The synthesis and antistaphylococcal activity of N-sulfonaminoethyloxime derivatives of dehydroabietic acid

A series of N-sulfonaminoethyloxime derivatives of dehydroabietic acid were synthesized and investigated for their antibacterial activity against Staphylococcus aureus Newman strain and multidrug-resistant strains (NRS-1, NRS-70, NRS-100, NRS-108 and NRS-271). Most of the target compounds having chloro, bromo, trifluoromethyl phenyl moiety exhibited potent in vitro antistaphylococcal activity. The meta-CF₃ phenyl derivative T23 showed the highest activity with MIC of 0.39–0.78?μg/mL against S. aureus Newman, while several analogues showed similar potent antibacterial activity with MIC values between 0.78 and 1.56?μg/mL against five multidrug-resistant S. aureus. The stability of T35 in plasma of SD rat and the cellular cytotoxicity were also evaluated.     

Design,synthesis, antiviral activity,and SARs of 13a-substituted phenanthroindolizidine alkaloid derivatives

On the basis of our previous structure–activity relationship (SAR) and antiviral mechanism studies, a series of 13a-substituted phenanthroindolizidine alkaloid analogues (3a–16a, 3b, 4b, 6b, 7b, 10b, and 14b) were designed targeting tobacco mosaic virus (TMV) RNA, synthesized, and evaluated for their antiviral activity against TMV for the first time. The bioassay results showed that most of the synthesized compounds (such as 4a, 6a, 7a, 11a, 14a, 6b, and 14b) exhibited good to excellent antiviral activity against TMV both in vitro and in vivo. Especially, for inactivation effect and curative effect, compounds 4a, 6a, 7a, 11a, 14a, and 14b showed higher activity at both concentrations (500 μg mL⁻¹ and 100 μg mL⁻¹) than commercial Ningnanmycin. Preliminary SARs showed that the substituted groups with hydrogen donor at 13a position were found to be favorable for keeping high antiviral activity. The present work demonstrates that 13a-substituted phenanthroindolizidines can be used as possible lead compounds for developing anti-TMV agents.     

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.     

Design,synthesis, and biological activity of novel tetrahydropyrazolopyridone derivatives as FXa inhibitors with potent anticoagulant activity

A series of novel tetrahydropyrazolopyridone derivatives containing 1,3,4-triazole, triazolylmethyl, and partially saturated heterocyclic moieties as P2 binding element was designed, synthesized, and evaluated in vitro for anticoagulant activity in human and rabbit plasma. All compounds showed moderate to significant potency, and compounds 15b, 15c, 20b, 20c, and 22b were further examined for their inhibitory activity against human FXa in vitro. While compounds 15c and 22b were tested for rat venous thrombosis in vivo. The most promising compound 15c, with an IC₅₀ (FXa) value of 0.14 μM and 98% inhibition rate, warranted further investigation as an FXa inhibitor.     

Design and synthesis of 21-alkynylaryl pregnenolone derivatives and evaluation of their anticancer activity

A series of novel C21-alkynylaryl derivatives of pregnenolone were synthesized and screened for anticancer activity against a panel of seven human cancer cell lines (LNCaP, A549, MCF7, HeLa, A431, HepG2, HT29). The data revealed that these compounds can be potential antitumour agents against the specific cell models. Compound 6f bearing a 2-trifluoromethylphenyl group displayed improved cytotoxicity towards all cancer cell lines used. A431 cells were the most sensitive with derivatives 6e–6h bearing electron withdrawing substituents exhibiting high potency with IC₅₀ values ranging between 2.18 and 0.54 μM and drastic inhibition of the prosurvival PI3K-Akt/PKB pathway.     

Design,synthesis and anti-influenza A virus activity of novel 2,4-disubstituted quinazoline derivatives

Four 2,4-disubstituted quinazoline series containing various amide moieties were designed and synthesized as new anti-influenza A virus agents using the strategies of bio-isosterism and scaffold hopping. Many of them exhibit potent in vitro anti-influenza A virus activity and low cytotoxicity (CC₅₀: >100 μM). Particularly, compounds 10a5 and 17a show better activity (IC₅₀: 3.70–4.19 μM) and higher selective index (SI: >27.03, >23.87, respectively) against influenza A/WSN/33 virus (H1N1), opening a new direction for quinazoline derivatives in anti-influenza A virus field.     

Design,synthesis and antifungal activity of amide and imine derivatives containing a kakuol moiety

In continuation of our program to discover new potential antifungal agents, a series of amide and imine derivatives containing a kakuol moiety were synthesized and characterized by the spectroscopic analysis. By using the mycelium growth rate method, the target compounds were evaluated systematically for antifungal activities in vitro against four plant pathogenic fungi, and structure–activity relationships (SAR) were derived. Compounds 7d, 7e, 7h, 7i and 7r showed obvious inhibitory activity against the corresponding tested fungi at 50 μg/mL. Especially, compounds 7e and 7r displayed more potent antifungal activity against B. cinerea than that of thiabendazole (a positive control). Moreover, compound 7e also exhibited good activity against A. alternata with EC₅₀ values of 11.0 µg/mL, and the value was slightly superior to that of thiabendazole (EC₅₀ = 14.9 µg/mL). SAR analysis showed that the ether group was a highly sensitive structural moiety to the activity and the type as well as position of substituents on benzene ring could make some effects on the activity.     

