A Coumarin-Based Analogue of Thiacetazone as Dual Covalent Inhibitor and Potential Fluorescent Label of HadA in Mycobacterium tuberculosis.

A novel coumarin-based molecule, designed as a fluorescent surrogate of a thiacetazone-derived antitubercular agent, was quickly and easily synthesized from readily available starting materials. This small molecule, coined Coum-TAC, exhibited a combination of appropriate physicochemical and biological properties, including resistance toward hydrolysis and excellent antitubercular efficiency similar to that of well-known thiacetazone derivatives, as well as efficient covalent labeling of HadA, a relevant therapeutic target to combat Mycobacterium tuberculosis. More remarkably, Coum-TAC was successfully implemented as an imaging probe that is capable of labeling Mycobacterium tuberculosis in a selective manner, with an enrichment at the level of the poles, thus giving for the first time relevant insights about the polar localization of HadA in the mycobacteria.

Synthesis, In Silico, and In Vitro Evaluation of Anti-Leishmanial Activity of Oxadiazoles and Indolizine Containing Compounds Flagged against Anti-Targets.

Due to the lack of approved vaccines against human leishmaniasis and the limitations of the current chemotherapy inducing side effects and drug resistance, development of new, effective chemotherapeutic agents is essential. This study describes the synthesis of a series of novel oxadiazoles and indolizine-containing compounds. The compounds were screened in silico using an EIIP/AQVN filter followed by ligand-based virtual screening and molecular docking to parasite arginase. Top hits were further screened versus human arginase and finally against an anti-target battery to tag their possible interactions with proteins essential for the metabolism and clearance of many substances. Eight candidate compounds were selected for further experimental testing. The results show measurable in vitro anti-leishmanial activity for three compounds. One compound with an IC50 value of 2.18 µM on Leishmania donovani intramacrophage amastigotes is clearly better positioned than the others as an interesting molecular template for further development of new anti-leishmanial agents.

Copper(I)-USY as a Ligand-Free and Recyclable Catalyst for Ullmann-Type O-, N-, S-, and C-Arylation Reactions: Scope and Application to Total Synthesis.

The copper(I)-doped zeolite CuI-USY proved to be a versatile, efficient, and recyclable catalyst for various Ullmann-type coupling reactions. Easy to prepare and cheap, this catalytic material enables the arylation and heteroarylation of diverse O-, N-, S-, and C-nucleophiles under ligand-free conditions while exhibiting large functional group compatibility. The facility of this catalyst to promote C-O bond formation was further demonstrated with the total synthesis of 3-methylobovatol, a naturally occurring diaryl ether of biological relevance. From a mechanistic viewpoint, two competitive pathways depending on the nature of the nucleophile and consistent with the obtained results have been proposed.

Cu(I)-USY as a Ligand-Free and Recyclable Catalytic System for the Ullmann-Type Diaryl Ether Synthesis.

The catalytic potential of copper(I)-exchanged zeolites was evaluated in the Ullmann-type synthesis of diaryl ethers. Among four investigated zeolites (i.e., USY, MOR, ß, and ZSM5), Cu(I)-USY was the best catalyst and proved efficient under ligand-free conditions in toluene at 120 °C. Cu(I)-USY was also easy to recover and was recyclable up to five times without significant loss of activity.

Characterization of the antiproliferative activity of Xylopia aethiopica.

BACKGROUND: Xylopia aethiopica, a plant found throughout West Africa, has both nutritional and medicinal uses. The present study aims to characterize the effects of extracts of this plant on cancer cells. RESULTS: We report that X. aethiopica extract prepared with 70% ethanol has antiproliferative activity against a panel of cancer cell lines. The IC50 was estimated at 12 µg/ml against HCT116 colon cancer cells, 7.5 µg/ml and > 25 µg/ml against U937 and KG1a leukemia cells, respectively. Upon fractionation of the extract by HPLC, the active fraction induced DNA damage, cell cycle arrest in G1 phase and apoptotic cell death. By using NMR and mass spectrometry, we determined the structure of the active natural product in the HPLC fraction as ent-15-oxokaur-16-en-19-oic acid. CONCLUSION: The main cytotoxic and DNA-damaging compound in ethanolic extracts of Xylopia aethiopica is ent-15-oxokaur-16-en-19-oic acid.

