Natural products-based insecticidal agents 7. Semisynthesis and insecticidal activity of novel 4α-alkyloxy-2-chloropodophyllotoxin derivatives against Mythimna separata Walker in vivo

In continuation of our program aimed at the discovery and development of natural products-based insecticidal agents, 16 novel 4α-alkyloxy-2-chloropodophyllotoxin derivatives were semisynthesized from podophyllotoxin, and preliminarily evaluated for their insecticidal activity against the pre-third-instar larvae of Mythimna separata Walker in vivo. Among all the tested derivatives, especially compounds 4b, 4e, 4g, and 4p exhibited more promising and pronounced insecticidal activity than toosendanin, a commercial insecticide derived from Melia azedarach. Generally, it was obviously demonstrated that the length of straight-chain or branched-chain alkyloxy, and heteroatom-containing cycloalkyloxy at the C-4 position of 2-chloropodophyllotoxin were very important for the insecticidal activity.     

Natural products-based insecticidal agents 5. Design,semisynthesis and insecticidal activity of novel 4′-substituted benzenesulfonate derivatives of 4-deoxypodophyllotoxin against Mythimna separata Walker in vivo

In an attempt to find the effective phytopesticides, eight novel 4′-substituted benzenesulfonate derivatives of 4-deoxypodophyllotoxin were synthesized and preliminarily tested against the pre-third-instar larvae of Mythimna separata Walker in vivo at the concentration of 1 mg/mL. Among all of the tested analogs, compounds 5a, 5c, 5d, and 5h showed the higher insecticidal activity than 4-deoxypodophyllotoxin. Especially 5a exhibited the most potent insecticidal activity compared with toosendanin, a commercial insecticide derived from Melia azedarach.     

Synthesis of 4β-acyloxypodophyllotoxin analogs modified in the C and E rings as insecticidal agents against Mythimna separata Walker

To discover the new natural-product-based insecticidal agents, four series of sixty novel 4β-acyloxypodophyllotoxin analogs modified in the C and E rings were prepared, and their insecticidal activity was tested against the pre-third-instar larvae of oriental armyworm, Mythimna separata (Walker) in vivo at the concentration of 1 mg/mL. It demonstrated that the position of the dioxo group on the E-ring of 4′-demethylepipodophyllotoxin was regioselectively controlled by the chlorine atom at its C-2′ position when 2′-chloro-4′-demethylepipodophyllotoxin was oxidized by sodium periodate. Among all the derivatives, IIIi exhibited the best potent insecticidal activity with the final mortality rate of 63.3%. To alkylacyloxy series, the proper length of the side chain at the C-4 position of Ia–g, IIa–g and IIIa–g was important for their insecticidal activity.     

Synthesis of some ester derivatives of 4′-demethoxyepipodophyllotoxin/2′-chloro-4′-demethoxyepipodophyllotoxin as insecticidal agents against oriental armyworm,Mythimna separata Walker

Podophyllotoxin is a naturally occurring non-alkaloid toxin isolated from the roots and rhizomes of Podophyllum peltatum and P. hexandrum. In continuation of our program aimed at the discovery and development of natural product-based insecticides, two series of ester derivatives of 4′-demethoxyepipodophyllotoxin/2′-chloro-4′-demethoxyepipodophyllotoxin were prepared. The structures of the target compounds were well characterized by 1H NMR, IR, optical rotation and mp. The precise three-dimensional structural information of 8j was further determined by single-crystal X-ray diffraction. Their insecticidal activity was tested against Mythimna separata Walker. These compounds showed delayed insecticidal activity. Among all derivatives, some compounds showed more potent insecticidal activity than toosendanin against M. separata; especially compounds 8k and 9k exhibited the most potent activity with the final mortality rates of 71.4%. Their structure–activity relationships were discussed.     

Synthesis and structure–activity relationship of novel cinnamamide derivatives as antidepressant agents

Cinnamamide 3a, a leading compound with antidepressant-like activity, and its derivatives were synthesized and their antidepressant activity and structure–activity relationship were investigated. Most of the compounds with trifluoromethyl group in methylenedioxyphenyl moiety (3f, 4b–c and 6a–b) exhibited significant antidepressant activity, measured in terms of percentage decrease in immobility duration by tail suspension test. In addition, the dose-dependent antidepressant effect of the most potent compound 3f was subsequently confirmed in tail suspension test and forced swim test. The test results showed that 3f was equal to or more effective than the standard drug fluoxetine at a concentration of 10 mg/kg. Furthermore, compound 3f did not show any central nervous system stimulant properties in the open-field test and the preliminary results were promising enough to warrant further detailed antidepressant research around this scaffold.     

