CN115141208B - Podophyllotoxin compound containing various ester structures and preparation method and application thereof - Google Patents
Podophyllotoxin compound containing various ester structures and preparation method and application thereof Download PDFInfo
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- CN115141208B CN115141208B CN202210939268.6A CN202210939268A CN115141208B CN 115141208 B CN115141208 B CN 115141208B CN 202210939268 A CN202210939268 A CN 202210939268A CN 115141208 B CN115141208 B CN 115141208B
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- CN
- China
- Prior art keywords
- podophyllotoxin
- piperazinyl
- compound
- ester group
- containing various
- Prior art date
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- -1 Podophyllotoxin compound Chemical class 0.000 title claims abstract description 121
- YVCVYCSAAZQOJI-UHFFFAOYSA-N podophyllotoxin Natural products COC1=C(O)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YVCVYCSAAZQOJI-UHFFFAOYSA-N 0.000 title claims abstract description 12
- YJGVMLPVUAXIQN-UHFFFAOYSA-N epipodophyllotoxin Natural products COC1=C(OC)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YJGVMLPVUAXIQN-UHFFFAOYSA-N 0.000 title claims abstract description 11
- 229960001237 podophyllotoxin Drugs 0.000 title claims abstract description 11
- 150000002148 esters Chemical group 0.000 title abstract description 16
- 238000002360 preparation method Methods 0.000 title abstract description 11
- 150000001875 compounds Chemical class 0.000 claims description 39
- YJGVMLPVUAXIQN-XVVDYKMHSA-N podophyllotoxin Chemical group COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@H](O)[C@@H]3[C@@H]2C(OC3)=O)=C1 YJGVMLPVUAXIQN-XVVDYKMHSA-N 0.000 claims description 29
- 241000196324 Embryophyta Species 0.000 claims description 19
- 230000001580 bacterial effect Effects 0.000 claims description 19
- 241000607479 Yersinia pestis Species 0.000 claims description 17
- 125000004185 ester group Chemical group 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 13
- 240000007594 Oryza sativa Species 0.000 claims description 12
- 235000007164 Oryza sativa Nutrition 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 12
- 235000009566 rice Nutrition 0.000 claims description 12
- 241000238631 Hexapoda Species 0.000 claims description 9
- 201000010099 disease Diseases 0.000 claims description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 8
- 239000000843 powder Substances 0.000 claims description 6
- 239000002917 insecticide Substances 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 239000002671 adjuvant Substances 0.000 claims description 3
- 239000012752 auxiliary agent Substances 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 239000002552 dosage form Substances 0.000 claims description 3
- 239000000839 emulsion Substances 0.000 claims description 3
- 230000000855 fungicidal effect Effects 0.000 claims description 3
- 239000000417 fungicide Substances 0.000 claims description 3
- 239000008187 granular material Substances 0.000 claims description 3
- 230000002363 herbicidal effect Effects 0.000 claims description 3
- 239000004009 herbicide Substances 0.000 claims description 3
- 239000003094 microcapsule Substances 0.000 claims description 3
- 239000003921 oil Substances 0.000 claims description 3
- 239000000779 smoke Substances 0.000 claims description 3
- 239000007921 spray Substances 0.000 claims description 3
- 239000000375 suspending agent Substances 0.000 claims description 3
- 239000004562 water dispersible granule Substances 0.000 claims description 3
- 239000004563 wettable powder Substances 0.000 claims description 3
- 241000894006 Bacteria Species 0.000 description 16
- 230000000694 effects Effects 0.000 description 16
- 125000000217 alkyl group Chemical group 0.000 description 14
- 125000003118 aryl group Chemical group 0.000 description 11
- 229910052739 hydrogen Inorganic materials 0.000 description 11
- 238000006467 substitution reaction Methods 0.000 description 11
- 125000001072 heteroaryl group Chemical group 0.000 description 10
- 239000001257 hydrogen Substances 0.000 description 10
- 239000002609 medium Substances 0.000 description 10
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
- 241000207199 Citrus Species 0.000 description 8
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 8
- 235000020971 citrus fruits Nutrition 0.000 description 8
- 229910052805 deuterium Inorganic materials 0.000 description 8
- 229910052736 halogen Inorganic materials 0.000 description 8
- 150000002367 halogens Chemical class 0.000 description 8
- 150000002431 hydrogen Chemical class 0.000 description 8
- 150000003839 salts Chemical class 0.000 description 8
- 125000001424 substituent group Chemical group 0.000 description 8
- 125000003342 alkenyl group Chemical group 0.000 description 7
- 229910052799 carbon Inorganic materials 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
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- 125000003545 alkoxy group Chemical group 0.000 description 6
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- 230000001276 controlling effect Effects 0.000 description 6
- 125000000753 cycloalkyl group Chemical group 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 239000000575 pesticide Substances 0.000 description 6
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 5
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 5
- 244000052616 bacterial pathogen Species 0.000 description 5
- 125000002619 bicyclic group Chemical group 0.000 description 5
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- 125000005842 heteroatom Chemical group 0.000 description 5
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 5
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 5
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 5
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 5
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 5
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
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- 239000000243 solution Substances 0.000 description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- 208000035143 Bacterial infection Diseases 0.000 description 4
- 240000008067 Cucumis sativus Species 0.000 description 4
- 235000010799 Cucumis sativus var sativus Nutrition 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 244000298697 Actinidia deliciosa Species 0.000 description 3
- 235000009436 Actinidia deliciosa Nutrition 0.000 description 3
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 3
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 235000007688 Lycopersicon esculentum Nutrition 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 3
