Design,synthesis and anticancer activity of novel nopinone-based thiosemicarbazone derivatives

A series of new nopinone-based thiosemicarbazone derivatives were designed and synthesized as potent anticancer agents. All these compounds were identified by ¹H NMR, ¹³C NMR, HR-MS spectra analyses. In the in vitro anticancer activity, most derivatives showed considerable cytotoxic activity against three human cancer cell lines (MDA-MB-231, SMMC-7721 and Hela). Among them, compound 4i exhibited most potent antitumor activity against three cancer cell lines with the IC₅₀ values of 2.79 ± 0.38, 2.64 ± 0.17 and 3.64 ± 0.13 μM, respectively. Furthermore, the cell cycle analysis indicated that compound 4i caused cell cycle arrest of MDA-MB-231 cells at G2/M phase. The Annexin V-FITC/7-AAD dual staining assay also revealed that compound 4i induced the early apoptosis of MDA-MB-231 cells.     

Synthesis and in vitro cytotoxic evaluation of new 1H-benzo[d]imidazole derivatives of dehydroabietic acid

A series of new 1H-benzo[d]imidazole derivatives of dehydroabietic acid were designed and synthesized as potent antitumor agents. Structures of the target molecules were characterized using MS, IR, ¹H NMR, ¹³C NMR and elemental analyses. In the in vitro cytotoxic assay, most compounds showed significant cytotoxic activities against two hepatocarcinoma cells (SMMC-7721 and HepG2) and reduced cytotoxicity against noncancerous human hepatocyte (LO2). Among them, compound 7b exhibited the best cytotoxicity against SMMC-7721 cells (IC₅₀: 0.36 ± 0.13 μM), while 7e was most potent to HepG2 cells (IC₅₀: 0.12 ± 0.03 μM). The cell cycle analysis indicated that compound 7b caused cell cycle arrest of SMMC-7721 cells at G2/M phase. Further, compound 7b also induced the apoptosis of SMMC-7721 cells in Annexin V-APC/7-AAD binding assay.     

Design,synthesis and in vitro anticancer activity of novel quinoline and oxadiazole derivatives of ursolic acid

A series of new quinoline derivatives of ursolic acid were designed and synthesized in an attempt to develop potential anticancer agents. The structures of these compounds were identified by ¹H NMR, ¹³C NMR, IR and ESI-MS spectra analysis. The target compounds were evaluated for their in vitro cytotoxicity against three human cancer cell lines (MDA-MB-231, Hela and SMMC-7721). From the results, compounds 3a–d displayed significant antitumor activity against three cancer cell lines. Especially, compound 3b was found to be the most potent derivative with IC₅₀ values of 0.61 ± 0.07, 0.36 ± 0.05, 12.49 ± 0.08 μM against MDA-MB-231, HeLa and SMMC-7721 cells, respectively, stronger than positive control etoposide. Furthermore, the Annexin V-FITC/PI dual staining assay revealed that compound 3b could significantly induce the apoptosis of MDA-MB-231 cells in a dose-dependent manner. The cell cycle analysis also indicated that compound 3b could cause cell cycle arrest of MDA-MB-231 cells at G0/G1 phase.     

Discovery of a cobalt complex with high MEK1 binding affinity

A series of Schiff base ligands (L¹–L⁵) and their cobalt(II) complexes (1–5) were designed and synthesized for MEK1 binding experiment. The biological evaluation results showed that Bis(N,N′-disalicylidene)-3,4-phenylenediamine-cobalt(II) 1 and Bis(N,N′-disalicylidene)-1,2-cyclohexanediamine-cobalt(II) 2 are much more effective than the parent Schiff bases (L¹ and L²). Importantly, 2 exhibited MEK1 binding affinity with IC₅₀71 nM, which is so far the best result for metal complexes and more potent than U0126 (7.02 μM) and AZD6244 (2.20 μM). Docking study was used to elucidate the binding modes of complex 2 with MEK1. Thus cobalt(II) complex 2 may be further developed as a novel MEK1 inhibitor.     

