Synthesis and antitubercular activity of 7-chloro-4-quinolinylhydrazones derivatives

A series of twenty-one 7-chloro-4-quinolinylhydrazones (3a–u) have been synthesized and evaluated for their in vitro antibacterial activity against Mycobacterium tuberculosis H₃₇Rv. The compounds 3f, 3i and 3o were non-cytotoxic and exhibited an important minimum inhibitory concentration (MIC) activity (2.5 μg/mL), which can be compared with that of the first line drugs, ethambutol (3.12 μg/mL) and rifampicin (2.0 μg/mL). These results can be considered an important start point for the rational design of new leads for anti-TB compounds.     

Synthesis and evaluation of antitubercular activity of glycosyl thio- and sulfonyl acetamide derivatives

A series of glycosyl thioacetamide and glycosyl sulfonyl acetamide derivatives have been prepared following a convenient reaction protocol and evaluated for their antitubercular activity against Mycobacterium tuberculosis H₃₇Rv. Amongst 32 compounds evaluated 3 compounds were effective in inhibiting mycobacterial growth at MIC of 6.25 μg/mL, 6 compounds at MIC of 3.125 μg/mL and 1 compound at MIC of 1.56 μg/mL. All active compounds were found nontoxic in Vero cell lines and mice bone marrow macrophages.     

Evaluation of antiprotozoal and antimycobacterial activities of the resin glycosides and the other metabolites of Scrophularia cryptophila

Resin glycosides are secondary metabolites exclusive to the convolvulaceous plants. In this study, crypthophilic acids A–C (1–3), the first resin glycosides occurring in another family (Scrophulariaceae), and the other constituents of Scrophularia cryptophila were examined for in vitro antiprotozoal and antimycobacterial potentials. Except for crypthophilic acid B (2), all tested compounds exhibited growth-inhibitory effect against Trypanosoma brucei rhodesiense, with l-tryptophan (6) and buddlejasaponin III (7) being the most potent ones (IC₅₀'s 4.1 and 9.7 μg/ml). In contrast, the activity towards Trypanosoma cruzi was poor, and only crypthophilic acid C (3), 6 and 7 were trypanocidal at concentrations above 40 μg/ml. With the exception of 2 and 6, all compounds were active against Leishmania donovani. Harpagide (4) and 3 emerged as the best leishmanicidal agents (IC₅₀'s 2.0 and 5.8 μg/ml). Only compounds 3, 6 and 7 showed antimalarial activity against Plasmodium falciparum with IC₅₀ values of 4.2, 16.6 and 22.4 μg/ml. Overall the best and broadest spectrum activity was presented by compounds 3 and 7, as they inhibited all four parasitic protozoa. None of the isolates had significant activity against Mycobacterium tuberculosis (MICs >100 μg/ml) or were toxic towards mammalian (L6) cells. This is the first report of antiprotozoal activity for natural resin glycosides, as well as for harpagide (4), acetylharpagide (5), tryptophan (6) and buddlejasaponin III (7).     

Design and synthesis of bile acid-based amino sterols as antimicrobial agents

New bile acid-based amino sterols were synthesized in good yields from C-3β-oxiranes as key intermediates. These derivatives were evaluated for their in vitro antimicrobial properties against human pathogens. These compounds showed better antibacterial activity as compared to antifungal activity. Compounds 21 and 22 showed comparable antibacterial activity to gentamicin against Staphylococcus aureus with IC₅₀ values of 5.14 and 4.46 μg/mL. This is the first report for the synthesis of C-3β-oxiranes on the steroids having A/B cis ring junction and these oxiranes have been used for the synthesis of amino sterols 17, 18, 21, and 22.     

