SP-141 targets Trs85 to inhibit rice blast fungus infection and functions as a potential broad-spectrum antifungal agent.

Rice blast is a devastating disease worldwide, threatening rice production and food security. The blast fungus Magnaporthe oryzae invades the host via the appressorium, a specialized pressure-generating structure that generates enormous turgor pressure to penetrate the host cuticle. However, owing to ongoing evolution of fungicide resistance, it is vitally important to identify new targets and fungicides. Here, we show that Trs85, a subunit of the transport protein particle III complex, is essential for appressorium-mediated infection in M. oryzae. We explain how Trs85 regulates autophagy through Ypt1 (a small guanosine triphosphatase protein) in M. oryzae. We then identify a key conserved amphipathic α helix within Trs85 that is associated with pathogenicity of M. oryzae. Through computer-aided screening, we identify a lead compound, SP-141, that affects autophagy and the Trs85-Ypt1 interaction. SP-141 demonstrates a substantial capacity to effectively inhibit infection caused by the rice blast fungus while also exhibiting wide-ranging potential as an antifungal agent with broad-spectrum activity. Taken together, our data show that Trs85 is a potential new target and that SP-141 has potential for the control of rice blast. Our findings thus provide a novel strategy that may help in the fight against rice blast.

Association between circadian rhythm disorder with depressive and anxiety symptoms of college students in Jinzhou City / 中国学校卫生

Objective@#To explore the association between circadian rhythm with depressive and anxiety symptoms of college students in Jinzhou City, to provide a theoretical basis for targeted depression and anxiety prevention among college students.@*Methods@#A total of 1 938 college students were selected by convenient sampling method from November to December 2020 for questionnaire survey. The relationship between circadian rhythm and depression and anxiety symptoms was analyzed by using questionnaire,survey including Self Rating Depression Scale (SDS), Self Rating Anxiety Scale (SAS) and Munich Chronotype Questionnaire (MCTQ).@*Results@#There were significant differences in the distribution of depressive symptoms in different majors, smoking, drinking and physical exercise ( χ 2=46.80, 5.88, 5.76, 12.23, P <0.05). There were significant differences in the distribution of anxiety symptoms in different majors, smoking and drinking ( χ 2=9.41, 5.80, 5.56, P <0.05). Stratified analysis showed that the depressive symptoms of different chronotype were statistically varied by age, gender, professional, grade, registered residence, body mass index, smoking, drinking, and sports( χ 2=8.16, 14.42, 12.25, 6.19, 10.99, 15.29, 17.41, 15.63, 7.47, 9.59, 10.51 , P <0.05). The anxiety symptoms of different chronotype were statistically different in age (21 years) and smoking (no), ( χ 2= 8.34 , 7.16, P <0.05). Spearman rank correlation showed that the corrected Mid sleep on Free Days Corrected for Sleep Debt on Work Days (MSFsc) was positively correlated with the standard scores of depression and anxiety ( r s=0.10, 0.09), and social jet lag was positively correlated with the standard scores of depression and anxiety ( r s=0.09, 0.05)( P <0.05). After controlling for age, major, smoking and drinking, binary Logistic regression showed that mean sleep length was inversely correlated with depressive symptoms ( OR =0.82), and weekly insomnia frequency was positively correlated with depressive symptoms ( OR=1.14 ).Early type and intermediate type of chronotypes were negatively correlated with depression ( OR =0.66,0.57). Intermediate type of chronotype was negatively correlated with anxiety symptoms ( OR =0.65).@*Conclusion@#Circadian rhythm is related to depressive and anxiety symptoms,among which the average sleep length, early rise and intermediate sleep patterns are negatively related to depression symptoms, and intermediate sleep patterns and anxiety symptoms, suggesting that circadian rhythm disorder may affect depression and anxiety symptoms.

Design, Synthesis, and Fungicidal Evaluation of Novel Pyrazole-furan and Pyrazole-pyrrole Carboxamide as Succinate Dehydrogenase Inhibitors.

