Structural variation of the 3-acetamido-4,5,6-trihydroxyazepane iminosugar through epimerization and C-alkylation leads to low micromolar HexAB and NagZ inhibitors.

We report the synthesis of seven-membered iminosugars derived from a 3S-acetamido-4R,5R,6S-trihydroxyazepane scaffold and their evaluation as inhibitors of functionally related exo-N-acetylhexosaminidases including human O-GlcNAcase (OGA), human lysosomal ß-hexosaminidase (HexAB), and Escherichia coli NagZ. Capitalizing on the flexibility of azepanes and the active site tolerances of hexosaminidases, we explore the effects of epimerization of stereocenters at C-3, C-5 and C-6 and C-alkylation at the C-2 or C-7 positions. Accordingly, epimerization at C-6 (L-ido) and at C-5 (D-galacto) led to selective HexAB inhibitors whereas introduction of a propyl group at C-7 on the C-3 epimer furnished a potent NagZ inhibitor.

Selective trihydroxylated azepane inhibitors of NagZ, a glycosidase involved in Pseudomonas aeruginosa resistance to ß-lactam antibiotics.

The synthesis of a series of d-gluco-like configured 4,5,6-trihydroxyazepanes bearing a triazole, a sulfonamide or a fluorinated acetamide moiety at C-3 is described. These synthetic derivatives have been tested for their ability to selectively inhibit the muropeptide recycling glucosaminidase NagZ and to thereby increase sensitivity of Pseudomonas aeruginosa to ß-lactams, a pathway with substantial therapeutic potential. While introduction of triazole and sulfamide groups failed to lead to glucosaminidase inhibitors, the NHCOCF3 analog proved to be a selective inhibitor of NagZ over other glucosaminidases including human O-GlcNAcase and lysosomal hexosaminidases HexA and B.

Synthetic deoxynojirimycin derivatives bearing a thiolated, fluorinated or unsaturated N-alkyl chain: identification of potent α-glucosidase and trehalase inhibitors as well as F508del-CFTR correctors.

The synthesis of eleven 1-deoxynojirimycin (DNJ) derivatives presenting either a monofluoro, difluoro, thiolated or unsaturated N-alkyl chain of various length is described. Exploiting the unsaturated moiety on the nitrogen, fluorine has been introduced through a HF/SbF5 superacid catalysed hydrofluorination and thiol-ene click chemistry allowed introduction of sulfur. The synthetic derivatives have been tested for their ability to inhibit glycosidases and correct F508del-CFTR. Two of the unsaturated iminosugars exhibited potency similar to Miglustat as F508del-CFTR correctors. The thioalkyl iminosugars as well as the corresponding alkyl iminosugars demonstrated low micromolar α-glucosidases and trehalases inhibition. Introduction of fluorine abolished F508del-CFTR correction and trehalase inhibition.

γ-Aminoalcohol rearrangement applied to pentahydroxylated azepanes provides pyrrolidines epimeric to homoDMDP.

A series of pentahydroxylated pyrrolidines, displaying five contiguous stereogenic centres and epimeric to α-glucosidase inhibitor homoDMDP, have been synthesized. The key step involves a γ-aminoalcohol rearrangement applied to polyhydroxylated azepanes. These five-membered iminosugars demonstrate micromolar inhibition of glycosidases.

N- and C-alkylation of seven-membered iminosugars generates potent glucocerebrosidase inhibitors and F508del-CFTR correctors.

