole-4-carboxamide series of compounds,the introduction of methyl group at 1-position and trifluoromethyl group at 3-position of pyrazole ring is beneficial to the improvement of activity.In the pyrazole-5-carboxamide series of compounds,the introduction of large isobutyl group at the 3-position of pyrazole ring can reduce the fungicidal activity.Among nicotinamide series of compounds,the introduction of chlorine atom at the 2-position can significantly improve the activity of the compounds.3.Synthesis,fungicidal activity and 3D-QSAR of pyrazole carbohydrazide derivatives containing a benzothiazole group.Twenty-six pyrazole carbohydrazide derivatives containing a benzothiazole group were designed and synthesized by introducing benzothiazole-pyrazole heterocycle and phenylhydrazine into the same molecular structures.The molecular structures were confirmed by 1H NMR,13C NMR,19F NMR,IR and HRMS.The structure of compound 10z was further analyzed by X-ray single crystal diffraction.The inhibitory activities of the compounds against B.cinerea,R.solani,F.graminearum and A.solani were determined.At the concentration of 10 ?g/mL,the compounds showed certain inhibitory activities against four tested pathogenic fungi.The inhibitory rates of these compounds against above four fungi were 6.24%-66.24%,6.28%-92.51%,4.40%-90.15%and 5.24%-50.55%,respectively.The inhibitory activity of the target compounds against R.solani was significantly higher than that of the other three fungi.The EC50 values of inhibiting R.solani were determined.The EC50 values of 10d,10j,10h,10i,10n,10o,10q,10r,10s,10t and 10u were 0.24,0.18,0.73,0.71,0.71,0.56,0.22,0.45,0.38,0.22 and 0.15 ?g/mL,respectively,which were superior to those of the control agent boscalid.The 3D-QSAR structure-activity relationship between the molecular structures of the target compounds and their inhibitory activities against R.solani was analyzed by constructing a CoMFA molecular model.The introduction of negative charged groups such as F,Cl or Br at the 4-position of benzene ring of phenylhydrazine can improve the activity of compounds,but the introduction of large nitro or double substituents will reduce the activity of compounds.4.Synthesis,fungicidal activity and 3D-QSAR structure-activity relationship of thiazolyl carbohydrazide derivatives.Thirty-three thiazolyl carbohydrazide derivatives and two thiazolyl carboxamide derivatives were designed and synthesized by splicing substituted thiazolyl formyl groups with phenylhydrazine groups.Their structures were confirmed by 1H NMR,13C NMR,19F NMR,IR and HRMS.The inhibitory activities of these compounds against B.cinerea,R.solani,F.graminearum and A.solani were determined.At 25 ?g/mL,the inhibitory activities of these compounds against above four pathogenic fungi were high,ranging from 11.17%to 100%,47.14%to 100%,8.63%to 100%,and 5.25%to 100%,respectively.The inhibitory activities of the target compounds against R.solani and F.graminearum were higher than those of the other two fungi.The EC50 values of compounds 9a,9d,9f-9h,10d-10h,10k,12a and lla-lli against R.solani were lower than 1 ?g/mL,which were superior to that of the control agent boscalid.The EC50 values of compounds 9e-9g,10a,10e-10g,11a,llc-llg and 11i against F.graminearum were lower than 1 ?g/mL too,which were also better than that of the control agent boscalid.The 3D-QSAR structure-activity relationship between the molecular structures of the target compounds and their inhibitory activities against R.solani was analyzed by constructing a CoMSIA molecular model.The introduction of negatively charged group on phenylhydrazine ring,especially at the 4-position of phenylhydrazine ring,such as halogen F or Cl,is conducive to the improvement of activity.The introduction of smaller substituents at the 2-position of thiazole ring is beneficial to the improvement of activity.5.Synthesis,insecticidal activity and molecular docking of ether derivatives containing coumarin and benzothiazole groups.Thirty ether derivatives containing coumarin and benzothiazole groups were designed and synthesized by using coumarin and benzothiazole groups as active fragments and alkyl ethers as bridging groups of different lengths.Their structures were confirmed by 1H NMR,13C NMR,IR and HRMS.The molecular structure of compound 6v was further analyzed by X-ray single crystal diffraction.The lethal activities of the target compound against Plutella xylostella and Aphis fabae were determined.At 400 ?g/mL,the compounds showed certain insecticidal activity against P.xylostella and A.fabae.The mortalities of these compounds against P.xylostella were 3.33%-100%,and the rates of compounds 6d,6k,6w and 6z were 86.21%-100%.The mortalities of these compounds against A.fabae were higher than that of P.xylostella,and the rates were 16.22%-96.51%.The control rates of compounds 6e,61,6s,6t and 6u to aphids reached 92.13%-96.51%.The results indicated that the mortalities of the compounds 6u-6z and 6aa-6dd with ether bonds at meta-position of phenyl rings were higher than those of other para-position homologues.When the alkylene in ether group was butylene,the corresponding compounds possess higher insecticidal activity.The inhibitory activity of the compounds on acetylcholinesterase from the brain of Drosophila melanogaster was determined by an improved Ellman colorimetric method.The compounds 6d,6u,6o,6r and 6y exhibited higher inhibitory activity on the enzyme,and the inhibitory rates were 46.87%-64.42%.In the compound 6a-6j,with the ether bond at para-position of the benzene ring,the highest inhibitory activity contributed by the compound 6d was 46.87%.In the compound 6k-6t,with the ether bond at para-position of the benzene ring and OCH3 group at the benzene ring,the inhibitory activity of compound 6r was the highest,reaching 63.71%.In the compounds 6u-6z and 6aa-6dd,with the ether bond at meta-position of the benzene ring,the compound 6y has the highest inhibitory activity to the enzyme,reaching 64.42%.The compounds 6d,6r and 6y were selected to simulatively dock with the crystal structure of acetylcholinesterase,respectively.Hydrogen bonding and van der Waals interaction were found between each compound molecule and the amino acid residues of the enzyme,and ?-? interaction was also found between the compound 6y and the amino acid residue of the enzyme.