- 240000003768 Solanum lycopersicum Species 0.000 description 3
- 235000002595 Solanum tuberosum Nutrition 0.000 description 3
- 244000061456 Solanum tuberosum Species 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 230000000875 corresponding effect Effects 0.000 description 3
- 230000003013 cytotoxicity Effects 0.000 description 3
- 231100000135 cytotoxicity Toxicity 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 125000001188 haloalkyl group Chemical group 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
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- 239000007788 liquid Substances 0.000 description 3
- 125000002950 monocyclic group Chemical group 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 125000004193 piperazinyl group Chemical group 0.000 description 3
- 238000012827 research and development Methods 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- 125000001831 (C6-C10) heteroaryl group Chemical group 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- YCWRFIYBUQBHJI-UHFFFAOYSA-N 2-(4-aminophenyl)acetonitrile Chemical group NC1=CC=C(CC#N)C=C1 YCWRFIYBUQBHJI-UHFFFAOYSA-N 0.000 description 2
- 125000006280 2-bromobenzyl group Chemical group [H]C1=C([H])C(Br)=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 125000006282 2-chlorobenzyl group Chemical group [H]C1=C([H])C(Cl)=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 125000004847 2-fluorobenzyl group Chemical group [H]C1=C([H])C(F)=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 125000006290 2-hydroxybenzyl group Chemical group [H]OC1=C(C([H])=C([H])C([H])=C1[H])C([H])([H])* 0.000 description 2
- 125000002927 2-methoxybenzyl group Chemical group [H]C1=C([H])C([H])=C(C(OC([H])([H])[H])=C1[H])C([H])([H])* 0.000 description 2
- 125000006179 2-methyl benzyl group Chemical group [H]C1=C([H])C(=C(C([H])=C1[H])C([H])([H])*)C([H])([H])[H] 0.000 description 2
- 125000006494 2-trifluoromethyl benzyl group Chemical group [H]C1=C([H])C([H])=C(C(=C1[H])C([H])([H])*)C(F)(F)F 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- 125000006279 3-bromobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(Br)=C1[H])C([H])([H])* 0.000 description 2
- 125000003852 3-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(Cl)=C1[H])C([H])([H])* 0.000 description 2
- 125000006284 3-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(F)=C1[H])C([H])([H])* 0.000 description 2
- 125000006497 3-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1[H])C([H])([H])* 0.000 description 2
- 125000006180 3-methyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C(=C1[H])C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000006495 3-trifluoromethyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C(=C1[H])C([H])([H])*)C(F)(F)F 0.000 description 2
- YVCVYCSAAZQOJI-JHQYFNNDSA-N 4'-demethylepipodophyllotoxin Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O)[C@@H]3[C@@H]2C(OC3)=O)=C1 YVCVYCSAAZQOJI-JHQYFNNDSA-N 0.000 description 2
- YVCVYCSAAZQOJI-BTINSWFASA-N 4'-demethylpodophyllotoxin Chemical group COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@H](O)[C@@H]3[C@@H]2C(OC3)=O)=C1 YVCVYCSAAZQOJI-BTINSWFASA-N 0.000 description 2
- 125000006281 4-bromobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Br)C([H])([H])* 0.000 description 2
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- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 241000228212 Aspergillus Species 0.000 description 2
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- FDZZZRQASAIRJF-UHFFFAOYSA-M malachite green Chemical compound [Cl-].C1=CC(N(C)C)=CC=C1C(C=1C=CC=CC=1)=C1C=CC(=[N+](C)C)C=C1 FDZZZRQASAIRJF-UHFFFAOYSA-M 0.000 description 2
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- GUUBJKMBDULZTE-UHFFFAOYSA-M potassium;2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid;hydroxide Chemical compound [OH-].[K+].OCCN1CCN(CCS(O)(=O)=O)CC1 GUUBJKMBDULZTE-UHFFFAOYSA-M 0.000 description 2
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- 239000011780 sodium chloride Substances 0.000 description 2
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000000547 substituted alkyl group Chemical group 0.000 description 2
- 125000004434 sulfur atom Chemical group 0.000 description 2
- 125000006168 tricyclic group Chemical group 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- WOAHJDHKFWSLKE-UHFFFAOYSA-N 1,2-benzoquinone Chemical compound O=C1C=CC=CC1=O WOAHJDHKFWSLKE-UHFFFAOYSA-N 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- OXQGTIUCKGYOAA-UHFFFAOYSA-N 2-Ethylbutanoic acid Chemical compound CCC(CC)C(O)=O OXQGTIUCKGYOAA-UHFFFAOYSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000006040 2-hexenyl group Chemical group 0.000 description 1
- 125000006022 2-methyl-2-propenyl group Chemical group 0.000 description 1
- 125000006024 2-pentenyl group Chemical group 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- 125000006041 3-hexenyl group Chemical group 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- 125000006042 4-hexenyl group Chemical group 0.000 description 1
- 125000003119 4-methyl-3-pentenyl group Chemical group [H]\C(=C(/C([H])([H])[H])C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000006043 5-hexenyl group Chemical group 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 235000009434 Actinidia chinensis Nutrition 0.000 description 1
- 241000133570 Berberidaceae Species 0.000 description 1
- 240000007124 Brassica oleracea Species 0.000 description 1
- 235000003899 Brassica oleracea var acephala Nutrition 0.000 description 1
- 235000011301 Brassica oleracea var capitata Nutrition 0.000 description 1
- 235000001169 Brassica oleracea var oleracea Nutrition 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 101100400999 Caenorhabditis elegans mel-28 gene Proteins 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 235000004035 Cryptotaenia japonica Nutrition 0.000 description 1
- 241000332747 Dysosma versipellis Species 0.000 description 1
- 239000004593 Epoxy Substances 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 229940122242 GTPase inhibitor Drugs 0.000 description 1
- 241000409991 Mythimna separata Species 0.000 description 1
- 241001477931 Mythimna unipuncta Species 0.000 description 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 241001495452 Podophyllum Species 0.000 description 1
- 238000004617 QSAR study Methods 0.000 description 1
- 244000182022 Salvia sclarea Species 0.000 description 1
- 235000002911 Salvia sclarea Nutrition 0.000 description 1
- 241000700584 Simplexvirus Species 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 102000007641 Trefoil Factors Human genes 0.000 description 1
