Natural products-based insecticidal agents 4. Semisynthesis and insecticidal activity of novel esters of 2-chloropodophyllotoxin against Mythimna separata Walker in vivo

By using podophyllotoxin as a lead compound, eight novel esters of 2-chloropodophyllotoxin were designed, semisynthesized, and preliminarily evaluated for their insecticidal activity against the pre-third-instar larvae of Mythimna separata Walker in vivo for the first time. Among all the tested compounds, especially three esters of 2-chloropodophyllotoxin 8a, 8c, and 8g, and one intermediate 6 showed more promising and pronounced insecticidal activity than toosendanin, a commercial insecticide derived from Melia azedarach.     

Natural products-based insecticidal agents 6. Design,semisynthesis, and insecticidal activity of novel monomethyl phthalate derivatives of podophyllotoxin against Mythimna separata Walker in vivo

To discover the more potent analogs, 12 novel monomethyl phthalate derivatives of podophyllotoxin were synthesized and preliminarily tested against the pre-third-instar larvae of Mythimna separata Walker in vivo at the concentration of 1 mg/mL. Compounds 8e–i showed the higher insecticidal activity than podophyllotoxin. Especially 8g exhibited the most potent insecticidal activity compared with toosendanin, a commercially available insecticide derived from Melia azedarach. The structure–activity relationships demonstrated that trans-lactone, 4β-substitution, 2β-chlorine substitution, and 4′-methoxy group were the important structural properties of podophyllotoxins for good insecticidal activity.     

Natural-product-based insecticidal agents 14. Semisynthesis and insecticidal activity of new piperine-based hydrazone derivatives against Mythimna separata Walker in vivo

In continuation of our program aimed at the discovery and development of natural-product-based insecticidal agents, twenty-six new piperine-based hydrazone derivatives were synthesized from piperine, an alkaloid isolated from Piper nigrum Linn. The single-crystal structures of 6c, 6q and 6w were unambiguously confirmed by X-ray crystallography. Their insecticidal activity was evaluated against the pre-third-instar larvae of Mythimna separata Walker in vivo. Especially compounds 6b, 6i and 6r, the final mortality rates of which, at the concentration of 1 mg/mL, were 62.1%, 65.5% and 65.5%, respectively, exhibited more pronounced insecticidal activity compared to toosendanin at 1 mg/mL, a commercial botanical insecticide isolated from Melia azedarach. It suggested that introduction of the substituents at the C-2 position on the phenyl ring of the hydrazone derivatives was important for their insecticidal activity.     

Synthesis and insecticidal activity of new oxime derivatives of podophyllotoxin-based phenazines against Mythimna separata Walker

To discover new natural-product-based insecticidal agents, a series of novel oxime derivatives of podophyllotoxin-based phenazines modified in the C, D and E rings of podophyllotoxin were prepared and tested as insecticidal agents against the pre-third-instar larvae of oriental armyworm, Mythimna separata (Walker) in vivo at 1 mg/mL. The steric configuration of IIIc was unambiguously confirmed by single-crystal X-ray diffraction analysis. Compounds IIIa–d, and IIIi exhibited an equal or higher insecticidal activity than toosendanin.     

Synthesis and insecticidal activity of novel hydrazone compounds derived from a naturally occurring lignan podophyllotoxin against Mythimna separata (Walker)

In continuation of our program aimed at the discovery and development of natural-product-based insecticidal agents, a series of novel hydrazone derivatives of podophyllotoxin, which is a naturally occurring aryltetralin lignan and isolated as the main secondary metabolite from the roots and rhizomes of Podophyllum species, were synthesized and evaluated as insecticidal agents against the pre-third-instar larvae of oriental armyworm, Mythimna separata (Walker) in vivo at 1 mg/mL. Especially compounds 8i, 8j, 8t, and 8u showed the more potent insecticidal activity with the final mortality rates greater than 60%.     