The identification of novel succinate dehydrogenase (SDH) inhibitors represents one of the most attractive directions in the field of fungicide research and development. During our continuous efforts to pursue inhibitors belonging to this class, some structurally novel pyrazole-furan carboxamide and pyrazole-pyrrole carboxamide derivatives have been discovered via the introduction of scaffold hopping and bioisosterism to compound 1, a remarkably potent lead obtained by pharmacophore-based virtual screening. As a result of the evaluation against three destructive fungi, including Sclerotinia sclerotiorum, Rhizoctonia solani, and Pyricularia grisea, a majority of them displayed potent fungicidal activities. In particular, compounds 12I-i, 12III-f, and 12III-o exhibited excellent fungicidal activity against S. sclerotiorum and R. solani comparable to that of commercial SDHI thifluzamide and 1.

Discovery of Novel Succinate Dehydrogenase Inhibitors by the Integration of in Silico Library Design and Pharmacophore Mapping.

Succinate dehydrogenase (SDH) has been demonstrated as a promising target for fungicide discovery. Crystal structure data have indicated that the carboxyl "core" of current SDH inhibitors contributed largely to their binding affinity. Thus, identifying novel carboxyl "core" SDH inhibitors would remarkably improve the biological potency of current SDHI fungicides. Herein, we report the discovery and optimization of novel carboxyl scaffold SDH inhibitor via the integration of in silico library design and a highly specific amide feature-based pharmacophore model. To our delight, a promising SDH inhibitor, A16c (IC50 = 1.07 µM), with a novel pyrazol-benzoic scaffold was identified, which displayed excellent activity against Rhizoctonia solani (EC50 = 11.0 µM) and improved potency against Sclerotinia sclerotiorum (EC50 = 5.5 µM) and Phyricularia grisea (EC50 = 12.0 µM) in comparison with the positive control thifluzamide, with EC50 values of 0.09, 33.2, and 33.4 µM, respectively. The results showed that our virtual screening strategy could serve as a powerful tool to accelerate the discovery of novel SDH inhibitors.

Synthesis, antifungal activity, and QSAR study of novel trichodermin derivatives.

In an attempt to discover more potential antifungal agents, in this study, 21 novel trichodermin derivatives containing conjugated oxime ester (5a-5u) were designed and synthesized and were screened for in vitro antifungal activity. The bioassay tests showed that some of them exhibited good inhibitory activity against the tested pathogenic fungi. Compound 5a exhibited better activity against Pyricularia oryzae and Sclerotonia sclerotiorum than trichodermin, and compound 5j showed particular activity against P.oryzae and Botrytis cinerea. The quantitative structure-activity relationship (QSAR) indicated that log P and hardness were two critical parameters for the biological activities. The result suggested that these would be potential lead compounds for the development of fungicides with further structure modification.

Synthesis and biological evaluation of novel trichodermin derivatives as antifungal agents.

To discover more potential antifungal agents, 17 novel trichodermin derivatives were designed and synthesized by modification of 3 and 4a. The structures of all the synthesized compounds were confirmed by (1)H NMR, ESI-MS and HRMS. Their antifungal activities against Ustilaginoidea oryzae and Pyricularia oryzae were evaluated. Most of the target compounds showed potent inhibitory activity, in which 4g showed superior inhibitory effects than 4a and commercial fungicide prochloraz. Furthermore, 4h demonstrated comparable inhibitory activity to 4a. Moreover, 4i and 4l exhibited excellent inhibitory activity for Pyricularia oryzae. Additionally, compound 9 was found to be more active against all tested fungal strains than 3, with EC50 values of 0.47 and 3.71 mg L(-1), respectively.

Structure, bioactivity and implications for environmental remediation of complexes comprising the fungicide hexaconazole bound to copper.