- 235000015724 Trifolium pratense Nutrition 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 241001660687 Xantho Species 0.000 description 1
- 241000589634 Xanthomonas Species 0.000 description 1
- 241000589655 Xanthomonas citri Species 0.000 description 1
- 241000589652 Xanthomonas oryzae Species 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000003647 acryloyl group Chemical group O=C([*])C([H])=C([H])[H] 0.000 description 1
- 125000004450 alkenylene group Chemical group 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 125000004419 alkynylene group Chemical group 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 150000001412 amines Chemical group 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 1
- 238000003149 assay kit Methods 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000002047 benzodioxolyl group Chemical group O1OC(C2=C1C=CC=C2)* 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 150000001735 carboxylic acids Chemical group 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000004617 chromonyl group Chemical group O1C(=CC(C2=CC=CC=C12)=O)* 0.000 description 1
- 125000000490 cinnamyl group Chemical group C(C=CC1=CC=CC=C1)* 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 150000004985 diamines Chemical class 0.000 description 1
- 125000004188 dichlorophenyl group Chemical group 0.000 description 1
- 125000004611 dihydroisoindolyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 description 1
- 238000003113 dilution method Methods 0.000 description 1
- 150000002081 enamines Chemical class 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000010228 ex vivo assay Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000006379 fluoropyridyl group Chemical group 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 101150111615 ftsZ gene Proteins 0.000 description 1
- 244000000004 fungal plant pathogen Species 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 125000005980 hexynyl group Chemical group 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- BPHPUYQFMNQIOC-NXRLNHOXSA-N isopropyl beta-D-thiogalactopyranoside Chemical compound CC(C)S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O BPHPUYQFMNQIOC-NXRLNHOXSA-N 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 229920005610 lignin Polymers 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000003032 molecular docking Methods 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000003032 phytopathogenic effect Effects 0.000 description 1
- 108010025221 plasma protein Z Proteins 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 238000002731 protein assay Methods 0.000 description 1
- 239000012460 protein solution Substances 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Chemical group COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001680 trimethoxyphenyl group Chemical group 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000001018 virulence Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01G—HORTICULTURE; CULTIVATION OF VEGETABLES, FLOWERS, RICE, FRUIT, VINES, HOPS OR SEAWEED; FORESTRY; WATERING
- A01G13/00—Protecting plants
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
- A01P1/00—Disinfectants; Antimicrobial compounds or mixtures thereof
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
- A01P3/00—Fungicides
Landscapes
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Environmental Sciences (AREA)
- Wood Science & Technology (AREA)
- Plant Pathology (AREA)
- Engineering & Computer Science (AREA)
- Pest Control & Pesticides (AREA)
- Zoology (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Dentistry (AREA)
- Agronomy & Crop Science (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Toxicology (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention relates to the technical field of pharmaceutical chemistry, in particular to a podophyllotoxin compound containing various ester structures and a preparation method and application thereof.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemistry, in particular to podophyllotoxin compounds containing various ester group structures, and a preparation method and application thereof.
Background
The rapid occurrence and development of plant bacterial diseases, especially refractory bacterial infections to various major crops (such as rice, citrus, kiwi, potato, cabbage, tomato, etc.), severely reduces the yield and quality of the crop. According to incomplete statistics, the effective control of plant pathogenic bacteria by pesticides accounts for at least 30% of the total yield of agricultural products worldwide, however, the use of traditional pesticides in large doses and frequently causes immeasurable damage to already vulnerable ecosystems, while the emergence of plant pathogenic bacteria resistant to antimicrobial agents makes the previously manageable plant bacterial lesions difficult to control. Therefore, there is an urgent need to develop novel pesticides with remarkable effects and unique actions.
4' -norpodophyllotoxin (DMEP) is an aryltetraalkyl lignin, which is isolated from dysosma versipellis of Podophyllum of berberidaceae, and provides a structural framework for a variety of compounds with different biological activities. The reported podophyllotoxin compounds have wide biological activities such as insect resistance, virus resistance, bacteria resistance, cancer resistance and the like. In order to find antibacterial active compounds with unique effects, the invention synthesizes a series of podophyllotoxin compounds containing various ester group structures based on the 4' -demethyl podophyllotoxin structure, and provides an important scientific basis for the research and development and creation of new pesticides through the exploration of the antibacterial activity and corresponding action targets thereof.
The study of the bioactivity of podophyllotoxins has progressed as follows:
in 2003, castro et al [ Castro, m.a.; corral, J.M.M.D.; gordaliza, m.; go' mez-Zurita, m.a.; puente, M.L.D.L.; betancur-Galvis, L.A.; sierra, j.; several E-ring modified podophyllotoxin derivatives were prepared by Feliciano, A.S. anti-viral Synthesis, cytotoxicity and antiviral activity of podophyllotoxin analogues modified in the E-ring [ J ]. Eur.J.Med. Chem.2003,38,899-911 ], and evaluated for cytotoxicity against four tumor cell lines (P-388, A-549, HT-29 and MEL-28) and anti-herpes activity against herpes simplex virus. By partial oxidation of the trimethoxyphenyl group to the o-quinone and further condensation with diamines and enamines to form different heterocycles. Biological activity tests indicate that most compounds retain their cytotoxicity at the mM level, and that part exhibits anti-herpesvirus activity.