Elderberry flavonoids bind to and prevent H1N1 infection in vitro

A ionization technique in mass spectrometry called Direct Analysis in Real Time Mass Spectrometry (DART TOF-MS) coupled with a Direct Binding Assay was used to identify and characterize anti-viral components of an elderberry fruit (Sambucus nigra L.) extract without either derivatization or separation by standard chromatographic techniques. The elderberry extract inhibited Human Influenza A (H1N1) infection in vitro with an IC₅₀ value of 252 ± 34 μg/mL. The Direct Binding Assay established that flavonoids from the elderberry extract bind to H1N1 virions and, when bound, block the ability of the viruses to infect host cells. Two compounds were identified, 5,7,3′,4′-tetra-O-methylquercetin (1) and 5,7-dihydroxy-4-oxo-2-(3,4,5-trihydroxyphenyl)chroman-3-yl-3,4,5-trihydroxycyclohexanecarboxylate (2), as H1N1-bound chemical species. Compound 1 and dihydromyricetin (3), the corresponding 3-hydroxyflavonone of 2, were synthesized and shown to inhibit H1N1 infection in vitro by binding to H1N1 virions, blocking host cell entry and/or recognition. Compound 1 gave an IC₅₀ of 0.13 μg/mL (0.36 μM) for H1N1 infection inhibition, while dihydromyricetin (3) achieved an IC₅₀ of 2.8 μg/mL (8.7 μM). The H1N1 inhibition activities of the elderberry flavonoids compare favorably to the known anti-influenza activities of Oseltamivir (Tamiflu^®; 0.32 μM) and Amantadine (27 μM).     

Synthesis of triazole-oxazolidinones via a one-pot reaction and evaluation of their antimicrobial activity

C-5-substituted triazole-oxazolidinones were synthesized using a bromide catalyzed cycloaddition between aryl isocyanates and epibromohydrin followed by a three-component Huisgen cycloaddition. The library of compounds was screened for antibacterial activity against Mycobacterium smegmatis ATCC 14468, Bacillus subtilis ATCC 6633, and Enterococcus faecalis ATCC 29212. Notably, the 3-(4-acetyl-phenyl)-5-(1H-1,2,3-triazol-1-yl)methyl)-oxazolidin-2-one (18) showed an MIC of 1 μg/mL against M. smegmatis ATCC 14468, fourfold lower than the MIC measured for isoniazid.     

Synthesis and biological activity of 17α-alkynylamide derivatives of estradiol

Seven estradiol (E₂) derivatives with an alkynylamide side chain at the 17α position were synthesized starting from ethynylestradiol (EE₂). The main chemical step was the coupling reaction of the acetylide ion of EE₂ with carbon dioxide, glutaric anhydride or bromoalkyl ortho ester. The synthesis of these compounds is fast (3–6 steps according to the compound) and is easily achieved with good yield. Five compounds with different side chain lenghts were evaluated for uterotrophic and antiuterotrophic activity in the CD-1 mouse. None of the tested compounds shows estrogenic activity in this sensitive in vitro system. At low doses (1 and 3 μg), a 14–57% inhibition of E₂-induced uterine growth was observed while no additional inhibition was observed at the 10, 20 and 30 μg doses. In human breast carcinoma cells in culture, all compounds show estrogenic activity at high concentrations while only compound 39 (N-buty,N-methyl-8-[3′,17′β-dihydroxy estra-1′,3′,5′(10′)-trien-17′α-yl]-7-octynamide) possesses antiproliferative or antiestrogenic effects. No significant correlation could be demonstrated between alkynylamide side chain length and estrogenic or antiestrogenic activity. Among the compounds tested, the derivative of EE₂ possessing a five-methylene (CH₂) side chain (compound 39) possesses the best antiestrogenic activity (44 ± 7% in the CD-1 mouse uterus assay at the 3μg dose and 57 ± 4% at 0.1 nM in human ZR-75-1 cancer cells in culture).     

