Design, synthesis and fungicidal activity of 11-alkoxyimino-5,6-dihydro-dibenzo[b,e] azepine-6-one derivatives.

BACKGROUND: Macrocyclic compounds with an oxime ether side chain, discovered in Wang's group, showed good fungicidal activity. However, the long synthetic route makes the cost too high for them to be developed further as practical fungicides. Alternative compounds with good fungicidal activity and an easier synthesis than the above-mentioned macrolactams were sought, and a series of 11-alkoxyimino-5,6-dihydro-dibenzo[b,e]azepine-6-one derivatives (4) were designed and bioassayed. RESULTS: The structures were confirmed by (1) H NMR, (13) C NMR and LC-MS. The bioassay showed that about half of the 11-alkoxyimino-5,6-dihydro-dibenzo[b,e]azepine-6-one derivatives (4) displayed good fungicidal activity against Sclerotinia sclerotiorum (Lib.) de Bary, with EC50 values <15 µg mL(-1) . 11-(n-Butyloxyimino)-5,6-dihydro-dibenzo[b,e]azepine-6-one (4A-05), 11-(4-nitrobenzyloxyimino)-5,6-dihydro-dibenzo[b,e]azepine-6-one (4A-12) and 11-(2-chloro-6-fluorobenzyloxyimino)-5,6-dihydro-dibenzo[b,e]azepine-6-one (4A-21) displayed excellent fungicidal activity, with EC50 values of <2.5 µg mL(-1) , much better than the commercial fungicide chlorothalonil with an EC50 value of 7.16 µg mL(-1) . In addition, about half of the 11-alkoxyimino-5,6-dihydro-dibenzo[b,e]azepine-6-one derivatives (4) had good fungicidal activity against Botrytis cinerea (De Bary) Whetzel, with EC50 values of <10 µg mL(-1) . 11-(2-Fluorobenzyloxyimino)-5,6-dihydro-dibenzo[b,e]azepine-6-one (4A-16), 11-(3-fluorobenzyloxyimino)-5,6-dihydro-dibenzo[b,e]azepine-6-one (4A-17) and 11-(2-chloro-6-fluorobenzyloxyimino)-5,6-dihydro-dibenzo[b,e]azepine-6-one (4A-21) displayed excellent fungicidal activity, with EC50 values of 3.73, 2.54 and 3.20 µg mL(-1) respectively, comparable with the commercial fungicide procymidon with an EC50 value of 2.45 µg mL(-1) . Their structure-activity relationship is discussed. CONCLUSIONS: The present work demonstrates that the title compounds show promise as fungicides.

Synthesis of 2-amino-6-oxocyclohexenylsulfonamides and their activity against Botrytis cinerea.

BACKGROUND: With the objective of exploring the fungicidal activity of 2-oxocyclohexylsulfonamides (2), a series of novel 2-amino-6-oxocyclohexenylsulfonamides (6 to 23) were synthesised, and their fungicidal activities against Botrytis cinerea Pers. were evaluated in vitro and in vivo. RESULTS: The compounds were characterised by IR, 1H NMR and elemental analysis. Bioassay results of mycelial growth showed that compounds 6 to 23 had a moderate antifungal activity against B. cinerea. N-(2-methylphenyl)-2-(2-methylphenylamino)-4,4-dimethyl-6-oxocyclohexenylsulfonamide (13) and N-(2-chlorophenyl)-2-(2-chlorophenylamino)-6-oxocyclohexenylsulfonamide (21) showed best antifungal activities, with EC50 values of 8.05 and 10.56 µg mL(-1) respectively. Commercial fungicide procymidone provided an EC50 value of 0.63 µg mL(-1) . The conidial germination assay showed that most of compounds 6 to 23 possessed excellent inhibition of spore germination and germ-tube elongation of conidia of B. cinerea. For in vivo control of B. cinerea colonising cucumber leaves, the compound N-cyclohexyl-2-(cyclohexylamino)-4,4-dimethyl-6-oxocyclohexenylsulfonamide (19) showed a better control effect than the commercial fungicide procymidone. CONCLUSION: The present work demonstrated that 2-amino-6-oxocyclohexenylsulfonamides can be used as possible new lead compounds for further developing novel fungicides against B. cinerea.

Synthesis, fungicidal activity, and structure-activity relationship of spiro-compounds containing macrolactam (macrolactone) and thiadiazoline rings.