The glycosidase inhibitory properties of synthetic C-alkyl and N-alkyl six-membered iminosugars have been extensively studied leading to therapeutic candidates. The related seven-membered iminocyclitols have been less examined despite the report of promising structures. Using an in house ring enlargement/C-alkylation as well as cross-metathesis methodologies as the key steps, we have undertaken the synthesis and biological evaluation of a library of fourteen 2C- and eight N-alkyl tetrahydroxylated azepanes starting from an easily available glucopyranose-derived azidolactol. Four, six, nine and twelve carbon atom alkyl chains have been introduced. The study of two distinct D-gluco and L-ido stereochemistries for the tetrol pattern as well as R and S configurations for the C-2 carbon bearing the C-alkyl chain is reported. We observed that C-alkylation of the L-ido tetrahydroxylated azepane converts it from an α-L-fucosidase to a ß-glucosidase and ß-galactosidase inhibitor while N-alkylation of the D-gluco iminosugar significantly improves its inhibition profile leading to potent ß-glucosidase, ß-galactosidase, α-L-rhamnosidase and ß-glucuronidase inhibitors whatever the stereochemistry of the alkyl chain. Interestingly, the N-alkyl chain length usually parallels the azepane inhibitor potency as exemplified by the identification of a potent glucocerebrosidase inhibitor (Ki 1 µM) bearing a twelve carbon atom chain. Additionally, several C-alkyl azepanes demonstrated promising F508del-CFTR correction unlike the parent tetrahydroxyazepanes. None of the C-alkyl and N-alkyl azepanes did inhibit ER α-glucosidases I or II.

Novel imino sugar α-glucosidase inhibitors as antiviral compounds.

Deoxynojirimycin (DNJ) based imino sugars display antiviral activity in the tissue culture surrogate model of Hepatitis C (HCV), bovine viral diarrhoea virus (BVDV), mediated by inhibition of ER α-glucosidases. Here, the antiviral activities of neoglycoconjugates derived from deoxynojirimycin, and a novel compound derived from deoxygalactonojirimycin, by click chemistry with functionalised adamantanes are presented. Their antiviral potency, in terms of both viral infectivity and virion secretion, with respect to their effect on α-glucosidase inhibition, are reported. The distinct correlation between the ability of long alkyl chain derivatives to inhibit ER α-glucosidases and their anti-viral effect is demonstrated. Increasing alkyl linker length between DNJ and triazole groups increases α-glucosidase inhibition and reduces the production of viral progeny RNA and the maturation of the envelope polypeptide. Disruption to viral glycoprotein processing, with increased glucosylation on BVDV E2 species, is representative of α-glucosidase inhibition, whilst derivatives with longer alkyl linkers also show a further decrease in infectivity of secreted virions, an effect proposed to be distinct from α-glucosidase inhibition.

[Epidemiological, clinical and evolutionary aspects of severe traumatic brain injury in the multipurpose intensive care unit of Gabriel Touré Teaching Hospital]. / Aspects epidemiologiques, cliniques et evolutifs des traumatises cranio-encephaliques graves au service de reanimation polyvalente du CHU Gabriel Toure.

Among traumas, cranial involvement occupies a special place due to their severity and the importance of the sequelae that they can cause. They are said to be serious when the Glasgow Scale (GCS) ≤ 8. The frequency of severe brain injury in the population in African studies ranges from 3.5 to 7. Mortality is, however, poorly known in developing countries, which led us to initiate this work, which aimed to study the epidemiological, clinical and evolutionary aspects of severe traumatic brain injury in the multipurpose intensive care unit of Gabriel Touré University Hospital. MATERIAL AND METHOD: 24-month retrospective study, descriptive and analytical, including all severe traumatic brain injury patients hospitalized in the resuscitation department of Gabriel Touré University Hospital during this study period. RESULTS: During the periodof 1165 patients admitted to the service, 72 were hospitalized for severe cranio-encephalic trauma for a prevalence of 6%. The age group of 21 - 40 years was the majority with (23) or 44.4% and the average age was 30.93 ± 18.8 years with extremes of 8 months and 79 years.The male sex was predominant with (65) or 90.3%, and a sex ratio of 9.28. During our study, (57) or 79.2% of serious traumatic brain injuries were due to road accidents with motorcycle-motorcycle collisions as a mechanism in (20) or 27.8%. Shopkeepers, and students were the most affected social strata with respectively (22) or 30.6% and (20) or 27.8%. Patient transport was provided by non-medical ambulances for (31) or 43.1% and admission time was between 30 minutes and 6 hours in (16) or 22.2% of cases. (62) or 86.1% had GCS between 6-8 and bilateral mydriasis was present in (10) or 13.9% of patients. (9)or 12.5% of patients had hypotension (systolic blood pressure<90 mm Hg) on admission and average blood pressure<90 mmHg was observed in (32) or 44.4% of patients. (23) or 31.9% had a SPO2 <90%. Cranio-encephalic scanning was performed in 62 or 86.1% and discovered as lesions (25) or 34.9% hemorrhagic contusions followed by extradural hematomas (13) or 18.1%. (63) or 87.5%, patients were intubated-ventilated-sedated in addition to resuscitation. (28) or 38.9% of patients had undergone a surgical intervention with (9) or 12.5% having osmotherapy.The evolution was marked by death of (48) or 66.7%. CONCLUSION: Severe cranio-encephalic trauma represents a major cause of morbidity and mortality. The establishment of pre-hospital medicine will allow better care and reduction of mortality by early and continuous management of ACSOS and respiratory and / or hemodynamic distress, which are very often associated with severe TCE.