Synthesis and antibacterial activity of 4″,11-di-O-arylalkylcarbamoyl azithromycin derivatives

A series of new 4″,11-di-O-arylalkylcarbamoyl azithromycin derivatives were designed, synthesized and evaluated for their in vitro antibacterial activities. Some derivatives exhibited greatly improved activity against erythromycin-resistant bacteria. Among them, compounds 5f and 5k were found to have potent activity against erythromycin-resistant Streptococcus pneumoniae whose resistance was encoded by the erm or mef gene.     

Synthesis and anti-leishmanial activity of 1-aryl-β-carboline derivatives against Leishmania donovani

β-carbolines from various natural and synthetic sources have been known to show diverse biological activities. As a part of our current ongoing project to search for potent natural product-derived anti-leishmanial compounds, we have synthesized a series of substituted 1-aryl-β-carboline derivatives. A total of 22 compounds were synthesized and tested in vitro against Leishmania donovani, out of which 6 compounds (4, 5, 10, 11, 19 and 22) showed notably more activity than the standard miltefosine (IC(50) 12.07±0.82 μM), with compound 4 being the most potent (IC(50) 2.16±0.26 μM).     

Synthesis of novel strobilurin–pyrimidine derivatives and their antiproliferative activity against human cancer cell lines

A series of new strobilurin–pyrimidine analogs were designed and synthesized based on the structures of our previously discovered antiproliferative compounds I and II. Biological evaluation with two human cancer cell lines (A549 and HL60) showed that most of these compounds possessed moderate to potent antiproliferative activity. Two potent candidates (8f, IC₅₀ = 2.2 nM and 11d, IC₅₀ = 3.4 nM) were identified with nanomolar activity against leukemia cancer cell line HL60 for further development. This activity represents a 1000- to 2500-fold improvement compared to the parent compounds I and II and is 20- to 30-fold better than the chemotherapy drug, doxorubicin. The present work provides strong incentive for further development of these strobilurin–pyrimidine analogs as potential antitumor agents for the treatment of leukemia.     

Synthesis and structure–activity relationship of 4-azaheterocycle benzenesulfonamide derivatives as new microtubule-targeting agents

A series of 1-sulfonyl indolines was synthesized and evaluated for antiproliferative activity. The most potent compounds 9a and 9e showed significant cytotoxicity (IC₅₀ in the range of 0.055–0.105 and 0.039–0.112 μM, respectively) against four human cancer cell lines HCT116, PC3, HepG2 and SK-OV-3. The structure–activity relationship of this series of sulfonamides, including the influence of azaheterocycle rings, substituent at the different positions of indoline, and the cyclopropane moiety, was described.     

Synthesis and 2D QSAR of O-sulphonated β-aminols derivatives as novel antifungal and antibacterial agents

Synthesis of a series of β-aminol derivatives using regioselective opening reaction catalyzed by SiO(2) (60-120mesh) and O-sulphonation in THF-KOH system, comprising tert-butoxycarbonyl at secondary nitrogen and evaluate for various stains of bacteria and fungi. SAR study of synthesized compound using backward regression analysis.     

Synthesis and biological evaluation of 9α- and 9β-hydroxyamino-parthenolides as novel anticancer agents

A series of 9α-hydroxyamino-parthenolides 3–10, 9β-hydroxyamino-parthenolides 11–13 and 9α-hydroxy-1β,10α-epoxyamino-parthenolides 15–19 were efficiently synthesized starting from 9α-hydroxyparthenolide 1 and 9β-hydroxyparthenolide 2, which were isolated from Anvillea radiata. Compounds 1–13 and 15–19 were evaluated for their in vitro anticancer activity by the MTT colorimetric assay against one murine and six human cancer cell lines. This work provides new details about the structural requisites for anticancer activity.     