Additive effects on the improvement of insecticidal activity: Design,synthesis, and insecticidal activity of novel pymetrozine derivatives

A series of new pymetrozine analogues containing both methyl on the imine carbon and phenoxy group at the pyridine ring were designed and synthesized. Their insecticidal activities against bean aphid (Aphis craccivora), mosquito larvae (Culex pipiens pallens), cotton bollworm (Helicoverpa armigera), corn borer (Ostrinia nubilalis) and oriental armyworm (Mythimna separata) were evaluated. The results of bioassays indicated that most of the target compounds showed good insecticidal activity against bean aphid; especially, IIIf (80%) and IIIl (80%) exhibited higher aphicidal activity than pymetrozine (30%) at 5 mg/kg, and the two compounds still showed 20% and 30% mortality at 2.5 mg/kg, respectively, whereas pymetrozine displayed no activity at the same concentration. These compounds exhibited a completely different structure–activity relationship to that of known pymetrozine derivatives, in which it is thought introducing alkyl group on the imine carbon could be detrimental to the activities. Our new result suggested that the methyl on the imine carbon and phenoxy group at the pyridine ring of phenoxy group may play additive effects on the improvement of aphicidal activity. Besides this, compound IIIs, containing an allyl at the para position of phenoxy group, exhibited excellent insecticidal activity against mosquito larvae, lepidoptera pests cotton bollworm, corn borer and oriental armyworm.     

Design,synthesis, insecticidal activity and molecular docking of doramectin derivatives

A series of new doramectin derivatives containing carbamate, ester and sulfonate were synthesized, and their structures were characterized by ¹H and ¹³C nuclear magnetic resonance (NMR) and high-resolution mass spectrum (HRMS). Their insecticidal activities against oriental armyworm, diamondback moth, and corn borer were evaluated and compared with the parent doramectin and commercial avermectins, metolcarb, fenpropathrin. Among all compounds, three compounds (3a, 3g and 3h) showed excellent insecticidal effect. In particular, compound 3g containing cyclopropyl carbamate against oriental armyworm, diamondback moth, and corn borer, exhibited the most promising insecticidal activity with the final mortality rate of 66.67%, 36.67%, 40.00% at the concentration of 12.5 mg/L, respectively. The LC₅₀ values of 3g were 5.8859, 22.3214, and 22.0205 mg/L, showing 6.74, 2.23, 2.21-fold higher potency than parent doramectin (LC₅₀ values of 39.6907, 49.7736, and 48.6129 mg/L) and 6.83, 1.93, 3.36-fold higher potency than commercial avermectins (LC₅₀ values of 40.2489, 42.9922, and 73.9508 mg/L). Additionally, molecular docking simulations revealed that 3g displayed stronger hydrogen-bonding action in binding with the GABA receptor than parent doramectin, which were crucial for keeping high insecticidal activity. The present work demonstrated that these compounds containing alkyl carbamate group could be considered as potential candidates for the development of novel pesticides in the future.     

Design,synthesis and insecticidal evaluation of aryloxy dihalopropene derivatives

Plutella xylostella (P. xylostella) is a highly migratory, cosmopolitan species and one of the most important pest of cruciferous crops worldwide. Pyridalyl as a novel class of insecticides has good efficacy against P. xylostella. On the basis of the commercial insecticide pyridalyl, a series of new aryloxy dihalopropene derivatives were designed and synthesized by using Intermediate Derivatization Methods. Their chemical structures were confirmed by ¹H NMR, high-resolution mass spectrum (HRMS), and single-crystal X-ray diffraction analysis. The insecticidal activities of the new compounds against P. xylostella were evaluated. The results of bioassays indicated that most of the compounds showed moderate to high activities at the tested concentration, especially compounds 10e and 10g displayed more than 75% insecticidal activity against P. xylostella at 6.25 mg/L, while pyridalyl showed 50% insecticidal activity at the same concentration. The field trials result of the insecticidal activities showed that compound 10e as a 10% emulsifiable concentrate (EC) was effective in the control of P. xylostella at 75–150 g a.i./ha, and the mortality of P. xylostella for treatment with compound 10e at 75 g a.i./ha was equivalent to pyridalyl at 105 g a.i./ha.     

