Synthesis and antibacterial evaluation of novel 11-O-aralkylcarbamoyl-3-O-descladinosylclarithromycin derivatives

A series of novel 11-O-aralkylcarbamoyl-3-O-descladinosylclarithromycin derivatives were designed, synthesized and evaluated for their in vitro antibacterial activity. The results showed that the majority of the target compounds displayed potent activity against erythromycin-susceptible S. pyogenes, erythromycin-resistant S. pneumoniae A22072 expressing the mef gene and S. pneumoniae AB11 expressing the mef and erm genes. Besides, most of the target compounds exhibited moderate activity against erythromycin-susceptible S. aureus ATCC25923 and B. subtilis ATCC9372. In particular, compounds 11a, 11b, 11c, 11e, 11f and 11h were found to exert favorable antibacterial activity against erythromycin-susceptible S. pyogenes with the MIC values of 0.015–0.125?μg/mL. Furthermore, compounds 10e, 11a, 11b and 11c showed superior activity against erythromycin-resistant S. pneumoniae A22072 with the MIC values of 0.25–0.5?μg/mL. Additionally, compound 11c was the most effective against all the erythromycin-resistant S. pneumoniae strains (A22072, B1 and AB11), exhibiting 8-, 8- and 32-fold more potent activity than clarithromycin, respectively.     

Synthesis and antibacterial evaluation of novel 11-O-carbamoyl clarithromycin ketolides

A series of novel 11-O-carbamoyl clarithromycin ketolides were designed, synthesized and evaluated for their in vitro antibacterial activity. The results showed that the majority of the target compounds displayed improved activity compared with references against erythromycin-resistant S. pneumoniae A22072 expressing the mef gene, S. pneumoniae B1 expressing the erm gene and S. pneumoniae AB11 expressing the mef and erm genes. In particular, compounds 9, 18, 19 and 22 showed the most potent activity against erythromycin-resistant S. pneumoniae A22072 with the MIC values of 0.5 μg/mL. Furthermore, compounds 11, 18, 19, 24 and 29 were also found to exhibit favorable antibacterial activity against erythromycin-susceptible S. pyogenes with the MIC values of 0.125–1 μg/mL, and moderate activity against erythromycin-susceptible S. aureus ATCC25923 and B. subtilis ATCC9372.     

‘Inverted’ analogs of the antibiotic gramicidin S with an improved biological profile

A series of gramicidin S derivatives 4–15 are presented that have four ornithine residues as polar protonated side chains and two central hydrophobic amino acids with unaltered turn regions. These peptides were screened against human erthrocytes and our standard panel of Gram negative- and Gram positive bacteria, including four MRSA strains. Based on the antibacterial- and hemolytic data, peptides 13 and 14 have an improved biological profile compared to the clinically applied topical antibiotic gramicidin S.     

A 9,13-epoxylabdane from Colophospermum mopane

A new diterpene, 8(S),13(S)-dihydrogrindelic acid (2) was isolated from the seeds of Colophospermum mopane along with its previously described C-13 epimer (1). The structure of 2 was established primarily by NMR which required some revisions on the NMR shift assignments of 1. The importance of 1 and 2 as the missing links in the biosynthesis of 9,13-epoxylabdanes is briefly discussed.     

Taxonomy of Gundlachia (Compositae: Astereae)

Gundlachia, a genus of shrubs occurring in the Caribbean islands, is treated as comprising two species, one of which has six varieties. Five new combinations are made: Gundlachia corymbosa var. apiculata (Britton & S. F. Blake) M. A. Lane, G. corymbosa var. compacta (Urb. & Ekman) M. A. Lane, G. corymbosa var. cubana (Britton & S. F. Blake) M. A. Lane, G. corymbosa var. foliosa (Britton & S. F. Blake) M. A. Lane, and G. corymbosa var. ocoana (Urb. & Ekman) M. A. Lane. Gundlachia is probably most closely related to Gymnosperma.     

Sphaeromeria,a genus closer to Artemisia than to Tanacetum (Asteraceae: Anthemideae)

A new species,Sphaeromeria ruthiae, from Zion National Park, and three new combinations,S. martirensis,S. compacta, andS. potentilloides var.nitrophila, are presented. Morphological and anatomical evidence is used to support the recognition ofSphaeromeria as distinct fromTanacetum.     