Synthesis,in vitro structure–activity relationship,and in vivo studies of 2-arylthiazolidine-4-carboxylic acid amides as anticancer agents

A series of (2RS,4R)-2-arylthiazolidine-4-carboxylic acid amide (ATCAA) was synthesized. Antiproliferative activity against melanoma and prostate cancer cells compared with control cells (fibroblast and RH7777, respectively) was evaluated. Compound 3id showed the best selectivity and growth-inhibition activity against three melanoma cell lines (B16-F1, A375, and WM-164). Compounds 15b and 3ac had good selectivity and potency against four prostate cancer cell lines (DU 145, PC-3, LNCaP, and PPC-1). The structure–activity relationship (SAR) of the side chain, the thiazolidine ring, and phenyl substituents is discussed. Cell cycle analysis showed that the percentage of cancer cells undergoing apoptosis (sub-G1 phase) increased after treatment with 1b and 3ad, which also strongly inhibited melanoma colony formation. In vivo studies on nude mice bearing A375 melanoma tumors showed that compound 1b inhibited tumor growth in a dose-dependent manner. At a dose of 10 mg/kg, 1b significantly inhibited melanoma tumor growth and showed higher efficacy than did dacarbazine at 60 mg/kg.     

Synthesis,structure–activity relationships and biological evaluation of dehydroandrographolide and andrographolide derivatives as novel anti-hepatitis B virus agents

Dehydroandrographolide and andrographolide, two natural diterpenoids isolated from Andrographis paniculata possessed activity against HBV DNA replication with IC₅₀ values of 22.58 and 54.07 μM and low SI values of 8.7 and 3.7 in our random assay. Consequently, 48 derivatives of dehydroandrographolide and andrographolide were synthesized and evaluated for their anti-HBV properties to yield a series of active derivatives with lower cytotoxicity, including 14 derivatives against HBsAg secretion, 19 derivatives against HBeAg secretion and 38 derivatives against HBV DNA replication. Interestingly, compound 4e could inhibit not only HBsAg and HBeAg secretions but also HBV DNA replication with SI values of 20.3, 125.0 and 104.9. Furthermore, the most active compound 2c with SI value higher than 165.1 inhibiting HBV DNA replication was revealed with the optimal log P value of 1.78 and log D values. Structure–activity relationships (SARs) of the derivatives were disclosed for guiding the future research toward the discovery of new anti-HBV drugs.     

Synthesis, antiproliferative activity in cancer cells and theoretical studies of novel 6α,7β-dihydroxyvouacapan-17β-oic acid Mannich base derivatives

Natural products are great prototypes for the design of new anticancer agents. The plant-derived natural product 6α,7β-dihydroxyvouacapan-17β-oic acid (1) is promising for the development of more potent antiproliferative agents against human cancer cells. Indeed, its lactone derivative 6α-hydroxyvouacapan-7β,17β-lactone (2), a non-natural furanoditerpene, exhibited higher anticancer activity than compound 1. Herein, we describe the synthesis and antiproliferative activity of six new Mannich derivatives of compound 2 against nine cancer cell lines. Overall, our results revealed that Mannich derivatives 3-8 were more potent than compound 2 in inhibiting the proliferation of cancer cells. Theoretical studies also supported our findings, revealing the nucleophilic character of furan ring as an important feature for antiproliferative activity of the studied Mannich derivatives.     

Synthesis and biological evaluation of novel 4β-(1,3,4-oxadiazole-2-amino)-podophyllotoxin derivatives

A series of new 4β-(1,3,4-oxadiazole-2-amino)-podophyllotoxin derivatives were designed and synthesized. Their cytotoxicity in vitro against six tumor cell lines (DU-145, SGC-7901, A549, SH-SY5Y, HepG2 and HeLa) were evaluated by standard MTT assay. The pharmacological results showed that most of the newly synthesized podophyllotoxin derivatives displayed potent cytotoxicity against at least one of the tested tumor cells; and among the new derivatives, 11b was more potent than podophyllotoxin against HepG2 and Hela cell lines. Furthermore, 11b exhibited much better selectivity toward the normal cell lines L929 and Vero than etoposide, 5-Fu and podophyllotoxin. The possible antitumor mechanism of 11b is to inhibit the activity of DNA topoisomerase II, result in the S-phase arrest, and then cause apoptotic cell death.     