In 2007, anil Kumar et al [ Anil Kumar, k.; kumar Singh, s.; siva Kumar, b.; doble, M.Synthesis, anti-fungal activity evaluation and QSAR studies on podophyllotoxin derivatives [ J ]. Cent. Eur. J. Chem.2007,5,880-897 ] 7 were synthesized and tested for the antibacterial and cytotoxicity test of 7C-4 substituted (trans-cinnamyl, cis-cinnamyl, o-methoxycinnamyl, dimethylacryloyl, p-methoxyphenylacetyl, 3, 4-dimethoxyphenylacetyl) podophyllotoxin derivatives against four plant pathogenic fungi (potato anthracnose, fusarium oxysporum, rhizoma verrucosum and Aspergillus candidum). The series of derivatives have high activity on fusarium oxysporum, moderate activity on potato anthracnose and minimum activity on aspergillus candidum.
In 2014, zhi et al [ Zhi, x.y.; yu, x; yang, c.; ding, g.d.; chen, h.; xu, H.Synthesis of4β -acyloxypodophyllotoxin analogs modified in the C and E rings as insecticidal agents against Mythimna separata Walker [ J ]. Biorg.Med.chem. Lett.2014,24,765-772 ], 60 novel 4 b-acyloxypodophyllotoxin analogs of the 4 series modified in the C and E rings were prepared and tested for insecticidal activity against armyworm trefoil larvae at a concentration of 1 mg/mL. The results indicate that when 2 '-chloro-4' -norpodophyllotoxin is oxidized by sodium periodate, the position on the E ring of4 '-norpodophyllotoxin is regioselectively controlled by the C-2' position. Of all derivatives, IIIi has the best insecticidal activity with a final mortality of 63.3%. For the alkyl epoxy series, the appropriate length of the side chain at the C-4 position of Ia-g, IIa-g and IIIa-g has a significant influence on its insecticidal activity.
Disclosure of Invention
(one) solving the technical problems
Aiming at the defects of the prior art, the invention provides podophyllotoxin compounds containing various ester group structures, and a preparation method and application thereof.
(II) technical scheme
In order to achieve the above purpose, the present invention provides the following technical solutions: the invention discloses podophyllotoxin compounds containing various ester group structures, which have the structure shown in a general formula (I):
wherein R is 1 One or more selected from hydrogen, deuterium, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted alkynyl, optionally substituted or unsubstituted alkoxy, optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted aryl, optionally substituted or unsubstituted heteroaryl;
comprising the following compounds:
further, the invention is improved by R 1 Selected from hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-One or more of C6 alkoxy, substituted or unsubstituted C6-C15 aryl, substituted or unsubstituted C6-C10 heteroaryl, wherein the substitution refers to substitution with one or more of C1-C6 alkyl, C1-C6 alkoxy, amino, hydroxy, halogen, nitro, trifluoromethyl.
Further, the invention is improved by R 1 Selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, propenyl, allyl, methoxy, ethoxy, propoxy, butoxy, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, wherein said substitution means substitution with one or more of C1-C6 alkyl, C1-C6 alkoxy, amino, hydroxy, halogen, nitro, trifluoromethyl.
Further, the invention is improved by R 1 Selected from the group consisting of hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, propenyl, allyl, methoxy, ethoxy, propoxy, butoxy, phenyl, benzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 2-aminobenzyl, 3-aminobenzyl, 4-aminobenzyl, 2-hydroxybenzyl, 3-hydroxybenzyl 4-hydroxybenzyl, 2-nitrobenzyl, 3-nitrobenzyl, 4-nitrobenzyl, 2-trifluoromethylbenzyl, 3-trifluoromethylbenzyl, 4-trifluoromethylbenzyl, morpholinyl, piperidinyl, 2-methylpiperidinyl, 3-methylpiperidinyl, 4-methylpiperidinyl, R-3-piperidinecarboxylic acid ethyl ester, S-3-piperidinecarboxylic acid ethyl ester, 4-piperidinecarboxylic acid methyl ester, pyrrolidinyl, R-3-hydroxypyrrolidinyl, S-3-hydroxypyrrolidinyl, piperazinyl, 1-methylpiperazinyl, 1-ethylpiperazinyl, 1-isopropylpiperazinyl, 1-tert-butylpiperazinyl, 1-acetylpiperazinyl, 1-benzylpiperazinyl, 1- (2-methoxybenzyl) piperazinyl, 1- (3-methoxybenzyl) piperazinyl, 1- (4-methoxybenzyl) piperazinyl, 1- (2-methylbenzyl) piperazinyl, 1-(3-methylbenzyl) piperazinyl, 1- (4-methylbenzyl) piperazinyl, 1- (2-chlorobenzyl) piperazinyl, 1- (3-chlorobenzyl) piperazinyl, 1- (4-chlorobenzyl) piperazinyl, 1- (2-fluorobenzyl) piperazinyl, 1- (3-fluorobenzyl) piperazinyl, 1- (4-fluorobenzyl) piperazinyl, 1- (2-bromobenzyl) piperazinyl, 1- (3-bromobenzyl) piperazinyl, 1- (4-bromobenzyl) piperazinyl, 1- (2-aminobenzyl) piperazinyl, 1- (3-aminobenzyl) piperazinyl, 1- (4-aminobenzyl) piperazinyl, 1- (2-hydroxybenzyl) piperazinyl, 1- (3-hydroxybenzyl) piperazinyl, 1- (4-hydroxybenzyl) piperazinyl, 1- (2-nitrobenzyl) piperazinyl, 1- (3-nitrobenzyl) piperazinyl, 1- (4-nitrobenzyl) piperazinyl, 1- (2-trifluoromethylpiperazinyl, 1- (3-nitrobenzyl) piperazinyl) 1- (3-nitrobenzyl) piperazinyl, and 1-trifluoromethylpiperazinyl.
A preparation method of podophyllotoxin compounds containing various ester structures comprises the following steps:
use of podophyllotoxin compounds containing various ester structures in compositions, comprising a compound according to any one of claims 1 to 4, and an agriculturally acceptable adjuvant or fungicide, insecticide or herbicide; the dosage forms of the auxiliary agent are selected from missible oil, powder, wettable powder, granules, water aqua, suspending agent, ultra-low volume spray, soluble powder, microcapsule, smoke agent, aqueous emulsion and water dispersible granule.
