Synthesis and comparison of the biological activity of monocyclic phosphonate, difluorophosphonate and phosphate analogs of the natural AChE inhibitor cyclophostin

Publication date: Available online 30 October 2015
Source:Bioorganic & Medicinal Chemistry
Author(s): Benjamin P. Martin, Elena Vasilieva, Cynthia M. Dupureur, Christopher D. Spilling
New monocyclic phosphate, phosphonate and difluorophosphonate analogs of the natural AChE inhibitor cyclophostin were synthesized and their activity toward human AChE examined. Surprisingly, the phosphate, phosphonate, and difluorophosphonate analogs all showed diminished activity when compared with the natural product.

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1,2,3-Triazole pharmacophore-based benzofused nitrogen/sulfur heterocycles with potential anti-Moraxella catarrhalis activity

Publication date: Available online 30 October 2015
Source:Bioorganic & Medicinal Chemistry
Author(s): Silvija Maračić, Tatjana Gazivoda Kraljević, Hana Čipčić Paljetak, Mihaela Perić, Mario Matijašić, Donatella Verbanac, Mario Cetina, Silvana Raić-Malić
Versatile 1,2,3-triazole pharmacophore-based benzofused heterocycles containing halogen-substituted aromatic (9–17 and 25–28), 7-substituted coumarin (18–23 and 29–30) or penciclovir-like subunit (31a,b–38a) were designed and synthesized to evaluate their antibacterial activities against selected Gram-positive and Gram-negative bacteria. Hybridization approach using environmetally friendly Cu(I)-catalyzed click reaction under microwave irradiation was adopted in the synthesis of regioselective 1,4-disubstituted 1,2,3-triazole tethered heterocycles (9–23 and 25–30), while post-N-alkylation of NH-1,2,3-triazoles afforded both 2,4- (31a–38a) and 1,4-disubstituted (31b–33b, 35b–37b) 1,2,3-triazole regioisomers. The compounds 18–23 and 25–30 revealed fluorescence in the violet region of the visible spectrum with a strong influence of phenyl spacer in 25–30 on both wavelength and emission intensity. Fusion of selected subunits led to new hybrid architecture, benzothiazole–1,2,3-triazole–coumarin 29 that demonstrated extremly narrow spectrum activity towards fastidious Gram-negative bacteria M. catarrhalis. Selected hybrid showed the potency against Moraxella catarrhalis (MIC ⩽ 0.25 μg/mL) comparable to that of reference antibiotic azithromycin, which suggested that further investigations are necessary to optimize this potential hit compound as a new anti-Moraxella catarrhalis agent.

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Discovery of bis-ary urea derivatives as potent and selective Limk inhibitors: Exploring Limk1 activity and Limk1/ROCK2 selectivity through a combined computational study

Publication date: Available online 30 October 2015
Source:Bioorganic & Medicinal Chemistry
Author(s): Jiaxin Cui, Mei Ding, Wei Deng, Yan Yin, Zhonghua Wang, Hong Zhou, Guofeng Sun, Yu Jiang, Yangbo Feng
Lim kinase (Limk), a proline/serine-rich sequence, can regulate the polymerization of the actin filaments by phosphorylating, and it is found to be highly involved in various human diseases. In this paper, 47 reported Limk1 inhibitors with bis-ary urea scaffold were used to design potent and selective Limk inhibitors by computational approaches. Firstly, the structure-Limk1 activity relationship models (3D-QSAR) and structure-Limk1/ROCK2 selectivity relationship models (3D-QSSR) were developed and both 3D-QSAR and 3D-QSSR models showed good correlative and predictive abilities. Then, the molecular docking and molecular dynamics (MD) simulations were employed to validate the optimal docking conformation and explore the binding affinities. Finally, five new compounds were designed and all of them exhibited good Limk1 inhibition and Limk1/ROCK2 selectivity after synthesis and biological evaluation, which demonstrated that the obtained information from computational studies were valuable to guide Limk inhibitors' design.

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Synthesis of di- and tri-saccharide fragments of Salmonella typhi Vi capsular polysaccharide and their zwitterionic analogues

Publication date: Available online 30 October 2015
Source:Bioorganic & Medicinal Chemistry
Author(s): Matteo Fusari, Silvia Fallarini, Grazia Lombardi, Luigi Lay
Zwitterionic polysaccharides (ZPS) behave like traditional T cell-dependent antigens, suggesting the design of new classes of vaccines alternative to currently used glycoconjugates and based on the artificial introduction of a zwitterionic charge motif onto the carbohydrate structure of pathogen antigens. Here we report the new synthesis and antigenic evaluation of di-/tri-saccharide fragments of Salmonella typhi Vi polysaccharide, as well as of their corresponding zwitterionic analogues. Our strategy is based on versatile intermediates enabling chain elongation either by iterative single monomer attachment or by faster and more flexible approach using disaccharide donors.The effect of structural modifications of the synthetic compounds on antigenic properties was evaluated by competitive ELISA. All the oligosaccharides were recognized by a specific anti-Vi polyclonal antibody in a concentration-dependent manner, and the introduction of a zwitterionic motif into the synthetic molecules did not prevent the binding.