BACKGROUND: In agricultural areas excessive amounts of toxic heavy metals are a growing threat to the environment and human health. Measures should be taken to minimise the risk of adverse health effects. Hence, we investigated the possibilities of hexaconazole (a commercial fungicidal) as a dual-function ligand that has heavy metal ions chelating and fungicidal activities. RESULTS: Metal chelation and fungicidal activities were studied by UV, elemental analysis, IR, thermogravimetric study and biological assays. Results showed that hexaconazole had selective binding capability with Cu(2+) over other ions such as Zn(2+), Cd(2+), Mn(2+), Fe(2+) and Co(2+). Soil leaching experiments showed that soil type had a limited effect on heavy-metal adsorption by hexaconazole; with decreasing pH, a notable rise of leaching effect was observed, which reached 22%. In addition, this complex exhibit better fungicidal activity against Blumeria graminis than the same dose of hexaconazole. CONCLUSION: This study demonstrates that hexaconazole had notable capabilities to chelate heavy metals as well as excellent fungicidal activity as a metal chelator. Given the mutual influence between pesticides and heavy metals in adsorption-desorption processes, these phenomena must be taken into account if they are to be applied rationally.

3-(2,5-Di-methyl-phen-yl)-8-meth-oxy-2-oxo-1-aza-spiro-[4.5]dec-3-en-4-yl 3-(2-bromo-4-fluoro-phen-yl)acrylate.

In the title compound, C27H27BrFNO4, which is an inhibitor of acetyl-CoA carboxyl-ase, the cyclo-hexane ring displays a chair comformation with the spiro-C and meth-oxy-bearing C atoms deviating by 0.681 (7) and -0.655 (1) Å, resppectively, from the mean plane formed by the other four C atoms of the spiro-C6 ring. The mean planes of the cyclo-hexane and 2-bromo-4-fluoro-phenyl rings are nearly perpendicular to that of the pyrrolidine ring, making dihedral angles 89.75 (6) and 87.60 (9)°, respectively. In the crystal, mol-ecules are linked via pairs of N-H⋯O hydrogen bonds, forming inversion dimers.

(1'S,4'S)-5-(2,5-Dimethyl-phen-yl)-4'-meth-oxy-6-oxa-3-aza-spiro-[bicyclo-[3.1.0]hexane-2,1'-cyclo-hexa-n]-4-one.

In the title compound, C18H23NO3, the cyclo-hexane ring has a chair conformation. The oxirane plane (OCC) makes a dihedral angle of 76.15 (13)° with that of the pyrrolidine ring to which it is fused. The mean plane of the cyclo-hexane ring and the benzene ring are almost normal to the pyrrolidine ring, with dihedral angles of 88.47 (8) and 77.85 (8)°, respectively. In the crystal, mol-ecules are linked via pairs of N-H⋯O hydrogen bonds, forming inversion dimers. These dimers are linked via pairs of C-H⋯O hydrogen bonds, forming chains along the a-axis direction.

Metabolism-based synthesis, biological evaluation and structure-activity relationship analysis of spirotetramat analogues as potential lipid biosynthesis inhibitors.

BACKGROUND: In previous studies, scientists found that, when spirotetramat was introduced into plants or animals, it was mainly metabolised at positions C-4 and C-8. That is to say, these two functional positions potentially played an important role in spirotetramat's bioactivities. In order to develop novel insecticides or miticides, the present authors designed and synthesised 35 spirotetramat analogues based on metabolite structures. RESULTS: All of the analogues have been identified on the basis of (1)H NMR, ESI-MS and elemental analysis data. The activities of these analogues were evaluated against three organisms, and biological assays indicated that compounds 5f, 5h and 5u possessed better insecticidal activities against bean aphids (Aphis fabae) than the lead compound spirotetramat. The LC50 of 5f, 5h and 5u against bean aphids reached 0.42, 0.28 and 2.53 mg L(-1) respectively. Moreover, some compounds possessed comparable activities against carmine spider mite (Tetranychus cinnabarinus) and oriental armyworm (Mythimna sepatara) with spirotetramat. The structure-activity relationships (SARs) indicated that the flexible bridge at position C-4 of spirotetramat was important for its bioactivities, and the size of the group at position C-8 would have great influence on the activities. Furthermore, the log P values lower than 6.0 may be favourable for insecticidal activities. CONCLUSION: The present work demonstrates that some spirotetramat analogues can be used as potential lead compounds for developing novel insecticides, and preliminary SAR analysis would provide information for the utilisation of spirotetramat analogues as potential lipid biosynthesis inhibitors.