Design,synthesis and biological activity evaluation of novel 2,6-difluorobenzamide derivatives through FtsZ inhibition

Novel series of 3-substituted 2,6-difluorobenzamide derivatives as FtsZ inhibitors were designed, synthesized and evaluated for their in vitro antibacterial activity against various phenotype of Gram-positive and Gram-negative bacteria, and their cell division inhibitory activity against three representative strains. As a result, 3-chloroalkoxy derivative 7, 3-bromoalkoxy derivative 12 and 3-alkyloxy derivative 17 were found to exhibit the best antibacterial activity against Bacillus subtilis with MICs of 0.25–1 μg/mL, and good activity (MIC < 10 μg/mL) against both susceptible and resistant Staphylococcus aureus. Additionally, all the three compounds displayed potent cell division inhibitory activity with MIC values of below 1 μg/mL against Bacillus subtilis and Staphylococcus aureus.     

Design,synthesis and biological activity of flavonoid derivatives as selective agonists for neuromedin U 2 receptor

Central neuromedin U 2 receptor (NMU2R) plays important roles in the regulation of food intake and body weight. Identification of NMU2R agonists may lead to the development of pharmaceutical agents to treat obesity. Based on the structure of rutin, a typical flavonoid and one of the NMU2R agonists we previously identified from an in-house made natural product library, 30 flavonoid derivatives have been synthesized and screened on a cell-based reporter gene assay. A number of compounds were found to be selective and highly potent to NMU2R. For example, the EC₅₀ value of compound NRA 4 is very close to that of NMU, the endogenous peptide ligand of NMU2R. Structure–activity relationship analysis revealed that a 3-hydroxyl group in ring C and a 2′-fluoride group in ring B were essential for this class of compounds to be active against NMU2R.     

Design,synthesis and evaluation of activity and pharmacokinetic profile of new derivatives of xanthone and piperazine in the central nervous system

Searching for CNS active cyclic amines derivatives containing heterocyclic xanthone core we designed and synthesized a set of fourteen novel 2- or 4-methylxanthone substituted by alkyl- or aryl-piperazine moieties. The compounds were evaluated in vivo for their potential antidepressant-like activity (in the forced swim test) and anxiolytic-like activity (four-plate test) and their inhibitory effect against rat 5-HT₂ receptor was checked. The pharmacokinetic analysis of active compounds done by a non-compartmental approach have shown a rapid absorption of all studied molecules from intraperitoneal cavity and good penetration the blood-brain barrier after i.p. administration with brain to plasma ratios varied from 2.8 to 31.6. Genotoxicity and biotransformation of active compounds were studied. Compound 19 interactions with major classes of GPCRs, uptake systems and ion channels were tested and results indicated that it binds to 5-HT_2A, 5-HT_2B receptors and sodium channels.     

Design,synthesis, and biological activity evaluation of a series of pleuromutilin derivatives with novel C14 side chains

In this work, according to the ‘me-too me-better’ design strategy, a peculiar side chain different from lefamulin at C14 position of pleuromutilin was introduced. A series of novel thioether pleuromutilin derivatives containing cyclohexane in the C14 chain was synthesized by ten-step synthesis reaction. All derivatives were characterized by Nuclear Magnetic Resonance (NMR) and High Resolution Mass Spectrometer (HRMS). Furthermore, majority of derivatives displayed moderate antibacterial activity in vitro. However, the compound 2C and 2J exhibited comparable or superior antibacterial activity to lefamulin. The summarized structure-activity relationship not only made the variety of pleuromutilin derivatives more diverse, but also provided new ideas for its design and development.     

Design,synthesis, biological activities,and dynamic simulation study of novel thiourea derivatives with gibberellin activity towards Arabidopsis thaliana

Computer-aided drug design has advanced by leaps and bounds, and has been widely used in various fields, and especially in the field of drug discovery. Although the crystal structure of the gibberellin (GA) receptor GID1A had been reported in previous studies, there is still a lack of designs of gibberellin functional analogue based GID1A. In the present study, a series of 30 thiourea derivatives were designed, synthesized and biologically assayed. The results suggested that the synthetic compounds had good GA-like activities. Furthermore, the structure-activity relationship of the synthetic compounds was discussed, and the dynamic simulation and docking study revealed the binding properties of the GID1A receptor and compounds Y1, Y11, and Y21.     