Two series of novel spiro-compounds containing macrolactam or macrolactone and thiadiazoline rings, 1-thia-2-alkylimino-3,4,9-triaza-10-oxospiro[4.15]eicosyl-3-ene (4F) and 1-thia-2-alkylimino-3,4-diaza-9-oxa-10-oxospiro[4.15]eicosyl-3-ene (4G), were synthesized from 12-oxo-1,15-pentadecanlactam and 12-oxo-1,15-pentadecanlactone, respectively. Their structures were confirmed by elemental analysis, (1)H NMR, and (13)C NMR. The conformation of compounds 4F was determined via the crystal structure of a representative compound (4F(6)). The bioassay showed that compounds 4F have much better fungicidal activity against five fungi ( Botrytis cinerea Pers., Sclerotinia sclerotiorum , Rhizoctonia solani Kuhn., Phomopsis asparagi Sacc., and Pyricularia oryzae Cav.) than compounds 4G. The fact above showed that the presence of a hydrogen-bonding donor for the fungicidal activity of macrocyclic compounds is very important. 4F(6) showed excellent fungicidal activity against P. oryzae, which is much better than the commercial fungicide isoprothiolane, and 4F(13) showed excellent fungicidal activity against P. oryzae and good fungicidal activity against P. asparagi.

Determination of 7B3 residues in cotton plants by liquid chromatography/mass spectrometry.

A method was developed for the determination of 7B3 (12-propyloxyimino-1,15-pentadecanlactam), a novel macrolactam fungicide, by liquid chromatography/mass spectrometry (LC/MS) with positive electrospray ionization (ESI+). The method used a reversed-phase C18 column and acetonitrile-water (60 + 40, v/v) mobile phase. The quick, easy, cheap, effective, rugged, and safe method was used for extraction of 7B3 from cotton plants, which involved the extraction of 10 g homogenized sample with 10 mL acetonitrile, followed by the addition of 4 g anhydrous MgSO4 and 1.0 g NaCl. After centrifugation, 1 mL of the buffered acetonitrile extract was transferred into a tube containing 50 mg primary secondary amine sorbent and 100 mg anhydrous MgSO4. After shaking and centrifugation, the final extract was transferred to an autosampler vial for concurrent analysis by LC/MS. The results of 7B3 determined by LC/MS in the selective ion monitoring mode were linear, and the matrix effect of the method was evaluated. The average recoveries of 7B3 fortified at different levels were within 84.1-100.2%, and the relative standard deviations were <7.5% for all samples analyzed. The method limit of detection and the limit of quantitation values were 0.03 and 0.1 mg/kg, respectively. The proposed method was successfully applied to determine 7B3 residues in practical samples. This method is sensitive, accurate, reliable, simple, and safe.

Synthesis and herbicidal activity of 12-(aryloxyacyloxyimino)-1,15-pentadecanlactone derivatives.

A series of novel 12-(aryloxyacyloxyimino)-1,15-pentadecanlactone derivatives (3) were synthesized, and their structures including configuration of C=N bond were confirmed by (1)H NMR, elemental analysis and X-ray diffraction analysis. The bioassay showed that some of them exhibited excellent herbicidal activity against Amaranthus tricolor L. The activity of compounds 3 except compounds 3A1-2 was much higher than the commercial herbicide 2,4-D and the activity of about half of compounds 3 was comparable to the commercial herbicide tribenuron-methyl. The further bioassay showed that the representative of compounds 3, 3A1-12, exhibited excellent herbicidal activity not only against dicotyledon, such as Amaranthus tricolor L., Cucumis sativus L., Glycine max L., and Phaseolus radiatus L., but also against monocotyledon, such as Zea mays L. and Oryza sativa L.

2-(4-Methoxyphenoxy)-6-methyl-3-oxo-3,6-dihydro-2H-pyran-4-yl benzoate.

The title compound, C(20)H(18)O(6), has been synthesized from 4-methoxy-phenyl 3-O-benzo-yloxy-α-l-rhamnopyran-oside by oxidation on treatment with pyridinium dichromate in the presence of acetic anhydride. In the mol-ecule, the pyran ring adopts an envelope conformation with the O atom at the flap position. Weak inter-molecular C-H⋯O hydrogen bonding is present in the crystal structure.

Design, synthesis, and fungicidal activity of macrolactones and macrolactams with a sulfonamide side chain.