The application of podophyllotoxin compounds containing various ester structures in the aspect of preventing and controlling agricultural diseases and insect pests comprises the application of any one of plant bacterial diseases or fungal diseases, plant leaf blight and plant canker, rice bacterial leaf blight, cucumber bacterial leaf blight, konjak bacterial leaf blight, citrus canker, grape canker, tomato canker, kiwi fruit canker, apple canker, cucumber gray mold bacteria, pepper wilt pathogen, sclerotium bacteria, wheat red mold bacteria, potato late blight bacteria and blueberry root rot.
A method for controlling agricultural pests with podophyllotoxin compounds containing various ester structures, which comprises allowing the compound of any one of claims 1 to 4, or the composition of claim 7 to act on a pest or its living environment.
A method of protecting plants from agricultural pests comprising contacting the plants with a compound according to any one of claims 1 to 4, or a composition according to claim 7.
(III) beneficial effects
Compared with the prior art, the invention provides podophyllotoxin compounds containing various ester group structures, and the preparation method and application thereof, and the podophyllotoxin compounds have the following beneficial effects:
the invention synthesizes a series of podophyllotoxin compounds containing various ester structures based on 4' -demethyl podophyllotoxin, and discovers that the compounds have good inhibition effect on pathogenic bacteria, and have good inhibition effect on pathogenic bacteria [ such as bacterial leaf blight of rice (Xanthomonas oryzae pv. Oryzae, xoo), citrus canker (Xanthomonas axonopodis pv. Citri, xac) and the like ], thereby providing an important scientific basis for the research and development and creation of new pesticides.
Drawings
FIG. 1 is a schematic representation of nuclear magnetic resonance hydrogen and carbon spectrum data of a compound of the present invention;
FIG. 2 is a diagram showing physicochemical properties of a target compound of the present invention;
FIG. 3 is a schematic diagram of EC50 of podophyllotoxin compounds containing various ester structures according to the present invention;
FIG. 4 is a schematic representation of the purification of recombinant XooFtsZ of the present invention;
FIG. 5 is a schematic representation of the inhibitory activity of compound B2 and berberine of the present invention on the activity of XooFtsZ GTPase;
Detailed Description
The following description of the embodiments of the present invention will be made clearly and completely with reference to the accompanying drawings, in which it is apparent that the embodiments described are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Referring to fig. 1-5, the podophyllotoxin compound containing various ester group structures has a structure shown as a general formula (I):
wherein R is 1 One or more selected from hydrogen, deuterium, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted alkynyl, optionally substituted or unsubstituted alkoxy, optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted aryl, optionally substituted or unsubstituted heteroaryl;
comprising the following compounds:
in this embodiment, preferably, R 1 One or more selected from hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, substituted or unsubstituted C6-C15 aryl, substituted or unsubstituted C6-C10 heteroaryl, wherein the substitution refers to substitution by one or more of C1-C6 alkyl, C1-C6 alkoxy, amino, hydroxy, halogen, nitro, trifluoromethyl.
In this embodiment, more preferably, R 1 Selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, propenyl, allyl, methoxy, ethoxy, propoxy, butoxy, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, wherein said substitution means substitution with one or more of C1-C6 alkyl, C1-C6 alkoxy, amino, hydroxy, halogen, nitro, trifluoromethyl.
In this embodiment, most preferably, R 1 Selected from the group consisting of hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, propenyl, allyl, methoxy, ethoxy, propoxy, butoxy, phenyl, benzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 2-aminobenzyl, 3-aminobenzyl, 4-aminobenzyl, 2-hydroxybenzyl, 3-hydroxybenzyl 4-hydroxybenzyl, 2-nitrobenzyl, 3-nitrobenzyl, 4-nitrobenzyl, 2-trifluoromethylbenzyl, 3-trifluoromethylbenzyl, 4-trifluoromethylbenzyl, morpholinyl, piperidinyl, 2-methylpiperidinyl, 3-methylpiperidinyl, 4-methylpiperidinyl, R-3-piperidinecarboxylic acid ethyl ester, S-3-piperidinecarboxylic acid ethyl ester, 4-piperidinecarboxylic acid methyl ester, pyrrolidinyl, R-3-hydroxypyrrolidinyl, S-3-hydroxypyrrolidinyl, piperazinyl, 1-methylpiperazinyl, 1-ethylpiperazinyl, 1-isopropylpiperazinyl, 1-tert-butylpiperazinyl, 1-acetylpiperazinyl, 1-benzylpiperazinyl, 1- (2-methoxybenzyl) piperazinyl, 1- (3-methoxybenzyl) piperazinyl, 1- (4-methoxybenzyl) piperazinyl, 1- (2-methylbenzyl) piperazinyl, 1- (3-methylbenzyl) piperazinyl, 1- (4-methylbenzyl) piperazinyl, 1- (2-chlorobenzyl) piperazinyl, 1- (3-chlorobenzyl) piperazinyl, 1- (4-chlorobenzyl) piperazinyl, 1- (2-fluorobenzyl) piperazinyl, 1- (3-fluorobenzyl) piperazinyl, 1- (4-fluorobenzyl) piperazinyl, 1- (2-bromobenzyl) piperazinyl, 1- (3-bromobenzyl) piperazinyl, 1- (4-bromobenzyl) piperazinyl, 1- (2-aminobenzyl) piperazinyl, 1- (3-aminobenzyl) piperazinyl, 1- (4-aminobenzyl) piperazinyl, 1- (2-hydroxybenzyl) piperazinyl, 1- (3-hydroxybenzyl) piperazinyl, 1- (4-hydroxybenzyl) piperazinyl, 1- (2-nitrobenzyl) piperazinyl, 1- (3-nitrobenzyl) piperazinyl, 1-trifluoromethyl-piperazinyl, 1-nitrobenzyl-trimethyl-piperazinyl, piperazinyl and 1-nitrobenzyl-trimethyl-piperazinyl-derivatives 1- (4-trifluoromethylbenzyl) piperazinyl.