Synthesis and bioactivity evaluation of novel spiromesifen derivatives.

BACKGROUND: The development of environmentally friendly and novel structural pesticides is now an area of intense research in the agriculture field. Spirocyclic tetronic acids such as spiromesifen are typical compounds of this kind. In order to discover novel compounds with improved and broader-spectrum insecticidal activities, a series of spiromesifen derivatives were synthesised and bioassayed. RESULTS: The derivatives were identified by (1) H NMR and MS. Preliminary bioassays demonstrated that some bioactivities of compounds 5a to 5u were better and had a broader spectrum than the lead compound spiromesifen. Moreover, these compounds showed better insecticidal activities against Mythimna sepatara and Aphis fabae than acaricidal activities against Tetranychus cinnabari. Furthermore, LC(50) of 5s against Aphis fabae reached 1.09 mg L(-1) . At the same time, compounds 5g, 5i, 5k and 5r also warrant further study because of their superior bioactivities to spiromesifen. What is more, suitable carbon chain length in the 4-position ester and the log P value of these spiromesifen derivatives dramatically influenced their insecticidal activities. Butyric or pentanoic ester and a log P value of 4.0-6.0 may be preferred. CONCLUSION: The present work demonstrates that some spiromesifen derivatives can be used as potential lead compounds for developing novel insecticides and acaricides.

3-tert-Butyl-2-oxo-1-oxaspiro-[4.5]dec-3-en-4-yl 4-chloro-benzoate.

The title tetronic acid derivative, C(20)H(23)ClO(4), which is a spiro-diclofen analogue, has two crystallographically independent mol-ecules in the asymmetric unit (Z' = 2). The cyclo-hexane rings in the respective mol-ecules A and B adopt chair conformations [four C atoms are planar with mean deviations of 0.013 (2) and 0.001 (2) Å, and the flap positions deviate by 0.653 (4) and -0.663 (3) Š(mol-ecule A) and 0.642 (4) and -0.643 (5) Š(mol-ecule B) from the plane]. The furan ring makes dihedral angles of 86.9 (1) (mol-ecule A) and 85.4 (1)° (mol-ecule B) with the respective benzene rings.

Design, synthesis, and biological activities of milbemycin analogues.

Milbemycins have received considerable interest in agricultural chemistry due to a special action mode, extremely high activity against arachnoide pests, low toxicity to mammals, and environmentally benign characteristics. Two series of novel milbemycin analogues (4Ia-6IIc) containing alkyl and aryl groups at the 4'- and 13-positions were designed and synthesized by five schemes. These analogues were identified by (1)H NMR, (13)C NMR, and elemental analysis (or HRMS). Their insecticidal activities against carmine spider mite, oriental armyworm, and black bean aphid were evaluated. The results showed that all of the title compounds had low acaricidal activity against carmine spider mite. However, most of them exhibited good insecticidal activities against oriental armyworm and black bean aphid at a concentration of 200 mg L(-1). The most potent substituents of 2,2-dimethylbutanoyl (4Ib), phenylacetyl (4IIm), and (Z)-1-(methoxyimino)-1-phenylacetyl (4IIn) exhibited the highest larvicidal activities, and its insecticidal LC(50) values against oriental armyworm were 0.250, 0.204, and 0.350 mg L(-1), while its insecticidal LC(50) values against black bean aphid were 0.150, 0.070, and 0.120 mg L(-1), respectively. These substituents provided some hints for further investigation on structure modification.

8-{[(E)-3-(2-Chloro-phen-yl)acrylo-yloxy]imino}-12,13-ep-oxy-trichethec-9-en-4-yl (E)-3-(2-chloro-phen-yl)acrylate.