Synthesis and antibacterial activity of novel 3-O-arylalkylcarbamoyl-3-O-descladinosyl-9-O-(2-chlorobenzyl)oxime clarithromycin derivatives

A novel series of 3-O-arylalkylcarbamoyl-3-O-descladinosyl-9-O-(2-chlorobenzyl)oxime clarithromycin derivatives, were designed, synthesized and evaluated for their in vitro antibacterial activity. These derivatives were found to have strong activity against susceptible and resistant bacteria strains. Among them, compounds 7a and 7q showed the most potent activity (0.125?µg/mL) against erythromycin-resistant S. pneumoniae expressing the mefA gene. Moreover, compounds 7f, 7i, 7p and 7z displayed remarkably improved activity (4?µg/mL) against penicillin-resistant S. aureus ATCC31007, and compounds 7a, 7b, 7f, 7p and 7z showed improved activity (8?µg/mL) against erythromycin-resistant S. pyogenes. In particular, compound 7z exhibited potent and balanced activity against the tested drug-susceptible and -resistant bacterial strains.     

The alkenic unreactivity of mono- and bi-cyclic derivatives of 3,6-dihydro-2-(methylthio)-2H-thiopyran S,S,S′,S′-tetraoxide

The inertness of the alkenic bond towards electrophilic additions in 3-exocyano-3-(methylthio)-2-thiabicyclo[2.2.1]hept-5-ene S,S,S′,S′-tetraoxide (5), 3,6-dihydro-2-(methylthio)-2H-thiopyran-2-carbonitrile S,S,S′,S′-tetraoxide (3), and 2-(acetamidomethyl)-3,6-dihydro-2-(methylthio)-2H-thiopyran S,S,S′,S′-tetraoxide (4) is attributed to the “supra-annular effect” and field effects. Conformational analysis of a pentadeuterated derivative of 4 (10) is reported. On the basis of the 220-MHz ¹H n.m.r.-spectral data of 10, the compound was concluded to adopt the ⁰H₂ conformation in chloroform solution.     

Insulin mimetic lanostane triterpenes from the cultivated mushroom Ganoderma orbiforme

Two new lanostane triterpenes, ganorbifoins A and B (1-2), together with the known compound (25S,3′S)-(+)-12α-hydroxy-3α-(3′-hydroxy-4′-methoxycarbonyl-3′-methylbutiryloxy)-24-methyllanosta-824-(31)-dien-26-oic acid (3) were isolated from the cultivated fruiting bodies of Ganoderma orbiforme. The structures of isolates were determined by extensive analysis of NMR and HRESIMS. All compounds induced glucose uptake in zebrafish-based system at the concentration of 10 μM. And the best performing compound is ganorbifoin A. Compounds 2 and 3 exhibited an inhibitory effect on nitric oxide production in LPS-induced BV-2 microglia cells at the concentration of 20 μM.     

Modified low molecular weight cyclic peptides as mimetics of BDNF with improved potency,proteolytic stability and transmembrane passage in vitro

We recently reported the development of the BDNF mimetic peptide cyclo-[dPAKKR] 1 which promotes the survival of cultured sensory neurons via a trkB independent mechanism [Fletcher, J. M.; Morton, C. M.; Zwar, R. A.; Murray, S. S.; O’Leary, P. D.; Hughes, R. A. J. Biol. Chem. 2008, 283, 33375]. In the present study we prepared a series of hydrophobically-modified analogues of 1 with an eye to improving its pharmacokinetic properties. Select members of this second generation of compounds showed improved biological activity, stability in plasma, and an ability to cross model biological membranes.     

Redefining the structure–activity relationships of 2,6-methano-3-benzazocines. Part 7: Syntheses and opioid receptor properties of cyclic variants of cyclazocine

A series of 7,8- and 8,9-fused triazole and imidazole analogues of cyclazocine have been made and characterized in opioid receptor binding and [³⁵S]GTPγS assays. Target compounds were designed to explore the SAR surrounding our lead molecule for this study, namely the 8,9-fused pyrrolo analogue 2 of cyclazocine. Compared to 2, many of the new compounds in this study displayed very high affinity for opioid receptors.     