As used herein, the term "alkyl" is intended to include branches having a specified number of carbon atomsAnd straight-chain saturated hydrocarbon radicals, e.g. "C 1-10 Alkyl "(or alkylene) is intended to be C1, C2, C3, C4, C5, C6, C7, C8, C9 and C10 alkyl; in addition, e.g. "C 1-6 Alkyl "represents an alkyl group having 1 to 6 carbon atoms; alkyl groups may be unsubstituted or substituted such that one or more of its hydrogen atoms is replaced by another chemical group; examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl) and the like.
"alkenyl" is a hydrocarbon that includes both straight or branched chain structures and has one or more carbon-carbon double bonds present at any stable point in the chain; for example "C 2-6 Alkenyl "(or alkenylene) is intended to include C2, C3, C4, C5 and C6 alkenyl groups; examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl and the like.
"alkynyl" is a hydrocarbon that includes both straight or branched structures and has one or more carbon-carbon triple bonds that occur at any stable point in the chain; for example "C 2-6 Alkynyl "(or alkynylene) is intended to include C2, C3, C4, C5, and C6 alkynyl; such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
The term "substituted" as used herein refers to substitution of any one or more hydrogen atoms on a specified atom or group with a selected specified group, provided that the specified atom's general valency is not exceeded, and if not otherwise specified, the substituents are named to the central structure, e.g., it is understood that when (cycloalkyl) alkyl is the possible substituent, the point of attachment of the substituent to the central structure is in the alkyl moiety, and the ring double bond as used herein is a double bond formed between two adjacent ring atoms (e.g., c= C, C =n or n=n). When referring to substitution, particularly polysubstituted, it is meant that a plurality of substituents are substituted at various positions on the indicated group, e.g. dichlorophenyl refers to 1, 2-dichlorophenyl, 1, 3-dichlorophenyl and 1, 4-dichlorophenyl.
Combinations of substituents and or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates, stable compounds or stable structures implying that the compounds are sufficiently stable when isolated from the reaction mixture in useful purity, and concomitantly formulated to form effective therapeutic agents. Preferably, the compounds at present do not comprise N-halogen, S (O) 2 H or S (O) H group.
The term "aryl" refers to a monocyclic or bicyclic aromatic hydrocarbon group having 6 to 12 carbon atoms in the ring portion, such as phenyl and naphthyl, each of which may be substituted.
The term "halogen" or "halogen atom" refers to chlorine, bromine, fluorine and iodine.
The term "haloalkyl" refers to a substituted alkyl group having one or more halogen substituents. For example, "haloalkyl" includes mono-, di-and trifluoromethyl; even though the halo in the haloalkyl is explicitly fluoro, chloro, bromo, iodo, it also refers to substituted alkyl groups having one or more fluoro, chloro, bromo, iodo substituents.
The term "heteroaryl" refers to substituted and unsubstituted aromatic 5-or 6-membered monocyclic groups, 9-or 10-membered bicyclic groups, and 11 to 14-membered tricyclic groups, having at least one heteroatom (O, S or N) in at least one ring, said heteroatom-containing ring preferably having 1,2 or 3 heteroatoms selected from O, S and N. Each ring of the heteroatom-containing heteroaryl group may contain one or two oxygen or sulfur atoms and/or from 1 to 4 nitrogen atoms provided that the total number of heteroatoms in each ring is 4 or less and that each ring has at least one carbon atom. The fused ring completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or unsaturated. The nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quaternized. Bicyclic or tricyclic heteroaryl groups must include at least one wholly aromatic ring and the nitrogen other fused rings may be aromatic or non-aromatic. Heteroaryl groups may be attached at any available nitrogen or carbon atom of any ring. When the valency permits, if the other ring is cycloalkyl or heterocycle, it is additionally optionally substituted with =o (oxygen).
Exemplary monocyclic heteroaryl groups include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, furanyl, thienyl, oxadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, and the like.
Exemplary bicyclic heteroaryl groups include indolyl, benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzofuranyl, indolizinyl, benzofuranyl, chromonyl, coumarin, benzofuranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridinyl, fluoropyridyl, dihydroisoindolyl, tetrahydroquinolinyl, and the like.
The compounds of the present invention are understood to include both the free form and salts thereof, if not otherwise specified; the term "salt" means an acid and/or base salt formed from inorganic and/or organic acids and bases. In addition, the term "salt" may include zwitterionic (inner salts), such as when the compounds of formula I contain basic moieties such as amine or pyridine or imidazole rings, and acidic moieties such as carboxylic acids. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, such as acceptable metal and amine salts, wherein the cation does not contribute significantly to the toxicity or bioactivity of the salt. However, other salts may be useful, such as by employing isolation or purification steps in the preparation process, and are therefore also included within the scope of the present invention.
Preferably C 1 -C 10 Alkyl refers to methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and isomers thereof; c (C) 1 -C 10 Alkoxy refers to methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, nonoxy, decyloxy and isomers thereof; c (C) 2 -C 5 Alkenyl refers to ethenyl, propenyl, allyl, butenyl, pentenyl and isomers thereof.
When referring to substituents as alkenyl, alkynyl, alkyl, halogen, aryl, heteroaryl, alkoxy, cycloalkyl, hydroxy, amino, mercapto, phosphino, or when referring to such substituents as in particular to a particular alkenyl, alkynyl, alkyl, halogen, aryl, heteroaryl, alkoxy, cycloalkyl, hydroxy, amino, mercapto, phosphino, one to three of the above substituents are meant. For example methylphenyl refers to one to three methyl-substituted phenyl groups.