Parmi les traumatismes, les atteintes crâniennes occupent une place particulière du fait de leur gravité et de l'importance des séquelles qu'elles peuvent entraîner. Ils sont dits graves quand le score de Glasgow (GCS) ≤ 8. La fréquence des traumatismes crânio-encéphaliques (TCE) graves au sein de la population dans les études africaines varie entre 3,5 et 7. La mortalité est cependant mal connue dans les pays en voie de développement ce qui nous a conduit à initier ce travail qui avait pour objetd'étudier les aspects épidémiologiques, cliniques et évolution des traumatisés crâniens graves au service de réanimation polyvalente du centre hospitalier universitaire Gabriel Touré. MATÉRIEL ET MÉTHODE: Etude, descriptive et analytique à collecte rétrospective s'étant déroulée sur 24 mois, incluant tous les patients traumatisés crânio-encéphaliques graves hospitalisés dans le service de réanimation du centre hospitalier universitaire Gabriel Touré durant cette période d'étude. RÉSULTATS: Durant la période sur 1165 patients admis dans le service.72 ont été hospitalisés pour traumatisme crânio-encéphalique grave soit une prévalence de 6%. La tranche d'âge de 21 - 40 ans était majoritaire avec(32) soit 44,4% et l'âge moyen était de 30,93 ±18,8 ans avec des extrêmes de 8 mois et 79 ans. Le sexe masculin était prédominant avec (65) soit 90,3%, et un sex-ratio de 9,28. Durant notre étude (57) soit 79,2% des TCE graves étaient dus aux accidents de la voie publique avec comme mécanisme les collisions moto-moto dans (20) soit27,8%. Les commerçants, et les élèves et étudiants étaient les couches sociales les plus touchées avec respectivement(22) soit 30,6% et (20) soit 27,8%. Le transport était assuré par des ambulances non médicalisées à(31) soit 43,1% et le délai d'admission était compris entre 30 minutes et 6 heures dans (16) soit 22,2% des cas.(62) soit 86,1% avaient GCS entre 6-8 et une mydriase bilatérale était présente chez (10) soit 13,9 % des patients. (9) soit 12,5% des patients avaient présenté une hypotension (pression artérielle systolique< 90 mm Hg) à l'admission et une pression artérielle systolique ≤ 90 mm Hg avait été observée chez (32) soit 44,4% des patients. Durant notre (23) soit 31,9% avaient une SPO2 < 90%. Le scanner cranio-encéphalique a été réalisé chez (62) soit 86,1% et retrouvait comme lésions, les contusions hémorragiques (25) soit 34,9% suivis des hématomes extraduraux (13) soit 18,1%.(63) soit 87,5% des patients ontété intubés -ventilés-sédatés en plus à des mesures de réanimation. (28) soit 38,9% des patients avaient subi une intervention chirurgicale associée chez (9) soit 12,5% à une osmothérapie. L'évolution a été marquée par une létalité de (48) soit 66,7%. CONCLUSION: Les traumatismes crânio-encéphaliques graves représentent une cause majeure de morbi-mortalité. La mise en place d'une médecine préhospitalière permettra une meilleure prise en charge et la réduction de lamortalité.Par une prise en charge précoce et continue des ACSOS et des détressés respiratoires et/ou hémodynamiques qui sont très souvent associées au TCE grave.