Discovery of medium ring thiophosphorus based heterocycles as antiproliferative agents

Hydrogen sulfide (H₂S) has been investigated for its potential in therapy. Recently, we reported novel H₂S donor molecules based on a thiophosphorus core, which slowly release H₂S and have improved anti-proliferative activity in cancer cell lines compared to the most widely studied H₂S donor GYY4137 (1). Herein, we have prepared new thiophosphorus organic H₂S donors with different ring sizes and evaluated them in two solid tumor cell lines and one normal cell line. A seven membered ring compound, 17, was found to be the most potent with sub-micromolar IC_50s in breast (0.76 μM) and ovarian (0.76 μM) cancer cell lines. No significant H₂S release was detected in aqueous solution for this compound. However, confocal imaging showed that H₂S was released from 17 inside cells at a similar level to the widely studied H₂S donor GYY4137, which was shown to release 10 μM H₂S after 12 h at a concentration of 400 μM. Comparison of 17 with its non-sulfur oxygen analogue, 26, provided evidence that the sulfur atom is important for its potency. However, the significant potency observed for 26 (5.94–11.0 μM) indicates that the high potency of 17 is not entirely due to release of H₂S. Additional mechanism(s) appear to be responsible for the observed activity, hence more detailed studies are required to better understand the role of H₂S in cancer with potent thiophosphorus agents.     

Phenolic constituents from the roots of Rosa laevigata (Rosaceae)

Chemical investigation of the root of Rosa laevigata led to the isolation of sixteen phenolic compounds, including seven flavonoids (1–7), five condensed tannins (8–12), two stilbenes (13 and 14) and two benzoic acid derivatives (15 and 16). Their structures were identified as (+)-catechin (1), (+)-gallocatechin (2), (2R, 3S, 4S)-cis- leucocyanidin (3), (2R, 3S, 4S)-cis-leucofisetinidin (4), (2S, 3R, 4R)-cis- leucofisetinidin (5), dehydrodicatechin A (6), phloridzin (7), procyanidin B3 (8), fisetinidol-(4α, 8)-catechin (9), guibourtinidol- (4α, 8)-catechin (10), ent- isetinidol -(4α, 6)-catechin (11), fisetinidol-(4β, 8)-catechin (12), (Z)-3-methoxy-5-hydroxy- stilbene (13), (Z)-piceid (14), gallic acid (15) and 4-hydroxybenzoic acid- 4-O-β-D-glucopyranoside (16). Among them, compounds 3–7, 9–14, and 16 were isolated from R. laevigata for the first time, and compounds 3–7, 9, 10, 12–14 and 16 were reported for the first time from the genus Rosa. The chemotaxonomic significance of these compounds was summarized.     

Xanthones and a benzophenone from the roots of Pentadesma butyracea and their antiproliferative activity

A new xanthone, 3,4-dihydro-8,10,12-trihydroxy-2,2-dimethylpyrano[2,3-b]xanthen-11(2H)-one or butyraxanthone E (1), along with the known compounds 30-epi-cambogin (2), 1,7-dihydroxyxanthone (3) and 1,5-dihydroxyxanthone (4) were isolated from the roots of Pentadesma butyracea. Their structures were elucidated by spectroscopic means and comparison with published data. Their antiproliferative activities were evaluated against Drosophila S2 cells and two human cancer cell lines, THP-1 (leukemia) and HCT116 (colon cancer). Compounds 1 and 2 showed moderate antiproliferative activity against Drosophila S2 cells and the HCT116 cell line, respectively. Compound 2 was active against Drosophila S2 cells.     

N-Sulfonyl dipeptide nitriles as inhibitors of human cathepsin S: In silico design,synthesis and biochemical characterization

A library of cathepsin S inhibitors of the dipeptide nitrile chemotype, bearing a bioisosteric sulfonamide moiety, was synthesized. Kinetic investigations were performed at four human cysteine proteases, i.e. cathepsins S, B, K and L. Compound 12 with a terminal 3-biphenyl sulfonamide substituent was the most potent (K_i = 4.02 nM; selectivity ratio cathepsin S/K = 5.8; S/L = 67) and 24 with a 4′-fluoro-4-biphenyl sulfonamide substituent the most selective cathepsin S inhibitor (K_i = 35.5 nM; selectivity ratio cathepsin S/K = 57; S/L = 31). In silico design and biochemical evaluation emphasized the impact of the sulfonamide linkage on selectivity and a possible switch of P2 and P3 substituents with respect to the occupation of the corresponding binding sites of cathepsin S.     

Active site mapping of trypsin,thrombin and matriptase-2 by sulfamoyl benzamidines

The benzamidine moiety, a well-known arginine mimetic, has been introduced in a variety of ligands, including peptidomimetic inhibitors of trypsin-like serine proteases. According to their primary substrate specificity, the benzamidine residue interacts with the negatively charged aspartate at the bottom of the S1 pocket of such enzymes. Six series of benzamidine derivatives (1–73) were synthesized and evaluated as inhibitors of two prototype serine proteases, that is, bovine trypsin and human thrombin. As a further target, human matriptase-2, a recently discovered type II transmembrane serine protease, was investigated. Matriptase-2 represents an important regulatory protease in iron homeostasis by down-regulation of the hepcidin expression. Compounds 1–73 were designed to contain a fixed sulfamoyl benzamidine moiety as arginine mimetic and a linker-connected additional substructure, such as a tert-butyl ester, carboxylate or second benzamidine functionality. A systematic mapping approach was performed with these inhibitors to scan the active site of the three target proteases. In particular, bisbenzamidines, able to interact with both the S1 and S3/S4 binding sites, showed notable affinity. In branched bisbenzamidines 66–73 containing a third hydrophobic residue, opposite effects of the stereochemistry on trypsin and thrombin inhibition were observed.     