By adopting the technical scheme, the invention synthesizes a series of podophyllotoxin compounds containing various ester structures based on 4' -nor podophyllotoxin, and discovers that the compounds have good inhibition effect on pathogenic bacteria, and have good inhibition effect on pathogenic bacteria (such as bacterial leaf blight bacteria (Xantho) of rice, citrus canker (Xanthomonas axonosporispv, clary, xac) and the like), thereby providing an important scientific basis for the research and development and the creation of new pesticides.
A preparation method of podophyllotoxin compounds containing various ester structures comprises the following steps:
use of podophyllotoxin compounds containing various ester structures in compositions, comprising a compound according to any one of claims 1 to 4, and an agriculturally acceptable adjuvant or fungicide, insecticide or herbicide; the dosage forms of the auxiliary agent are selected from missible oil, powder, wettable powder, granules, water aqua, suspending agent, ultra-low volume spray, soluble powder, microcapsule, smoke agent, aqueous emulsion and water dispersible granule.
The application of podophyllotoxin compounds containing various ester structures in the aspect of preventing and controlling agricultural diseases and insect pests comprises the application of any one of plant bacterial diseases or fungal diseases, plant leaf blight and plant canker, rice bacterial leaf blight, cucumber bacterial leaf blight, konjak bacterial leaf blight, citrus canker, grape canker, tomato canker, kiwi fruit canker, apple canker, cucumber gray mold bacteria, pepper wilt pathogen, sclerotium bacteria, wheat red mold bacteria, potato late blight bacteria and blueberry root rot.
A method for preventing and controlling agricultural diseases and insect pests by podophyllotoxin compounds containing various ester groups comprises enabling the compounds of any one of claims 1-4 or the composition of claim 7 to act on harmful substances or living environments thereof, wherein the method for preventing and controlling agricultural diseases and insect pests is not particularly limited, and conventional methods for preventing and controlling agricultural diseases and insect pests are adopted, and the method for using the podophyllotoxin compounds containing various ester groups can ensure that the podophyllotoxin compounds containing various ester groups effectively act on agricultural diseases and insect pests or living environments thereof.
A method for protecting plants from agricultural pests using podophyllotoxin compounds containing various ester structures, which comprises the steps of contacting plants with the compound according to any one of claims 1 to 4 or the composition according to claim 7, wherein the method for protecting plants from agricultural pests is not particularly limited, conventional methods for protecting plants from agricultural pests are employed, and the step of contacting plants with podophyllotoxin compounds containing various ester structures is ensured to be effective.
The method of the embodiment of the invention is only used for illustrating the invention, not limiting the invention, and simple modification of the preparation method of the invention under the premise of the conception of the invention is within the scope of the protection of the invention. All the starting materials and solvents used in the examples are commercially available products.
Example 1: target compound
Preparation of B14- ((5R, 5aR,8aR, 9S) -9-hydroxy-6-oxo-5,5a,6, 8a,9-hexahydrofuro [3',4':6,7] naphtho [2,3-d ] [1,3] dioxal-5-yl) -2,6-dimethoxyphenyl 2-ethylnutrate:
4' -Norpodophyllotoxin [ DMEP ]](100.00 mg, 249.76. Mu. Mol) 4-dimethylaminopyridine [ DMAP ]](30.51 mg, 249.76. Mu. Mol) and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride [ EDCI ]]A mixture of (47.88 mg, 249.76. Mu. Mol) was dissolved in 5mL of N, N' -dimethylformamide. The reaction was carried out at room temperature for 12 hours, and 2-ethylbutyric acid (29.01 mg, 249.76. Mu. Mol) was added to the mixture to participate in the reaction. After the reaction was completed, the crude product was extracted 3 times with 15mL of ethyl acetate. The organic phase is further washed with saturated aqueous ammonium chloride solution and water and then dried over anhydrous sodium sulfate. Finally, the solvent is removed under vacuum to obtain the compound B 1 By thin layer chromatography (CH 2 Cl 2 :CH 3 Oh=120:1-100:1, v:v).
The structure and nuclear magnetic resonance hydrogen spectrum and carbon spectrum data of the synthesized podophyllotoxin compound containing various ester structures are shown in figure 1, and the physicochemical properties are shown in figure 2.
Pharmacological examples:
EC 50 (median effective concentration) is an important index for evaluating the sensitivity of plant pathogenic bacteria to a compound, and is also an important parameter for setting the concentration of the compound when researching the action mechanism of the target compound. In the concentration gradient experiment, proper 5 concentrations are set by adopting a double dilution method, and finally the inhibition rate of the medicament to plant pathogenic bacteria and the medicament concentration are converted into logarithmic values, and the virulence curve is obtained by SPSS software regression analysis, so that EC is calculated 50 。
Testing the effective medium concentration EC of the target compound to plant pathogenic bacteria by using turbidity method 50 The test subjects were rice bacterial leaf blight bacteria (Xoo) and citrus canker bacteria (Xac). DMSO was dissolved in the medium as a blank. Putting rice bacterial leaf blight bacteria (rice bacterial leaf blight pathogenic bacteria are in an M210 solid culture medium) into an NB culture medium, and carrying out shake culture in a constant-temperature shaking table at 28 ℃ and 180rpm until the bacterial leaf blight bacteria are in a logarithmic growth phase for later use; the citrus canker fungus (on M210 solid medium) is placed in NB medium and shake-cultured in a thermostatic shaker at 28℃and 180rpm until logarithmic growth phase is ready for use. 5mL of toxic NB liquid culture medium with different concentrations (for example, 100,50,25,12.5,6.25 mug/mL) of the medicament (compound) is prepared, and is added into a test tube, 40 mu L of NB liquid culture medium containing phytopathogenic bacteria is respectively added, and the mixture is oscillated in a constant temperature shaking table at 28-30 ℃ and 180rpm, so that bacterial leaf blight of rice is cultivated for 36h and citrus canker is cultivated for 48h. Measuring OD of bacterial solutions with various concentrations on a spectrophotometer 595 Values, and additionally determining the OD of corresponding concentrations of toxic sterile NB liquid medium 595 Values.