Determination of trace amounts of ginkgolic acids in Ginkgo biloba L. leaf extracts and phytopharmaceuticals by liquid chromatography–electrospray mass spectrometry

Ginkgolic acids (GAs) are toxic phenolic compounds present in the fruits and leaves of Ginkgo biloba L. (Ginkgoacae). Their maximum level in phytopharmaceuticals containing ginkgo extracts has been recently restricted to 5 μg/g by the Commission E of the former Federal German Health Authority. In order to detect ginkgolic acids at these low levels, a sensitive and selective analytical method, based on liquid chromatography–electrospray mass spectrometry (LC–ES-MS) has been developed. The three main phenolic acids (1–3) of the chloroform fruit extract were isolated and used as standards for quantification. In the LC–ES-MS negative ion mode, calibration curves with good linearities (r=0.9973, n=6) were obtained in the range of 0.5–10 μg/g for compounds 1, 2 and between 0.1 and 7.5 μg/g (r=0.9949, n=6) for ginkgolic acid 3. The detection limits at a S/N ratio of 3 were 0.1 (3) and 0.25 μg/g (1, 2). Recoveries were around 101% at 5 μg/g for the substances detected in the leaf extracts. Good precision was achieved with relative standard deviations of less than 4% (n=6). The optimised method was applied to verify whether the amount of gingkolic acids was below 5 μg/g in a standardised leaf extract which is a constituent of a phytopreparation.     

Oleanane-type triterpene oligoglycosides with pancreatic lipase inhibitory activity from the pericarps of Sapindus rarak

The methanolic extract from the pericarps of Sapindus rarak DC. was found to show pancreatic lipase inhibitory activity (IC₅₀ = ca. 614 μg/mL). From the extract, oleanane-type triterpene oligoglycosides, rarasaponins I–III (1–3), and raraoside A (4), were isolated together with 13 known saponins and four known sesquiterpene glycosides. Among them, several saponin constituents including rarasaponins I (1, IC₅₀ = 131 μM) and II (2, 172 μM), and raraoside A (4, 151 μM) inhibited pancreatic lipase activity, which were stronger than that of theasaponin E₁ (270 μM).     

A new ecdysteroid and other constituents from two Dioscorea species

Phytochemical investigation of the rhizome of Dioscorea dumetorum has led to the isolation by several chromatographic steps on normal and reversed phase silica gel of a new ecdysteroid, (20R)-5β,11α,20-trihydroxyecdysone (1), and two known ecdysteroids, ajugasterone C (2) and herkesterone (3). Their structures were determined by spectroscopic methods including 1D- and 2D-NMR (COSY, TOCSY, HSQC and HMBC). This is the first report on the occurrence of phytoecdysteroids in the Dioscoreaceae family. These compounds were devoid of antifungal activity against three Candida species (Candida albicans, Candida glabrata and Candida tropicalis, MIC > 200 μg/ml).     

Synthesis of gibberellin derivatives with anti-tumor bioactivities

A series of gibberellin based molecules were designed and synthesized. Gibberellin derivatives bearing two α,β-unsaturated ketone units showed strong anticancer activities in MTT assay towards a number of human cancer cell lines including HT29, A549, HepG2 and MKN28. The most potent gibberellin derivative (compound 10, IC₅₀ = 2.9 μM against HT29) inhibited completely the topoisomerase I activity at 8 μg/mL level.     

Synthesis and antitumor activity of new d-seco and d-homo androstane derivatives

Starting from 3β-hydroxy-17-oxo-16,17-secoandrost-5-ene-16-nitrile (1), the new 16,17-secoandrostane derivatives 4–9 were synthesized. On the other hand, 3β-hydroxy-17-oxa-d-homoandrost-5-ene-16-one (10) yielded the new d-homo derivatives 12, 13 and 15. In vitro antiproliferative activity of selected compounds against three tumor cell lines (human breast adenocarcinoma ER+, MCF-7, human breast adenocarcinoma ER−, MDA-MB-231, prostate cancer AR−, PC-3, and normal fetal lung fibroblasts, MRC-5) was evaluated. Compounds 3 and 12 showed strong antiproliferative activity against PC-3 cells, the IC₅₀ values being 2 μM and 0.55 μM, respectively. Compounds 6 (10 μM) and 14 (9 μM) showed moderate activity against MDA-MB-231 cells. The synthesized compounds 1–3, 5–8, 10 and 12–15 were not toxic to normal fetal lung fibroblasts cells, MRC-5.     