Four series of novel macrolactones and macrolactams12-alkylsulfonamido-1,15-pentadecanlactones ( 5), 12-alkylsulfonamido-15-methyl-1,15-pentadecanlactones ( 6), 12-alkylsulfonamido-1,15-pentadecanlactams ( 7), and N-(alkylsulfonamidoethyl)-1,12-dodecanlactams ( 8)were designed and synthesized from readily available 2-nitrocyclododecanone or cyclododecanone. Their structures were confirmed by (1)H NMR, IR, and elemental analysis. The bioassay showed that these compounds displayed fair to excellent fungicidal activity against Rhizoctonia solani Kuhn and have a gradual increase of fungicidal activity in the order of 6, 7, 8, and 5. Among them, compounds 5a, 5b, and 5c displayed excellent fungicidal activity against R. solani comparable with the commercial fungicide carbendazim. Above results illustrated that the rule on the relationship between the activity and hydrogen-bonding, namely the macrocyclic compounds with a hydrogen-bonding acceptor and a hydrogen-bonding donor on the ring and having a three methylenes distance between two polarizable groups have the best fungicidal activity against R. solani, has a general suitability to the macrocyclic compounds, and pesticide molecules may combine with a target enzyme by hydrogen-bonding. The facts, which compound 6 has a much lower fungicidal activity against R. solani than compound 5 but their difference in chemical structure is only that there is a methyl group on the C15 for compound 6 and none but hydrogen atom on the C15 for compound 5, indicated that a methyl group plays an inhibitory role to the fungicidal activity. It suggests that the existence of a methyl group with a great volume between two polarizable groups would interfere in the interaction of pesticide molecules and the target enzyme.

2-(Methyl-sulfan-yl)cyclo-dodeca-none tosyl-hydrazone.

The title compound, C(20)H(32)N(2)O(2)S(2), has been synthesized by the reaction of α-methyl-sulfanylcyclo-dodeca-none and p-toluene-sulfonyl-hydrazine. In the crystal structure, the conformation of the non-benzenoid ring is [3333] and the methyl-sulfanyl group is in the α-side exo position. The mol-ecules are linked by inter-molecular N-H⋯S hydrogen bonds.

Synthesis and fungicidal activity of macrolactams and macrolactones with an oxime ether side chain.

Three series of novel macrolactams and macrolactones--12-alkoxyimino-tetradecanlactam, 12-alkoxyiminopentadecanlactam, and 12-alkoxyiminodecanlactone derivatives (7A, 7B, and 7C)--were synthesized from corresponding 12-oxomacrolactams and 12-oxomacrolactone. Their structures were confirmed by 1H NMR and elemental analysis. The Z and E isomers of 7A and 7B were separated, and their configurations were determined by 1H NMR. These compounds showed fair to excellent fungicidal activities against Rhizoctonia solani Kühn. It is interesting that the Z and E isomers of most of the compounds have quite different fungicidal activities. The fact that the compounds have a gradual increase of fungicidal activity in the order of 7A, 7C, and 7B indicated that the macrocyclic derivatives with a hydrogen-bonding acceptor (=N-O-) and a hydrogen-bonding donor (-CONH-) on the ring, and a three methylenes distance (CH2CH2CH2) between these two functional groups, exhibited the best fungicidal activity. The bioassay also showed that 7B not only has good fungicidal activity but also may have a broad spectrum of fungicidal activities.

Synthesis and fungicidal activity of novel 2-oxocycloalkylsulfonylureas.

A series of 2-oxocycloalkylsulfonylureas (2) have been synthesized in a six-step, three-pot reaction sequence from readily available cyclododecanone, cycloheptanone, and cyclohexanone. Their structures were confirmed by IR, 1H NMR, and elemental analysis. The bioassay indicated that some of them possess certain fungicidal activity against Gibberella zeae Petch. In general, compounds containing a 12-membered ring (2A) are more active than those containing a 6- or 7-membered ring (2B, 2C). In the series 2A, the compounds in which R is a disubstituted phenyl or pyrimidyl showed better activity than those in which R is a monosubstituted phenyl or pyrimidyl, and aryl-substituted compounds have somewhat higher activity than those substituted by pyrimidyl. The further bioassay showed that the representative of 2A, 2A15, has good fungicidal activities against not only G. zeae Petch but also Botrytis cinerea Pers, Colletotrichum orbiculare Arx, Pythium aphanidermatum Fitzp, Fusarium oxysporum Schl. f. sp. Vasinfectum, etc.