Corrected OD = bacteria-containing medium OD-sterile medium OD
Inhibition ratio = [ (corrected control medium bacterial liquid OD value-corrected toxic medium OD value)/(d value)
After correction, the OD value of the control culture medium bacterial liquid is multiplied by 100
The present invention is described with the aid of examples, but the contents of examples are not limited thereto, and the experimental results of the target compounds are shown in table 3.
As can be seen from FIG. 3, in the ex vivo assay, the target compound B 2 Exhibits a certain inhibitory activity against plant pathogenic bacteria rice bacterial leaf blight (Xanthomonas oryzae, xoo), its EC 50 153. Mu.g/mL.
Example 2: purification of recombinant XooFtsZ
The XooFtsZ gene sequences were obtained from NCBI database. Primer NdeI (5'-GGCCCCAAGGGGTTATGCTAGT-3'), primer HindIII (5'-GATCCCGCGAAATTAATACG-3'), PCR fragment was digested with NdeI and HindIII and ligated to the same digested vector pET30 (+) and the pET30 (+) transformed BL21Gold (DE 3) pLysS strain was incubated in LB medium at 37℃to OD595 = 0.6 to give XooFtsZ, 0.5mM IPTG-induced cells were added, incubated at 16℃for 14h, centrifuged (3000 Xg, 10min,4 ℃) to collect cells, and then sonicated in 2 ice-cold mixed buffers (20 mM phosphate (pH 7.4), 500mM NaCl,30mM imidazole, 1mM EDTA and 1mM dithiothreitol) for fluorescence titration experiments; 50mM HEPES-KOH (pH 7.4), 500mM NaCl,30mM imidazole, 1mM EDTA and 1mM dithiothreitol were used for the GTPase activity test. The supernatant was collected by centrifugation (11000 Xg, 10min,4 ℃) and purified by a Ni-NTA column, 10His-XooFtsZ was eluted with a linear gradient of 30-600mM imidazole, the protein solution was collected, desalted by a desalting column (5X 5mL HiTrap desalting column), and the corresponding experimental results were found in FIG. 4 using a protein assay kit (BCA kit) according to the protocol.
Purification of recombinant XooFtsZ, ftsZ was analyzed by 12% sds/PAGE, as shown in fig. 4. Lanes 1, purified XooFtsZ (35 μg) and 2, purified XooFtsZ (20 μg).
Example 3: preliminary screening for GTPase Activity
Experimental method and specific procedure of the experimentReference is made to the previous report [ Zhou, x; feng, y.m.; qi, p.y.; shao, w.b.; wu, z.b.; liu, l.w.; wang, y; ma, h.d.; wang, p.y.; li, Z; yang, S.Synthesis and docking study ofN- (Cinnamyl) -N' - (subbested) acryloyl hydrazide derivatives containing pyridinium moieties as a novel class of filamentous temperature-sensitive protein Z inhibitors against the intractable Xanthomonas oryzae pv.oryzae infections in rice [ J ]].J.Agric.Food Chem.2020,68,8132-8142.]GTPase activity was performed by measuring the amount of Pi released during XooFtsZ assembly using a standard malachite green assay kit (Cayman chemical, USA). First, 1. Mu. MXooFtsZ was incubated in 50mM HEPES-KOH buffer (pH 8.0) containing 50mM potassium chloride and 1mM EDTA on ice without or with varying concentrations of the compound for 10 minutes. Subsequently, 2.5mM magnesium chloride and 1.25mM Guanosine Triphosphate (GTP) were added to the reaction mixture and incubated at 28℃for 20 minutes. Then, 5. Mu.L of an acid solution was added to 50. Mu.L of the sample at 25℃to quench for 10min. After that, 15. Mu.L of malachite green solution was added to the sample and incubated at 25℃for 20min in the dark. Finally, the Pi release was measured at 620nm and measured by Cystation TM A 5 multimode reader (BioTek Instruments, inc.
To further investigate these compounds B 2 As shown in FIG. 5, the inhibitory activity of purified recombinant XooFtsZ in Compound B was determined 2 Or in vitro activity of GTPase in the presence of berberine as control GTPase inhibitor. Compound B 2 Inhibition of purified XooFtsZ GTPase at 200 μm and 100 μm was 54.8% and 48.6%, respectively, indicating compound B 2 Are potent XooFtsZ inhibitors.
Although embodiments of the present invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made therein without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (6)
1. An ester group-containing podophyllotoxin compound, which is characterized by having a structure shown in a formula (I):
，
formula (I).
2. A process for producing an ester group-containing podophyllotoxin compound according to claim 1, comprising the steps of:
。
3. a composition of podophyllotoxin compounds containing an ester group structure, comprising the compound of claim 1, and an agriculturally acceptable adjuvant or fungicide, insecticide or herbicide; the dosage forms of the auxiliary agent are selected from missible oil, powder, wettable powder, granules, water aqua, suspending agent, ultra-low volume spray, soluble powder, microcapsule, smoke agent, aqueous emulsion and water dispersible granule.
4. The use of podophyllotoxin compound containing ester group structure as claimed in claim 1 for preventing and controlling agricultural plant diseases and insect pests, wherein the agricultural plant diseases and insect pests are bacterial leaf blight of rice.
5. A method for controlling agricultural pests with an ester group-containing podophyllotoxin compound according to claim 1, which comprises allowing the compound of claim 1, or the composition of claim 3 to act on a pest or its living environment.
6. A method of protecting a plant from an agricultural pest comprising an ester group structure podophyllotoxin compound of claim 1, comprising the step of contacting the plant with a compound of claim 1, or a composition of claim 3.
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