Synthesis and insecticidal activity of new deoxypodophyllotoxin derivatives modified in the D-ring

In continuation of our program aimed at the discovery of new natural-product-based insecticidal agents, twenty-six deoxypodophyllotoxin derivatives modified in the D-ring were synthesized and evaluated as insecticidal agents against the pre-third-instar larvae of oriental armyworm, Mythimna separata (Walker) in vivo at 1 mg/mL. The configuration of three compounds 3, 4, and IIIi was unambiguously determined by single-crystal X-ray diffraction. It demonstrated that aminolysis of deoxypodophyllotoxin in the presence of pyrrolidine and piperidine could result in complete inversion of the configuration of the carbonyl group at its C-2 position. Five compounds IIa, IIi–k, and IIIh showed the equal or higher insecticidal activity than toosendanin. Especially IIj displayed the most potent insecticidal activity with the final mortality rate of 65.5%.     

Design,semisynthesis and potent cytotoxic activity of novel 10-fluorocamptothecin derivatives

Fluorination is a well-known strategy for improving the bioavailability of bioactive molecules in the lead optimization phase of drug discovery projects. In an attempt to improve the antitumor activity of camptothecins (CPTs), novel 10-fluoro-CPT derivatives were designed, synthesized and evaluated for cytotoxicity against five human cancer cell lines (A-549, MDA-MB-231, KB, KB-VIN and MCF-7). All of the derivatives showed more potent in vitro cytotoxic activity than the clinical CPT-derived drug irinotecan against the tumor cell lines tested, and most of them showed comparable or superior potency to topotecan. Remarkably, compounds 16b (IC₅₀, 67.0 nM) and 19b (IC₅₀, 99.2 nM) displayed the highest cytotoxicity against the multidrug-resistant (MDR) KB-VIN cell line and merit further development as preclinical drug candidates for treating cancer, including MDR phenotype. Our study suggested that incorporation of a fluorine atom into position 10 of CPT is an effective method for discovering new potent CPT derivatives.     

松油烯-４-醇对粘虫幼虫的生物活性

测定了杀虫植物砂地柏Sabina vulgaris Ant.的精油中主杀虫成分-松油烯-4-醇（terpinen 4.01）对粘虫Mythimna separata Walker幼虫的生物活性。结果表明,松油烯- 4-醇对粘虫主要表现为熏蒸作用,对粘虫3龄幼虫24 h的熏蒸LC₅₀为5.3473 μL/L ;还具一定触杀作用,对粘虫4龄幼虫24 h的LD₅₀为147.8 μg/虫。试虫的中毒症状可明显地分为兴奋、痉挛、麻痹和死亡4个阶段,而麻痹的部分试虫有复苏现象。可明显抑制Na⁺ ,K⁺ATP酶的活性,在兴奋期、痉挛期、麻痹期和复苏期,抑制率介于21.28%～34.92% 之间。离体条件下对Na⁺,K⁺ATP酶的I₅₀为133.75 μg·mL^-1;对AChE活性有一定的影响;对酯酶,在兴奋期,酶活力为对照的7.0%,在麻痹期则为对照的1.33倍,而复苏期试虫的酯酶活力与对照相当。     

Insight into dihalogenation of E-ring of podophyllotoxins,and their acyloxyation derivatives at the C4 position as insecticidal agents

Unexpected sequential E-ring dihalogenation of podophyllotoxin analogues is reported. It demonstrated that a chlorine/bromine atom was prior introduced at the C2′ position of podophyllotoxin, and the corresponding free rotation of E-ring around the C1–C1′ bond of 2′-chloro or 2′-bromopodophyllotoxin was restricted. When 2′-chloro or 2′-bromopodophyllotoxin reacted with N-chlorosuccinimide (NCS), the chlorine atom was regioselectively introduced at their C6′ position on the E-ring. Whereas 2′-chloro or 2′-bromopodophyllotoxin reacted with NBS, the bromine atom was regioselectively introduced at their C5 position on the B-ring. When 2′-chloropodophyllotoxin reacted with different carboxylic acids in the presence of BF₃·Et₂O, the steric effect of its E-ring for stereoselective synthesis of 4β-acyloxy-2′-chloropodophyllotoxin derivatives was observed. The insecticidal activity of 2′(2′,6′)-(di)halogen-substituted podophyllotoxin derivatives were evaluated with Mythimna separata Walker.     