The isolation of two new lanostane triterpenoid derivatives from the edible mushroom Astraeus asiaticus

Two lanostane triterpenoid derivatives, astrasiaone (2), (22S, 25R, 26R)-26-methoxy-22-26-epoxylanost-8-en-3-one, and astrasiate (3), (3α, 22S, 25R)-3, 22-dihydroxylanost-8-en-26 -oate, together with six known compounds, astraodorol (1), artabotryol B (4), artabotryol C1 (5), 6-dehydrocerevisterol (6), ergosterol (7) and hypaphorine (8) were isolated from the edible mushroom Astraeus asiaticus. 3 and 4 exhibited weak cytotoxicity against KB and NCI-H187 cancer cell lines. A comparison of the structures of 2 and 3 to that of 1, 4 and 5 suggest that these two new compounds could be the intermediate form that occurs during biogenesis.     

Synthesis and preliminary evaluation of a novel glutamine derivative: (2S,4S)4-[18F]FEBGln

We report the preparation of a novel glutamine derivative, (2S,4S)-2,5-diamino-4-(4-(2-fluoroethoxy)benzyl)-5-oxopentanoic acid, (2S, 4S)4-[¹⁸F]FEBGln ([¹⁸F]4), through efficient organic and radiosyntheses. In vitro assays of [¹⁸F]4 using MCF-7 cells showed that it entered cells via multiple amino acid transporter systems including system L and ASC2 transporters but not through the system A transporter. [¹⁸F]4 showed promising properties for tumor imaging and may serve as a lead compound for further optimizing and targeting the system L transporter associated with enhanced glutamine metabolism in cancer cells.     

Rational design and synthesis of topoisomerase I and II inhibitors based on oleanolic acid moiety for new anti-cancer drugs

Semisynthetic reactions were conducted on oleanolic acid, a common plant-derived oleanane-type triterpene. Ten rationally designed derivatives of oleanolic acid were synthesized based on docking studies and tested for their topoisomerase I and IIα inhibitory activity. Semisynthetic reactions targeted C-3, C-12, C-13, and C-17. Nine of the synthesized compounds were identified as new compounds. The structures of these compounds were confirmed by spectroscopic methods (1D, 2D NMR and MS). Five oleanolic acid analogues (S2, S3, S5, S7 and S9) showed higher activity than camptothecin (CPT) in the topoisomerase I DNA relaxation assay. Four oleanolic acid analogues (S2, S3, S5 and S6) showed higher activity than etoposide in a topoisomerase II assay. The results indicated that the C12–C13 double bond of the oleanolic acid skeleton is important for the inhibitory activity against both types of topoisomerases, while insertion of a longer chain at either position 3 or 17 increases the activity against topoisomerases by various degrees. Some of the synthesized compounds act as dual inhibitors for both topoisomerase I and IIα.     

Synthesis,ADME, docking studies and in vivo anti-hyperglycaemic potential estimation of novel Schiff base derivatives from octadec-9-enoic acid

A new series of octadec-9-enoic acid schiff base entities (S1-S30) were designed and synthesized targeting peroxisome proliferator activated receptor-gamma for agonist action. Molinspiration software (online) was used to estimate drug like molecular properties of the metabolites. Docking disquisition on co-crystallized protein of PPAR-γ (PDB ID 1FM9) was carried out which showed S21, S10 and S7 as best situated in the vital sites of receptor having docking scores −9.19, −8.68 and −8.64 respectively. Free binding energy measured using model of Maestro 9.0 and was in range of from −40.01 and −80.54 kcal/mol, significant when compared with pioglitazone (−51.58 Kcal/mol). Seven best docked derivatives were assessed for in-vivo oral glucose tolerance on normal rats and anti-hyperglycaemic activity by streptozotocin induced diabetes model. S21 unveiled to be the best measured analogue among all the synthesized entities. Encouraging outcomes motivates fatty acids for further development of more effective and safer compounds.