Cyclic ferrocenylnaphthalene diimide derivative as a new class of G-quadruplex DNA binding ligand

To identify an effective ligand that binds to a G-quadruplex structure but not a double-stranded DNA (dsDNA), a set of biophysical and biochemical experiments were carried out using newly synthesized cyclic ferrocenylnaphthalene diimide (cFNDI, 1) or the non-cyclic derivative (2) with various structures of G-quadruplex DNAs and dsDNA. Compound 1 bound strongly to G-quadruplexes DNAs (10⁶ M^?1 order) with diminished binding to dsDNA (10⁴ M^?1 order) in 100 mM AcOH-AcOK buffer (pH 5.5) containing 100 mM KCl. Interestingly, 1 showed an approximately 50-fold higher selectivity to mixed hybrid-type telomeric G-quadruplex DNA (K = 3.4 × 10⁶ M^?1 and a 2:1 stoichiometry) than dsDNA (K = 7.5 × 10⁴ M^?1) did. Furthermore, 1 showed higher thermal stability to G-quadruplex DNAs than it did to dsDNA with a preference for c-kit and c-myc G-quadruplex DNAs over telomeric and thrombin binding aptamers. Additionally, 1 exhibited telomerase inhibitory activity with a half-maximal inhibitory concentration (IC₅₀) of 0.4 μM. Compound 2 showed a preference for G-quadruplex; however, the binding affinity magnitude and preference were improved in 1 because the former had a cyclic structure.     

Design,synthesis and cytotoxic activities of scopoletin-isoxazole and scopoletin-pyrazole hybrids

12 novel scopoletin-isoxazole and scopoletin-pyrazole hybrids were designed, synthesized and their chemical structures were confirmed by HR-MS, IR, ¹H NMR and ¹³C NMR spectra. The anticancer activities of the newly synthesized compounds were evaluated in vitro against three human cancer cell lines including HCT-116, Hun7 and SW620 by MTT assay. The screening results showed that six compounds (9a, 9c, 9d, 12a, 18b and 18d) exhibited potent cytotoxic activities with IC₅₀ values below 20 μM. Besides, we have further evaluated the growth inhibitory activities of six compounds against the human normal tissue cell lines HFL-1. Especially, compound 9d displayed significant anti-proliferative activity with IC₅₀ values ranging from 8.76 μM to 9.83 μM and weak cytotoxicity with IC₅₀ value of 90.9 μM on normal cells HFL-1, which suggested that isoxazole-based hybrids of scopoletin were an effective chemical modification to improve the anticancer activity of scopoletin.     

Synthesis and hyperpolarisation of eNOS substrates for quantification of NO production by 1H NMR spectroscopy

Hyperpolarization enhances the intensity of the NMR signals of a molecule, whose in vivo metabolic fate can be monitored by MRI with higher sensitivity. SABRE is a hyperpolarization technique that could potentially be used to image nitric oxide (NO) production in vivo. This would be very important, because NO dysregulation is involved in several pathologies, including cardiovascular ones. The nitric oxide synthase (NOS) pathway leads to NO production via conversion of l-arginine into l-citrulline. NO is a free radical gas with a short half-life in vivo (≈5 s), therefore direct NO quantification is challenging. An indirect method – based on quantifying conversion of an l-Arg- to l-Cit-derivative by ¹H NMR spectroscopy – is herein proposed. A small library of pyridyl containing l-Arg derivatives was designed and synthesised. In vitro tests showed that compounds 4a–j and 11a–c were better or equivalent substrates for the eNOS enzyme (NO₂^? production = 19–46 μM) than native l-Arg (NO₂^? production = 25 μM). Enzymatic conversion of l-Arg to l-Cit derivatives could be monitored by ¹H NMR. The maximum hyperpolarization achieved by SABRE reached 870-fold NMR signal enhancement, which opens up exciting future perspectives of using these molecules as hyperpolarized MRI tracers in vivo.     