Synthesis and insecticidal activity studies of novel phenylpyrazole derivatives containing arylimine or carbimidate moiety

Phenylpyrazole insecticides are successful for crop protection and public hygiene by blocking gamma-aminobutyric acid (GABA)-gated chloride channels and glutamate-gated chloride (GluCl) channels. A series of novel phenylpyrazoles containing arylimine or 1-methoxyaryl groups were designed and synthesized. The addition reaction of methanol to the imines 1–11 was investigated and the cayno addition products 13–15 were obtained. The compounds 1–15 were confirmed by ¹H NMR and elemental analysis. The results of bioassay indicated that some compounds exhibited comparable bioactivity to fipronil against a broad spectrum of insects such as bean aphid (Aphis craccivora), mosquito (Culex pipiens pallens), diamondback moth (Plutella xylostella) and Oriental armyworm (Mythimna separata). Especially, the foliar contact activity against bean aphid of compound 7 at 10 µg mL⁻¹ was 68%, the larvacidal activity against mosquito of compounds 5, 13 and 15 at 0.0025 µg mL⁻¹ was 100%, the larvacidal activity against diamondback moth of compounds 9 and 11 at 0.05 µg mL⁻¹ was 100%, the larvacidal activity against Oriental armyworm of compound 9 at 1 µg mL⁻¹ was 100%. The 3-cayno moiety on pyrazole ring was essential for the high insecticidal activities against bean aphid, diamondback moth and Oriental armyworm, while the 3-carbimidate moiety on pyrazole ring was crucial to the excellent high insecticidal activities against mosquito.     

Design,synthesis and antistaphylococcal activity of marine pyrrole alkaloid derivatives

Abstract

A novel set of 16 hybrids of bromopyrrole alkaloids with aroyl hydrazone were designed, synthesized and evaluated for antibacterial and antibiofilm activities against methicillin-resistant Staphylococcus aureus (MRSA; ATCC 43866), methicillin-susceptible Staphylococcus aureus (MSSA; ATCC 35556) and Staphylococcus epidermidis (SE, S. epidermidis ATCC 35984). Of the 16 tested hybrids, 14 exhibited equal or superior antibiofilm activity against MSSA and MRSA relative to standard vancomycin. Compound 4m showed highest potency with antibiofilm activity of 0.39?µg/mL and 0.78?µg/mL against MSSA and MRSA, respectively. Thus, this compound could act as a potential lead for further development of new antistaphylococcal drugs.     

Synthesis and insecticidal activity in vitro and vivo of novel benzenesulfonyl derivatives based on potent target subunit H of V-ATPase

Two lead compounds with benzenesulfonamide were found through virtual screening based on the 3D structure of the subunit H of V-ATPase in previous study. 74 benzenesulfonyl derivatives were synthesized and their insecticidal activities were evaluated. The derivatives with propargyl substituents exhibit excellent insecticidal activities against Mythimna separata Walker. The LD₅₀ values of compounds A5.7 (28.0?μg·g^?1) and B5.7 (36.4?μg·g^?1) were significantly less than that of Celangulin V (344.0?μg·g^?1). Furthermore, Isothermal Titration Calorimetry (ITC) data indicate there is a strong binding affinity between A5.7 and V-ATPase Subunit H. These results demonstrate that it is a practical way to develop pesticides targeting at H subunit of V-ATPase.     