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Investigation of the mechanisms of Angelica dahurica root extract-induced vasorelaxation in isolated rat aortic rings

Background: The root of Angelica dahurica Bentham et Hooker (Umbelliferae) has been used as a traditional medicine for colds, headache, dizziness, toothache, supraorbital pain, nasal congestion, acne, ulcer, carbuncle, and rheumatism in China, Japan, and Korea. Interestingly, it has been used in the treatment of vascular diseases including hypertension. The aim of this study was to provide pharmacological evidence for the anti-hypertensive effect of A. dahurica by investigating the mechanism underlying its vasorelaxant effect. Methods: The vasorelaxant effects of a 70 % methanol extract of the A. dahurica root (ADE) on rat thoracic aorta and its underlying mechanisms were assessed. Isolated rat aortic rings were suspended in organ chambers containing 10 ml Krebs-Henseleit (K-H) solution and placed between 2 tungsten stirrups and connected to an isometric force transducer. Changes in tension were recorded via isometric transducers connected to a data acquisition system. Results: ADE causes concentration-dependent relaxation in both endothelium-intact and endothelium-denuded aortic rings precontracted with phenylephrine (PE; 1 μM) or potassium (KCl; 60 mM) in K-H solution. And pre-treatment with ADE (1 mg/ml) inhibited calcium-induced vasocontraction of aortic rings induced by PE or KCl. However, ADE pre-treatment did not affect the contraction induced by PE or caffeine in Ca 2+ -free K-H solution. Conclusions: These results suggested that the ADE has vasorelaxant effect and the vasorelaxant activity is mediated by endothelium-independent pathway that includes the blockade of extracellular calcium influx through the receptor-operated Ca 2+ channel and voltage-dependent calcium channel pathways.

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Retrospective case-series of Paecilomyces lilacinus ocular mycoses in Queensland, Australia

Background: The purpose of this study was to report: (1) the varying presentation of Paecilomyces ocular infections arising in Queensland; (2) the significance of immunosuppression as a primary determinant of disease; (3) the outcomes of voriconazole use; and (4) the ongoing need for both surgical and medical management of this devastating fungal infection. Methods: A retrospective case series of 21 culture proven individuals participated in this series and were identified via a review of the pathology reporting system utilized in the Queensland public health system. All culture proven individuals were subjected to a systematic chart review. Results: The primary risk factor for Paecilomyces lilacinus infection is immunosuppression with 81.25 % of individuals being on some form of immunosuppression (i.e. systemic or topical). Of the cases 71.43 % had an intact epithelial surface at the time of diagnosis, and 76 % had no previous ocular history. The final visual outcomes were nine cases with HM vision or worse, three cases with 6/48–6/60 vision, three cases 6/12–6/24, and six cases with 6/12 vision or better. Despite voriconazole use rates of greater than 80 %, protracted and poor treatment outcomes continue to be commonplace. Conclusions: Paecilomyces lilacinus is a filamentous fungus that has a predilection for immunosuppressed individuals. Despite in vitro and case reports demonstrating the effectiveness of voriconazole poor outcomes continue to be seen.

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Meningitis caused by Pasteurella multocida in a dog owner without a dog bite: clonal lineage identification by MALDI-TOF mass spectrometry

Background: Pasteurella multocida meningitis in an immunocompetent patient is rare and commonly occurs after animal bite. To our knowledge, only 48 cases have been reported in the literature since 1989. P. multocida meningitis is commonly linked to animal contagion. Here we report on a new case of P. multocida meningitis in an immunocompetent patient who is a dog owner without a dog bite. We used the matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry to investigate the clonal lineage between animal and human isolates.Case presentationIn our case, a 25-year-old immunocompetent French Caucasian woman with nothing notable in her medical history was admitted for meningitis caused by P. multocida. Clonal lineage of P. multocida strains from cerebrospinal fluid and blood culture and her dog's oral cavity has been recognized by MALDI-TOF mass spectrometry dendrograms and clustering of the 21 P. multocida isolates in our centres. She was treated by a combination of intravenous ceftriaxone (2 g/day) and oral levofloxacin (1 g/day). She was discharged on the 6th day of admission. The antimicrobial therapy was conducted for 15 days. The dog was treated by clavulanic-acid amoxicillin for 3 weeks by the veterinarian. The evolution of the patient at the 5th month after the end of the antimicrobial therapy was normal without any neurological after-effects. Conclusion: The meningitis caused by P. multocida could be considered a cause of human meningitis in dog lovers without an animal bite. MALDI-TOF mass spectrometry should be considered as it is an accurate tool to identify clonal lineage between animal and human isolates.

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