Synthesis,biological evaluation and molecular docking studies of chromone hydrazone derivatives as α-glucosidase inhibitors

A series of chromone hydrazone derivatives 4a–4p have been synthesized, characterized by ¹H NMR and ¹³C NMR and evaluated for their in vitro α-glucosidase inhibitory activity. Out of these tested compounds, six (4a, 4b, 4d, 4j, 4o and 4p) displayed potent α-glucosidase inhibitory activity with IC₅₀ values in the range of 20.1 ± 0.19 μM to 45.7 ± 0.23 μM, as compared to the standard drug acarbose (IC₅₀ = 817.38 ± 6.27 μM). Among this series, compound 4d (IC₅₀ = 20.1 ± 0.19 μM) with 4-sulfonamide substitution at phenyl part of hydrazide was found to be the most active compound. Lineweaver-Burk plot analysis indicated that compound 4d is a non-competitive inhibitor of α-glucosidase. The binding interactions of the most active analogs were confirmed through molecular docking studies. Docking studies showed 4d are interacting with the residues Glu-276, Asp-214, Asp-349 and Arg-439 through hydrogen bonds, arene-anion and arene-cation interactions. In summary, our studies shown that these chromone hydrazone derivatives are a new class of α-glucosidase inhibitors.     

Antileishmanial potential of fused 5-(pyrazin-2-yl)-4H-1,2,4-triazole-3-thiols: Synthesis,biological evaluations and computational studies

A series of newer 1,2,4-triazole-3-thiol derivatives 5(a–m) and 6(a–i) containing a triazole fused with pyrazine moiety of pharmacological significance have been synthesized. All the synthesized compounds were screened for their in vitro antileishmanial and antioxidant activities. Compounds 5f (IC₅₀ = 79.0 µM) and 6f (IC₅₀ = 79.0 µM) were shown significant antileishmanial activity when compared with standard sodium stibogluconate (IC₅₀ = 490.0 µM). Compounds 5b (IC₅₀ = 13.96 µM) and 6b (IC₅₀ = 13.96 µM) showed significant antioxidant activity. After performing molecular docking study and analyzing overall binding modes it was found that the synthesized compounds had potential to inhibit L. donovani pteridine reductase 1 enzyme. In silico ADME and metabolic site prediction studies were also held out to set an effective lead candidate for the future antileishmanial and antibacterial drug discovery initiatives.     

Study of antileishmanial activity of 2-aminobenzoyl amino acid hydrazides and their quinazoline derivatives

A new small library of 2-aminobenzoyl amino acid hydrazide derivatives and quinazolinones derivatives was synthesized and fully characterized by IR, NMR, and elemental analysis. The activity of the prepared compounds on the growth of Leishmania aethiopica promastigotes was evaluated. 2-Benzoyl amino acid hydrazide showed higher inhibitory effect than the quinazoline counterpart. The in vitro antipromastigote activity demonstrated that compounds 2a, 2b, 2f and 4a had IC₅₀ better than standard drug miltefosine and comparable activity to amphotericin B deoxycholate, which indicates their high antileishmanial activity against Leishmania. aethiopica. Among the prepared compounds; 2-amino-N-(6-hydrazinyl-6-oxohexyl)benzamide 2f (IC₅₀ = 0.051 μM) has the best activity, 154 folds more active than reference standard drug miltefosine (IC₅₀ = 7.832 μM), and half fold the activity of amphotericin B (IC₅₀ = 0.035 μM). In addition, this compound was safe and well tolerated by experimental animals orally up to 250 mg/kg and parenterally up to 100 mg/kg.     

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.     

Synthesis and biological activity of novel tert-amylphenoxyalkyl (homo)piperidine derivatives as histamine H3R ligands

As a continuation of our search for novel histamine H₃ receptor ligands a series of twenty new tert-amyl phenoxyalkylamine derivatives (2–21) was synthesized. Compounds of four to eight carbon atoms spacer alkyl chain were evaluated on their binding properties at human histamine H₃ receptor (hH₃R). The highest affinities were observed for pentyl derivatives 6–8 (K_i = 8.8–23.4 nM range) and among them piperidine derivative 6 with K_i = 8.8 nM. Structures 6, 7 were also classified as antagonists in cAMP accumulation assay (with EC₅₀ = 157 and 164 nM, respectively). Moreover, new compounds were also evaluated for anticonvulsant activity in Antiepileptic Screening Program (ASP) at National Institute of Neurological Disorders and Stroke (USA). Seven compounds (2–4, 9, 11, 12 and 20) showed anticonvulsant activity at maximal electroshock (MES) test in the dose of 30 mg/kg at 0.5 h. In the subcutaneous pentetrazole (scMET) test compound 4 showed protection at 100 and 300 mg/kg dose at mice, however compounds showed high neurotoxicity in rotarod test at used doses. Also, molecular modeling studies were undertaken, to explain affinity of compounds at hH₃R (taking into the consideration X-ray analysis of compound 18). In order to estimate “drug-likeness” of selected compounds in silico and experimental evaluation of lipophilicity, metabolic stability and cytotoxicity was performed.     