In the title compound, C(33)H(31)Cl(2)NO(6), the five-membered ring displays an envelope conformation, whereas the two six-membered rings both exhibit a chair conformation. As for the seven-membered ring, the dihedral angle between the mean planes formed by the four C atoms of the envelope unit and the three C and one O atoms of the six-membered chair is 69.08 (4)°, and these two mean planes are nearly perpendicular to the ep-oxy ring, making dihedral angles of 87.53 (4) and 88.67 (4)°, respectively.

Trichodermin (12,13-ep-oxy-trichethec-9-en-4ß-yl 4-fluoro-benzoate).

IN THE TITLE TRICHODERMIN COMPOUND (SYSTEMATIC NAME: 12,13-ep-oxy-trichothec-9-en-4ß-yl 4-fluoro-benzoate), C(22)H(25)FO(4), the five-membered ring displays an envelope conformation, whereas the two six-membered rings show the different conformations, viz. chair and half-chair. As for the seven-membered ring, the dihedral angle between the mean planes formed by the four C atoms of the envelope unit and the three C and one O atoms of the six-membered chair is 68.67 (2)°; these two mean planes are nearly perpendicular to the ep-oxy ring with angles of 87.97 (2)and 88.14 (2)°, respectively.

Trichodermol (4α-hydr-oxy-12,13-epoxy-trichothec-9-ene).

In the title compound, C(15)H(22)O(3), the five-membered ring displays an envelope conformation, whereas the two six-membered rings show different conformations, viz. chair and half-chair. In the crystal, mol-ecules are linked through inter-molecular O-H⋯O hydrogen bonds, forming chains running along the b axis.

3-(2,4-Dichloro-phen-yl)-2-oxo-1-oxa-spiro-[4.5]dec-3-en-4-yl 4-chloro-benzoate.

In the title spiro-diclofen derivative, C(22)H(17)Cl(3)O(4), the cyclo-hexane ring adopts a chair conformation [four C atoms are planar with a mean deviation of 0.018 Šand the two C atoms at the flap positions deviate by 0.613 (4) and -0.668 (5) Šfrom the plane]. The dihedral angles between the furan ring and the two benzene rings are 55.78 (3) and 49.92 (3)°. Weak inter-molecular C-H⋯Cl inter-actions are observed in the crystal structure.

3-(2,4-Dichloro-phen-yl)-2-oxo-1-oxaspiro-[4.5]dec-3-en-4-yl acetate.

In the title compound, C(17)H(16)Cl(2)O(4), the cyclo-hexyl ring displays a chair conformation [the four C atoms are planar with a mean deviation of 0.001 (2) Šand the two C atoms at the flap positions deviate by 0.625 (2) and -0.680 (2) Šfrom the plane]. The furan ring is planar with a mean deviation of 0.004 (2) Šand forms a dihedral angle of 46.73 (2)° with the benzene ring.

Dihalogenated trichodermin (4ß-acet-oxy-9,10-dibromo-12,13-epoxy-tri-chothec).

In the title dihalogenated trichodermin mol-ecule, C(17)H(24)Br(2)O(4) (systematic name: 9,10-dibromo-12,13-epoxy-trichothec-9-en-4ß-yl acetate), the five-membered ring displays an envelope conformation, whereas the two six-membered rings show the same conformation, viz. chair. As for the seven-membered ring, the dihedral angle between the mean planes formed by the four C atoms of the envelope unit and the three C and one O atoms of the six-membered chair is 69.08 (4)°; these two mean planes are nearly perpendicular to the ep-oxy ring with angles of 87.53 (4) and 88.67 (4)°, respectively.

4-Hydr-oxy-3-mesityl-1-oxaspiro-[4.4]non-3-en-2-one.

In the title compound, C(17)H(20)O(3), the five-membered cyclo-pentyl ring displays an envelope conformation, with the atom at the flap position 0.538 (3) Šout of the mean plane formed by the other four atoms. The dihedral angle between the benzene and furan rings is 63.34 (15)°. In the crystal structure, mol-ecules are linked through inter-molecular O-H⋯O hydrogen bonds, forming a zigzag chain along [101].