Novel semisynthetic derivatives of betulin and betulinic acid with cytotoxic activity

A series of new imidazole carboxylic esters (carbamates) and N-acylimidazole derivatives of betulin and betulinic acid (14–29) have been synthesized. The new compounds were screened for in vitro cytotoxicity activity against human cancer cell lines HepG2, Jurkat and HeLa. A number of compounds have shown IC₅₀ values lower than 2 μM against the cancer cell lines tested and the vast majority has shown a better cytotoxicity profile than betulinic acid, including the betulin derivatives. N-Acylimidazole derivatives 26 and 27 (IC₅₀ 0.8 and 1.7 μM in HepG2 cells) and the C-3 carbamate derivative 16 (IC₅₀ 2.0 μM in HepG2 cells) were the most promising compounds. Based on the observed cytotoxicity, structure–activity relationships have been established.     

1-(2-((Z)-6-(2-(Trifluoromethyl)phenyl)hexa-3-en-1,5-diynyl)phenyl)piperidin-2-one as a new potent apoptosis agent

Compounds 4a–f, 5a–f and 6–9, showed significant growth inhibition activity against human tumor cell lines. Of these compounds, 1-(2-((Z)-6-(2-(trifluoromethyl)phenyl)hexa-3-en-1,5-diynyl)phenyl)piperidin-2-one (8) displayed the most potent growth inhibition activity. Compound 8 also arrested cancer cells in G2/M phase and induced apoptosis via activation of caspase-3 and -9. According to western-blotting analysis, compound 8 can up-regulate Bax, down-regulate Bcl-2 and XIAP, as well as promote cytochrome c release.     

Furo[3′,2′:3,4]naphtho[1,2-d]imidazole derivatives as potential inhibitors of inflammatory factors in sepsis

Synthesis and anti-inflammatory effects of certain furo[3′,2′:3,4]naphtho[1,2-d]imidazole derivatives 12–18 were studied. These compounds were synthesized from naphtho[1,2-b]furan-4,5-dione (10) which in turn was prepared from the known 2-hydoxy-1,4-naphthoquinone (7) in a one pot reaction. Furo[3′,2′:3,4]naphtho[1,2-d]imidazole (12) was inactive (IC₅₀ value of >30 μM) while its 5-phenyl derivative 13, with an IC₅₀ value of 16.3 and 11.4 μM against lysozyme and β-glucuronidase release, respectively, was comparable to the positive trifluoperazine. The same potency was observed for 5-furan derivative 16 with an IC₅₀ value of 19.5 and 11.3 μM against lysozyme and β-glucuronidase release, respectively. An electron-withdrawing NO₂ substituted on 5-phenyl or 5-furanyl group led to the devoid of activity as in the cases of 14 and 17. Among them, compound 15 exhibited significant inhibitory effects, with an IC₅₀ value of 7.4 and 5.0 μM against lysozyme and β-glucuronidase release, respectively.For the LPS-induced NO production, the phenyl derivatives 12–15 were inactive while the nitrofuran counterparts 17 and 18 suppress LPS-induced NO production significantly, with an IC₅₀ value of 1.5 and 1.3 μM, respectively, which are more active than that of the positive 1400 W. Compounds 16–18 were capable of inhibiting LPS-induced iNOS protein expression at a dose-dependent manner in which compound 18, with an IC₅₀ of 0.52 μM in the inhibition of iNOS expression, is approximately fivefold more potent than that of the positive 1400 W. In the CLP rat animal model, compound 18 was found to be more active than the positive hydrocortisone in the inhibition of the iNOS mRNA expression in rat lung tissue. The sepsis-induced PGE2 production in rat serum decreased 150% by the pretreatment of 18 in a dose of 10 mg/kg.     