Novel lipophilic 7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid derivatives as potential antitumor agents: improved synthesis and in vitro evaluation.

A convenient route for the synthesis of some acyloxymethyl esters and carboxamides of levofloxacin (LV) with modulated lipophilicity is described. The synthesized compounds were evaluated in vitro for their growth inhibitory effect in five human cancer cell lines. The most efficient LV derivatives (ester 2e and amide 4d) displayed IC(50) values in the 0.2-2.2 µM range, while IC(50) values for parent LV ranged between 70 and 622 µM depending on the cell line. The esters displayed no in vivo toxicity up to 80 mg/kg when administered intraperitoneally. This study thus shows that LV analogs displayed antitumor efficacy, at least in vitro, a feature that appeared to be independent from the lipophilicity of the grafted substituent.

Revisiting the aldol reaction of cis-α,ß-epoxyaldehyde promoted by BF(3)·Et(2)O: direct access to 2-deoxy-2-fluoro heptulosonic ester analogues.

The aldol reaction between cis-3-((tert-butyldiphenylsilyloxy)methyl)oxirane-2-carbaldehyde and ethyl-2-(trimethylsilyloxy)-2-propenoate promoted by boron trifluoride diethyl etherate was reinvestigated. By varying the work-up conditions, a new 2-deoxy-2-fluoro heptulosonic ester analogue was synthesized. Derivatizations and detailed NMR analysis allowed the complete characterization of this fluoro analogue and its derivatives.

Preparation of 6,6,1',1',6',6'-hexadeutero sucrose.

The preparation of 6,6,1',1',6',6'-hexadeutero sucrose is reported. The synthesis is based on a triple oxidation of a protected sucrose 6,1',6'-triol to the corresponding 6,1',6'-tricarboxylic acid or ester, followed by reduction with lithium aluminium deuteride. This triple oxidation could be achieved either using cat. TEMPO-NaOCl (to the acid) or PDC-Ac(2)O-t-BuOH (to the t-butyl carboxylic ester).

Straightforward route for anchoring a glucosyl moiety onto nucleophilic species: reaction of amines and alcohols with carboxymethyl 3,4,6-tri-O-acetyl-alpha-D-glucopyranoside 2-O-lactone.

The base-catalyzed reaction of carboxymethyl 3,4,6-tri-O-acetyl-alpha-D-glucopyranoside 2-O-lactone (prepared from isomaltulose) with amino acids and fatty amines under basic catalysis gave a series of new pseudoglucopeptides, nonionic amphiphiles, and polymerizable derivatives. The same reaction applied to alcohols provided the corresponding 2-(alpha-D-glucopyranosyloxy)acetyl esters with either basic or acidic catalysts.

Synthetic Approaches to Novel Archaeal Tetraether Glycolipid Analogues.

Symmetrical and unsymmetrical archaeal tetraether glycolipid analogues have been prepared. The syntheses are based upon the elaboration of lipid cores from versatile chiral starting materials followed by simultaneous or sequential introduction of polar headgroups. Three pathways (A-C) were elaborated for the synthesis of stereochemically defined lipids 14-16 characterized by a straight bridging spacer and two dihydrocitronellyl chains attached to glycerol units at the sn-3 and sn-2 positions, respectively. Pathway C appeared to be particularly advantageous for the synthesis of tetraether 9, which possesses a cyclopentane unit as found in thermoacidophilic lipids. Diglycosylated lipids 4-6 were produced in 49-53% yields by reaction of diols 14-16 with beta-D-galactofuranosyl donor 31, whereas unsymmetrical lipids possessing either two different carbohydrate units 7 or a saccharidic moiety and a phosphate group 8 were efficiently prepared from monoprotected diol 35. These compounds represent the first examples of tetraether-type analogues containing a phosphate unit and/or glycosyl moieties.