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 antimycobacterial activity evaluation of natural oridonin derivatives

In an effort to develop novel potent antitubercular drugs, thirty-one oridonin derivatives were designed and prepared. All the compounds obtained were screened for their in vitro activities against Mycobacterium phlei, Mycobacterium smegmatis and Mycobacterium marinum. Among them, thirteen compounds showed significant inhibitory activity against M. phlei with MICs less than 2 μg/mL. Compounds 2k, 8d, 10c, 10d containing trans-cinnamic acid moiety were the most potent (MIC = 0.5 μg/mL), comparable to the well-known antitubercular drug streptomycin. The preliminary structure–activity relationships (SARs) were also analyzed.     

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.     

Design,synthesis and biological evaluation of novel pyrrole derivatives as potential ClpP1P2 inhibitor against Mycobacterium tuberculosis

In an effort to discover novel inhibitors of M. tuberculosis Caseinolytic proteases (ClpP1P2), a combination strategy of virtual high-throughput screening and in vitro assay was employed and a new pyrrole compound, 1-(2-chloro-6-fluorobenzyl)-2, 5-dimethyl-4-((phenethylamino)methyl)-1H-pyrrole-3-carboxylate was found to display inhibitory effects against H₃₇Ra with an MIC value of 77 µM. In order for discovery of more potent anti-tubercular agents that inhibit ClpP1P2 peptidase in M. tuberculosis, a series of pyrrole derivatives were designed and synthesized based on this hit compound. The synthesized compounds were evaluated for in vitro studies against ClpP1P2 peptidase and anti-tubercular activities were also evaluated. The most promising compounds 2-(4-bromophenyl)-N-((1-(2-chloro-6-fluorophenyl)-2, 5-dimethyl-1H- pyrrolyl)methyl)ethan-1-aminehydrochloride 7d, ethyl 4-(((4-bromophenethyl) amino) methyl)-2,5-dimethyl-1-phenyl-1H-pyrrole-3-carboxylate hydrochloride 13i, ethyl 1-(4-chlorophenyl)-4-(((2-fluorophenethyl)amino)methyl)-2-methyl-5-phenyl-1H-pyrrole-3-carboxylate hydrochloride 13n exhibited favorable anti-mycobacterial activity with MIC value at 5 µM against Mtb H₃₇Ra, respectively.     

Design,synthesis and antifungal activity evaluation of isocryptolepine derivatives

In this paper, the nitrogen atom was inserted into the anthracycline system of the isocryptolepine nucleus to obtain the “Aza”-type structure benzo[4,5]imidazo[1,2-c] quinazoline. A series of “Aza”-type derivatives were designed, synthesized and evaluated for their antifungal activity against six plant fungi in vitro. Among all derivatives, compounds A-0, B-1 and B-2 showed significant antifungal activity against B. cinerea with the EC₅₀ values of 2.72 μg/mL, 5.90 μg/mL and 4.00 μg/mL, respectively. Compound A-2 had the highest activity against M. oryzae with the EC₅₀ values of 8.81 μg/mL, and compound A-1 demonstrated the most control efficacy against R. solani (EC₅₀, 6.27 μg/mL). Moreover, compound A-0 was selected to investigate the in vivo tests against B. cinerea and the results indicated that the preventative efficacy of it up to 72.80% at 100 μg/mL. Preliminary mechanism studies revealed that after treatment with A-0 at 5 µg/mL, the B. cinerea mycelia appeared curved, collapsed and the cell membrane integrity may be damaged. The reactive oxygen species production, mitochondrial membrane potential and nuclear morphometry of mycelia have been changed, and the membrane function and cell proliferation of mycelia were destroyed. Compounds A-0, A-1, B-1 and B-2 presented weaker toxicities against two cells lines than isocryptolepine. This study lays the foundation for the future development of isocryptolepine derivatives as environmentally friendly and safe agricultural fungicides.     

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.     

Novel amide derivatives containing 1,3,4-thiadiazole moiety: Design,synthesis, nematocidal and antibacterial activities

A series of novel amide derivatives containing 1,3,4-thiadiazole moiety were synthesized and their bioactivities were evaluated. The compound 34 exhibited good nematocidal activities against Meloidogyne incognita in vitro and in vivo, the LC₅₀ value and control effect were 6.5?mg/L and 83.3%, respectively. Meanwhile, it exhibited exciting antibacterial activities against Xanthomonas oryzae pv. oryzae, Xanthomonas campestris pv. citri, and Ralstonia solanacearum, the EC₅₀ values were 0.4, 6.7 and 5.1?mg/L, respectively, which were better than positive controls. The curative and protection activities under the greenhouse conditions of compound 34 against rice bacterial blight were 47.9 and 55.8%, respectively. The structure-activity relationship were analyzed in detail.     

Novel amidrazone derivatives: Design,synthesis and activity evaluation

A series of new 6-styryl-naphthalene-2-amidrazone derivatives were synthesized and evaluated as potential ASIC1a inhibitors. Among them, compound 5e showed the most activity to inhibit [Ca²⁺]_i. elevation in acid-induced articular chondrocytes. Together with the important role of ASIC1a in the pathogenesis of tissue acidification diseases including rheumatoid arthritis, these results might provide a meaningful hint or inspiration in developing drugs targeting at tissue acidification diseases.