Design,synthesis and herbicidal activity study of aryl 2,6-disubstituted sulfonylureas as potent acetohydroxyacid synthase inhibitors

A series of sulfonylurea derivatives containing a 2,6-disubstituted aryl moiety were designed, synthesized and evaluated for their herbicidal activities. Most of these compounds showed excellent inhibitory rates against both monocotyledonous and dicotyledonous weeds, especially 10a, 10h and 10i. They exhibited equivalent or superior herbicidal efficiency than commercial chlorsulfuron at the dosage of 15 g/ha and the preliminary SAR was summarized. In order to illuminate the molecular mechanism of several potent compounds, their apparent inhibition constant (K_i^app) of Arabidopsis thaliana acetohydroxyacid synthase (AHAS) were determined and the results confirmed that these compounds were all potent AHAS inhibitors. 10i have a K_i^app of 11.5 nM, which is about 4 times as potent as chlorsulfuron (52.4 nM).     

Design,synthesis and in vitro anti-mycobacterial evaluation of gatifloxacin-1H-1,2,3-triazole-isatin hybrids

A set of novel gatifloxacin-1H-1,2,3-triazole-isatin hybrids 6a-l was designed, synthesized and evaluated for their in vitro anti-mycobacterial activities against M. tuberculosis (MTB) H₃₇Rv and MDR-TB as well as cytotoxicity. The results showed that all the targets (MIC: 0.025–3.12 μg/mL) exhibited excellent inhibitory activity against MTB H₃₇Rv and MDR-TB, but were much more toxic (CC₅₀: 7.8–62.5 μg/mL) than the parent gatifloxacin (GTFX) (CC₅₀: 125 μg/mL). Among them, 61 (MIC: 0.025 μg/mL) was 2–32 times more potent in vitro than the references INH (MIC: 0.05 μg/mL), GTFX (MIC: 0.78 μg/mL) and RIF (MIC: 0.39 μg/mL) against MTB H₃₇Rv. The most active conjugate 6 k (MIC: 0.06 μg/mL) was 16–>2048 times more potent than the three references (MIC: 1.0–>128 μg/mL) against MDR-TB. Both of the two hybrids warrant further investigations.     

Improved binding affinities of pyrrolidine derivatives as Mcl-1 inhibitors by modifying amino acid side chains

As an important member of anti-apoptotic Bcl-2 protein, myeloid cell leukemia sequence 1 (Mcl-1) protein is an attractive target for cancer therapy. In this study, a new series of pyrrolidine derivatives as Mcl-1 inhibitors were developed by mainly modifying the amino acid side chain of compound 1. Among them, compound 18 (K_i = 0.077 μM) exhibited better potent inhibitory activities towards Mcl-1 protein compared to positive control Gossypol (K_i = 0.18 μM). In addition, compound 40 possessed good antiproliferative activities against PC-3 cells (K_i = 8.45 μM), which was the same as positive control Gossypol (K_i = 7.54 μM).     

Radiosynthesis and evaluation of new PET ligands for peripheral cannabinoid receptor type 1 imaging