Author Correction: Effects of biochar, waste water irrigation and fertilization on soil properties in West African urban agriculture.

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Effects of biochar, waste water irrigation and fertilization on soil properties in West African urban agriculture.

In large areas of sub-Saharan Africa crop production must cope with low soil fertility. To increase soil fertility, the application of biochar (charred biomass) has been suggested. In urban areas, untreated waste water is widely used for irrigation because it is a nutrient-rich year-round water source. Uncertainty exists regarding the interactions between soil properties, biochar, waste water and fertilization over time. The aims of this study were to determine these interactions in two typical sandy, soil organic carbon (SOC) and nutrient depleted soils under urban vegetable production in Tamale (Ghana) and Ouagadougou (Burkina Faso) over two years. The addition of biochar at 2 kg m-2 made from rice husks and corn cobs initially doubled SOC stocks but SOC losses of 35% occurred thereafter. Both biochar types had no effect on soil pH, phosphorous availability and effective cation exchange capacity (CEC) but rice husk biochar retained nitrogen (N). Irrigation with domestic waste water increased soil pH and exchangeable sodium over time. Inorganic fertilization alone acidified soils, increased available phosphorous and decreased base saturation. Organic fertilization increased SOC, N and CEC. The results from both locations demonstrate that the effects of biochar and waste water were less pronounced than reported elsewhere.

Catching elusive glycosyl cations in a condensed phase with HF/SbF5 superacid.

Glycosyl cations are universally accepted key ionic intermediates in the mechanism of glycosylation, the reaction that covalently links carbohydrates to other molecules. These ions have remained hypothetical species so far because of their extremely short life in organic media as a consequence of their very high reactivity. Here, we report the use of liquid hydrofluoric acid-antimony pentafluoride (HF/SbF5) superacid to generate and stabilize the glycosyl cations derived from peracetylated 2-deoxy and 2-bromoglucopyranose in a condensed phase. Their persistence in this superacid medium allows their three-dimensional structure to be studied by NMR, aided by complementary computations. Their deuteration further confirms the impact of the structure of the glycosyl cation on the stereochemical outcome of its trapping.

(Aryloxy)methylsilane derivatives as new cholesterol biosynthesis inhibitors: synthesis and hypocholesterolemic activity of a new class of squalene epoxidase inhibitors.

A series of 3-substituted (aryloxy)silane derivatives of benzylamine (4, 4', or 4") was synthesized and evaluated for hypocholesterolemic activity. Most of the new silane derivatives were identified as potent inhibitors of pig liver squalene epoxidase with IC50 values in the submicromolar range. In vitro inhibition of cholesterol biosynthesis in Hep-G2 cells was observed with a very good potency for the ene-yne derivatives 4a, 4i, 4n, 4q, and 4u as well as for the yne-yne compound 4". In vivo, 4i, 4u, 4', and 4" were found to decrease cholesterol biosynthesis in rats upon oral administration with ED50 values in the range of 2-7 mg/kg. Therefore, these new (aryloxy)methylsilane derivatives of benzylamine represent a new class of potent squalene epoxidase inhibitors with promising hypocholesterolemic properties.

Synthesis of methyl beta-D-arabinofuranoside 5-[1D (and L)-myo-inositol 1-phosphate], the capping motif of the lipoarabinomannan of Mycobacterium smegmatis.

The total synthesis of methyl beta-D-arabinofuranoside 5-(myo-inositol 1-phosphate), the capping motif of the lipoarabinomannan (LAM) of Mycobacterium smegmatis, has been completed. The stereoselective synthesis of beta-D-arabinofuranosides has been achieved via an internal aglycon delivery approach using Ogawa and Ito's method. Coupling with enantiomeric myo-inositol derivatives gave the diastereoisomeric title compounds in good overall yield. Comparison with the natural product firmly established the proposed structure for the capping of the LAM but left the absolute configuration of the myo-inosityl moiety undetermined.