Synthesis and QSAR study of novel α-methylene-γ-butyrolactone derivatives as antifungal agents

Thirty-six new α-benzylidene-γ-lactone compounds based α-methylene-γ-butyrolactone substructure were prepared and characterized by spectroscopic analysis. All compounds were evaluated for antifungal activities in vitro against six plant pathogenic fungi and the half maximal inhibitory concentration (IC₅₀) against Botrytis cinerea and Colletotrichum lagenarium were investigated. Compounds 5c-3 and 5c-5 with the halogen atom exhibited excellent fungicidal activity against B. cinerea (IC₅₀ = 22.91, 18.89 μM). The structure-activity relationships (SARs) analysis indicated that the derivatives with electron-withdrawing substituents at the meta- or para-positions improves the activity. Via the heuristic method, the generated quantitative structure-activity relationship (QSAR) model (R² = 0.961) revealed a strong correlation of antifungal activity against B. cinerea with molecular structures of these compounds. Meanwhile, the cytotoxicity of 20 representative derivatives was tested in the human tumor cells line (HepG2) and the hepatic L02 cells line, the result indicated that the synthesized compounds showed significant inhibitory activity and limited selectivity. Compound 5c-5 has the highest fungicidal activity with IC₅₀ = 18.89 μM (against B. cinerea.) but low cytotoxicity with IC₅₀ = 35.4 μM (against HepG2 cell line) and IC₅₀ = 68.8 μM (against Hepatic L02 cell line). These encouraging results can be providing an alternative, promising use of α-benzylidene-γ-lactone through the design and exploration of eco-friendly fungicides with low toxicity and high efficiency.     

Synthesis of derivatives of cleistopholine and their anti-acetylcholinesterase and anti-β-amyloid aggregation activity

A series of 6- and 9-substituted cleistopholine derivatives has been designed, synthesized and investigated to inhibit the aggregation of acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and β-myloid (A β). Results showed that these synthetic compounds had excellent AChE inhibitory activity and a significant in vitro inhibitory potency toward the self-induced A β aggregation. When SH-SY5Y cells were treated with these substituted cleistopholine derivatives during they overexpressed the Swedish mutant form of human β -amyloid precursor protein (APPsw), A β 42 secretion levels were significantly reduced. According to a parallel artificial membrane permeation assay for BBB, seven out of these sixteen synthetic compounds probably could cross the blood-brain barrier (BBB) to reach their targets in the central nervous system (CNS).     

Synthesis and antihormonal properties of novel 11β-benzoxazole-substituted steroids

Early studies led to the identification of 11β-aryl-4',5'-dihydrospiro[estra-4,9-diene-17β,4'-oxazole] analogs with potent and more selective antiprogestational activity compared to antiglucocorticoid activity than mifepristone. In the present study, we replaced the 4'-dimethylaminophenyl group of mifepristone with the benzoxazol group to give 5a-d. We also prepared the 17β-formamido analogs 6a,b using a new synthetic strategy via the intermediate epoxide 21. These compounds were evaluated for their antagonist hormonal properties using the T47D cell-based alkaline phosphatase assay and the A549 cell-based functional assay. Compound 5c showed potent antagonist activity at GR with better selectivity for GR versus PR than mifepristone and is a promising lead for further development.     

Synthesis and anticancer activity of heteroaromatic linked 4β-amido podophyllotoxins as apoptotic inducing agents

A series of different heteroaromatic linked 4β-amidopodophyllotoxin conjugates (16a–i, 17a–i and 18a–d) were synthesized and evaluated for anticancer activity against five human cancer cell lines. Among the series, one of the compound 17g showed significant antiproliferative activity in A549 (lung cancer) cell line. Flow cytometric analysis showed that 17g arrested the cell cycle in the G2/M phase leading to caspase-3 dependent apoptotic cell death. Further, Hoechst 33258 staining and DNA fragmentation assay also suggests that 17g induces cell death by apoptosis.     

Synthesis and structure–activity relationships evaluation of benzothiazinone derivatives as potential anti-tubercular agents

N-Alkyl and heterocycle substituted 1,3-benzothiazin-4-one (BTZ) derivatives were synthesized. The anti-mycobacterial activities of these compounds were evaluated by determination of minimal inhibitory concentration (MIC) for Mycobacterium tuberculosis H37Ra and M. tuberculosis H37Rv. It was found that an extended or branched alkyl chain analog could enhance the potency, and activities of N-alkyl substituted BTZs were not affected by either nitro or trifluoromethyl at 6-position. Trifluoromethyl plays an important role in maintaining anti-tubercular activity in the piperazine or piperidine analogs. Compound 8o, which contains an azaspirodithiolane group, showed a MIC of 0.0001 μM against M. tuberculosis H37Rv, 20-fold more potent than BTZ043 racemate. These results suggested that the volume and lipophilicity of the substituents were important in maintaining activity. In addition, compound 8o was nontoxic to Vero cells and orally bioavailable in a preliminary pharmacokinetics study.