Cannabinoid receptor type 1 (CB1) is mainly expressed in the brain, as well as being expressed in functional relevant concentrations in various peripheral tissues. 1-(4-Chlorophenyl)-3-(3-(6-(pyrrolidin-1-yl)pyridin-2-yl)phenyl)urea (PSNCBAM-1, 1) was developed as a potent allosteric antagonist for CB1 and its oral administration led to reductions in the appetite and body weight of rats. Several analogs of 1 (compounds 2 and 3) were recently identified through a series of structure-activity relationship studies. Herein, we report the synthesis of radiolabeled analogs of these compounds using [¹¹C]COCl₂ and an evaluation of their potential as PET ligands for CB1 imaging using in vitro and in vivo techniques. [¹¹C]2 and [¹¹C]3 were successfully synthesized in two steps using [¹¹C]COCl₂. The radiochemical yields of [¹¹C]2 and [¹¹C]3 were 17 ± 8% and 20 ± 9% (decay-corrected to the end of bombardment, based on [¹¹C]CO₂). The specific activities of [¹¹C]2 and [¹¹C]3 were 42 ± 36 and 37 ± 13 GBq/μmol, respectively. The results of an in vitro binding assay using brown adipose tissue (BAT) homogenate showed that the binding affinity of 2 for CB1 (K_D = 15.3 µM) was much higher than that of 3 (K_D = 26.0 µM). PET studies with [¹¹C]2 showed a high uptake of radioactivity in BAT, which decreased in animals pretreated with AM281 (a selective antagonist for CB1). In conclusion, [¹¹C]2 may be a useful PET ligand for imaging peripheral CB1 in BAT.     

Design,synthesis and fungicidal activity of novel 2-substituted aminocycloalkylsulfonamides

A series of novel 2-substituted aminocycloalkylsulfonamides were designed and synthesized by highly selective N-alkylation reaction, whose structures were characterized by ¹H NMR, ¹³C NMR and HRMS. Among them, the configuration of compounds III12 and III20 were confirmed by X-ray single crystal diffraction. Bioassays demonstrated that the title compounds had considerable effects on different strains of Botrytis cinerea and Pyricularia grisea. Comparing with positive control procymidone (EC₅₀ = 10.31 mg/L), compounds III28, III29, III30 and III31 showed excellent fungicidal activity against a strain of B. cinerea (CY-09), with EC₅₀ values of 3.17, 3.04, 2.54 and 1.99 mg/L respectively. Their in vivo fungicidal activities were also better than the positive controls cyprodinil, procymidone, boscalid and carbendazim in pot experiments. Moreover, the fungicidal activity of III28 (EC₅₀ = 4.62 mg/L) against P. grisea was also better than that of the positive control isoprothiolane (EC₅₀ = 6.11 mg/L). Compound III28 would be great promise as a hit compound for further study based on the structure-activity relationship.     

Synthesis,structures and urease inhibitory activity of cobalt(III) complexes with Schiff bases

A series of new cobalt(III) complexes were prepared. They are [CoL¹(py)₃]·NO₃ (1), [CoL²(bipy)(N₃)]·CH₃OH (2), [CoL³(HL³)(N₃)]·NO₃ (3), and [CoL⁴(MeOH)(N₃)] (4), where L¹, L², L³ and L⁴ are the deprotonated form of N′-(2-hydroxy-5-methoxybenzylidene)-3-methylbenzohydrazide, N′-(2-hydroxybenzylidene)-3-hydroxylbenzohydrazide, 2-[(2-dimethylaminoethylimino)methyl]-4-methylphenol, and N,N′-bis(5-methylsalicylidene)-o-phenylenediamine, respectively, py is pyridine, and bipy is 2,2′-bipyridine. The complexes were characterized by infrared and UV–Vis spectra, and single crystal X-ray diffraction. The Co atoms in the complexes are in octahedral coordination. Complexes 1 and 4 show effective urease inhibitory activities, with IC₅₀ values of 4.27 and 0.35 μmol L⁻¹, respectively. Complex 2 has medium activity against urease, with IC₅₀ value of 68.7 μmol L⁻¹. While complex 3 has no activity against urease. Molecular docking study of the complexes with Helicobacter pylori urease was performed.     

Synthesis and bioactivity evaluation of 2,3-diaryl acrylonitrile derivatives as potential anticancer agents

Thirty novel derivatives of 2,3-diaryl acrylonitrile were synthesized and evaluated for biological activity. Preliminary investigations of antitumor activity in vitro showed that most of the synthesized compounds have significant antiproliferative effects on human cancer cell lines, such as BEL-7402, HeLa, and HCT116 with IC₅₀ values in the range of 0.13–60.23 μM without significant toxic effects on the non-cancerous human liver cell line L-02. In particular, compounds 4d and 4p were found to be the most potent against HeLa (4.20 μM) and HCT116 cells (0.13 μM), respectively, with superior or similar in vitro efficacy to that of the broad-spectrum anticancer drug taxol.     

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.