Synthesis and pharmacological evaluation of 6-naltrexamine analogs for alcohol cessation

A series of substituted aryl amide derivatives of 6-naltrexamine, 3 designed to be metabolically stable were synthesized and used to characterize the structural requirements for their potency to binding and functional activity of human mu (μ), delta (δ) and kappa (κ) opioid and nociceptin (NOP) receptors. Binding assays showed that 4–10 had subnanomolar K_i values for μ and κ opioid receptors. Functional assays for stimulation of [³⁵S]GTPγS binding showed that several compounds acted as partial or inverse agonists and antagonists of the μ and δ, κ opioid or NOP receptors. The compounds showed considerable stability in the presence of rat, mouse or human liver preparations and NADPH. The inhibitory activity on the functional activity of human cytochrome P450s was examined to determine any potential inhibition by 4–9. Only modest inhibition of CYP3A4, CYP2C9 and CYP2C19 was observed for a few of the analogs. As a representative example, radiolabeled 6 was examined in vivo and showed reasonable brain penetration. The inhibition of ethanol self-administration in rats trained to self-administer a 10% (w/v) ethanol solution, utilizing operant techniques showed 5–8 to have very potent efficacy (ED₅₀ values 19–50 μg/kg).     

3-Aryl-4-acyloxyethoxyfuran-2(5H)-ones as inhibitors of tyrosyl-tRNA synthetase: Synthesis,molecular docking and antibacterial evaluation

Thirty-eight 3-aryl-4-acyloxyethoxyfuran-2(5H)-ones were designed, prepared and tested for antibacterial activities. Some of them showed significant antibacterial activity against Gram-positive organism, Gram-negative organism and fungus. Out of these compounds, 4-(2-(3-chlorophenylformyloxy)ethoxy)-3-(4-chlorophenyl)furan-2(5H)-one (d40) showed the widest spectrum of activity with MIC₅₀ of 2.0 μg/mL against Staphylococcus aureus, 4.3 μg/mL against Escherichia coli, 1.5 μg/mL against Pseudomonas aeruginosa and 1.2 μg/mL against Candida albicans. Our data disclosed that MIC₅₀ values against whole cell bacteria are positive correlation with MIC₅₀ values against tyrosyl-tRNA synthetase. Meanwhile, molecular docking of d40 into S. aureus tyrosyl-tRNA synthetase active site was also performed, and the inhibitor tightly fitting the active site might be an important reason why it has high antimicrobial activity.     

Synthesis of C(7) modified chrysin derivatives designing to inhibit β-ketoacyl-acyl carrier protein synthase III (FabH) as antibiotics

As a naturally wide distributed flavone, chrysin exhibits numerous biological activities including anticancer, anti-inflammatory, and antimicrobials activities. β-Ketoacyl-acyl carrier protein synthase III (FabH) catalyzes the initial step of fatty acid biosynthesis via a type II fatty acid synthase in most bacteria. The important role of this essential enzyme combined with its unique structural features and ubiquitous occurrence in bacteria has made it an attractive new target for the development of antibacterial agents. We first used a structure-based approach to develop 18 novel chrysin analogues that target FabH for the development of new antibiotics. Structure-based design methods were used for the expansion of the chrysin derivatives including molecular docking and SAR research. Based on the results, 5-hydroxy-2-phenyl-7-(2-(piperazin-1-yl)ethoxy)-4H-chromen-4-one (3g) showed the most potent antibacterial activity with MIC of 1.56–6.25 μg/mL against the test bacterial stains, and docking simulation was performed to position compound 3g into the Escherichia coli FabH active site to determine the probable binding conformation. The biological assays indicated that compound 3g is a potent inhibitor of E. coli FabH as antibiotics.     

Design and synthesis of novel substituted quinazoline derivatives as antileishmanial agents

4-(Substituted-benzylidine)-2-substituted-5,6-dihydrobenzo[h]quinazoline (5a–p) and 4-(substituted-benzylidine)-2-substituted-3, 4, 5, 6-tetrahydrobenzo[h]quinazoline (6a–p) have been synthesized from 2-(substituted-benzylidine)tetralone-1(3a–d) and several substituted guanidine sulfates(4a–d).These compounds were tested for their in vitro antileishmanial activity. The compounds 6i, 6f, 6g show promising antileishmanial activity against Leishmania donovani.