Design and synthesis of aminocoumarin derivatives as DPP-IV inhibitors and anticancer agents

DPP-IV “a moonlighting protein” has immerged as promising pathway to control Type 2 diabetes as well as found to play key role in earlier stages of cancer. Here we have reported design, synthesis and applications of aminocoumarin derivatives as DPP-IV inhibitors. Compounds have been synthesized and studied for their DPP-IV inhibition activity. Three compounds have shown moderate inhibition at 100 µM concentration. All compounds were also screened for their anticancer activity against A549 (Lung cancer cell line), MCF-7 (Breast cancer cell line) using MTT assay. One of the compounds has shown very good anticancer activity with IC₅₀ value 24 ± 0.1 nM against A549 cell line.     

Synthesis and anthelmintic activity of arctigenin derivatives against Dactylogyrus intermedius in goldfish

To control the parasitic disease of Dactylogyrus intermedius, a series of new arctigenin derivatives were designed, synthesized and tested in our study. The anthelmintic activity of most of the derivatives ranged from 1 to 10 mg/L. Compared to traditional drug praziquantel (EC₅₀ = 2.69 mg/L), ether derivatives 2g and 2h exhibited slightly higher anti-parasitic activity, with the EC₅₀ values of 2.48 and 1.52 mg/L, respectively. Furthermore, the arctigenin-imidazole hybrids 4a and 4b also removed D. intermedius effectively, with the EC₅₀ values of 2.13 and 2.07 mg/L, respectively. The structure-activity relationship analysis indicated that four carbon atoms length of linker and imidazole substitute group could significantly increase the anthelmintic activity, and reduced the toxicity. Through the scanning electron microscope observation, compounds 4a and 4b caused the D. intermedius tegumental damage such as intensive wrinkles, holes and nodular structures. Overall, the structural optimization analysis of arctigenin suggested that 4a and 4b can be used for preventing and controlling Dactylogyrus infections and considered as promising lead compounds for the development of commercial drugs.     

Design and synthesis of biaryloxazolidinone derivatives containing a rhodanine or thiohydantoin moiety as novel antibacterial agents against Gram-positive bacteria

Novel biaryloxazolidinone derivatives containing a rhodanine or thiohydantoin moiety were designed, synthesized and evaluated for their antibacterial activity. The key compounds 7 and 9 were synthesized by the knoevenagel condensation of intermediate aldehyde 5 with rhodanine derivatives 6a?6b. The preliminary study showed that compounds 7, 9 and 10e exhibited potent antibacterial activity with MIC values of 0.125?µg/mL against S. aureus, MRSA, MSSA, LREF and VRE pathogens, using linezolid and radezolid as the positive controls. The most promising compound 10e exhibited potent antibacterial activity against tested clinical isolates of MRSA, MSSA, VRE and LREF with MIC values in the range of 0.125–0.5?µg/mL, and the potency of 10e against clinical isolates of LREF was 64-fold higher than that of linezolid. Moreover, compound 10e was non-cytotoxic with an IC₅₀ value of 91.04?μM against HepG2 cell. Together, compound 10e might serve as a novel antibacterial agent for further investigation.     

Design,synthesis and biological activity of pyrazinamide derivatives for anti-Mycobacterium tuberculosis

A total of 11 pyrazinamide derivatives were designed and synthesised using pyrazinamide as the lead compound, which was optimised by structural modification with alkyl chains, six-membered rings, and bioisosterism, respectively. The target compounds were synthesised using pyrazinecarboxylic acid as the starting material by acylation, amidation, and alkylation, respectively. Their structures were confirmed by ¹H NMR, ¹³C NMR, HRESIMS, and elemental analysis, respectively. The bioactivities of derivatives were assayed using bacteriostatic experiment and minimum inhibitory concentration experiment. It was showed that the derivatives had good inhibitory effect on Mycobacterium tuberculosis. The biological activity of derivative 1f was the best among all compounds, its antibacterial activity was 99.6%, and the minimum inhibitory concentration was 8.0?µg/mL.