1,721,150 research outputs found
Novel inhibitors of FtsZ as antimicrobial agents: synthesis and Structure Activity Relationship
No full textThe number and prevalence of drug-resistant bacterial strains are in constant growth1 and even the most recently approved antimicrobials act on a restricted number of “traditional” targets, thus increasing the probability for the development of resistance. This poses a number of challenges which remain largely unmet and there is a strong need for the discovery of potent and versatile drugs with innovative mechanisms of action.
FtsZ (Filamentous temperature sensitive Z) emerged as a promising target, due to its ubiquitous expression in bacteria and to its essential role in cell division.
In recent years, a variety of molecules proved able to interact with this protein and to selectively inhibit bacterial cell division. Our research group developed interesting derivatives displaying good antibacterial activities against Staphylococcus aureus (methicillin-resistant and sensible strains), vancomycin-resistant Enterococcus faecalis and Mycobacterium tuberculosis.
The aim of the present communication is to summarize the Structure-Activity Relationship for differently substituted heterocycles, linked by a methylenoxy-bridge to the 2,6-difluorobenzamide
Synthesis of N,N'-dibenzylethylenediamine via palladium-carbon-catalysed reductive alkylation
No full textReductive alkylation of ethylenediamine with benzaldehyde and hydrogen in the presence of Pd-C has been investigated in order to optimize the synthesis of N,N'-dibenzylethylenediamine; the efficiency of the procedure has been improved by minimizing undesired competing reactions of cyclization and hydrogenolysis
FOLATES, COMPOSITIONS AND USES THEREOF
No full textThe present invention relates to folates, compositions and uses thereof, in particular, the invention describes a crystalline or amorphous compound which is unsubstituted folate or reduced folate, or the natural or unatural isomers thereof, of at least one organic base, as well ac compositions and uses thereof. The compounds of the invention show a long lasting stability as well as a peculiarly high water-solubility
Development of a reliable synthetic scheme to isolate 2-hydroxy-2-benzodioxanylethoxy benzamides for the obtainment of fluorescent probles
No full textAiming at fighting antimicrobial resistance when acting on an innovative target, we developed a class of FtsZ inhibitors as promising new antimicrobials, which are structurally benzodioxane-benzamides. While characterizing the mechanism of action of this class of compounds, the need of a FtsZ fluorescent ligand to determine several biochemical data, such as confocal microscopy images of protein-ligand co-localization, arose. Therefore, starting from the structure of our strongest compound, which is able to interact and perturb both S. aureus and E. coli FtsZs, we decided to introduce an -OH group as an anchoring point for the preparation of both prodrugs and fluorescent probes, by inserting a proper dye (compound I-OH). This compound required the design of an ad hoc synthetic pathway, able to separate the two diastereomeric threo and erythro couples. A common intermediate of this synthesis is the epoxydic derivative (Scaffold A), obtained as a mixture of the two diastereomeric pairs, and soon chromatographied achieving the isolated diastereoisomers, which parallelly underwent ring opening, yielding to the final desired compounds (I-OH threo and I-OH erythro). After their isolation, each couple of enantiomers were linked to a proper fluorescent dye through a suitable spacer (Figure 1). With this work, we developed a synthetic scheme applicable to all the benzodioxane-benzamides FtsZ inhibitors, regardless the substitution of the benzodioxane moiety, to obtain hydroxylated derivatives
Solvent and substrate dependent regioselective synthesis of 2 and 3 substituted 2,3-dihydro-1,4-benzoxathiine
No full textThe 1,4-benzoxathiane scaffold is a common moiety present in several therapeutic agents, acting as adrenoceptor antagonists, or as anticancer agents.
Very recently, designing novel antibacterial agents, and aiming to afford 2- and 3- substituted benzoxathiine derivatives, we initially followed an established synthetic scheme we were used to apply for the 1,4-benzodioxane scaffold.
We then broaden the reaction conditions, finding an easy and reliable method for the obtainment of both 2,3-dihydro-1,4-benzoxathiine-2-yl derivatives and 2,3-dihydro-1,4-benzoxathiine-3-yl ones.
As a result, we observed that the right choice of an appropriate solvent and a correct substrate allow the exclusive formation of one of the two possible regioisomers. The relative solvation of O- and S- anions induced the regioselectivity; specifically, when the 1,2-mercaptophenol is treated with an organic base, in a lipophilic solvent, in the absence of water and in the presence of a lipophilic 2-bromo acryl derivative, the thiolate succeeds as nucleophile and thus the 2-substituted compound is fully accomplished.
On the other hand, the treatment in the presence of water and with a polar reactive let the phenoxide to manage the nucleophilic substitution and therefore to afford 3-substituted compounds
Synthesis and structure-activity relationship of novel inhibitors of the prokaryotic divisome protein FtsZ
No full textAntimicrobial resistance is an ever growing cause for concern among health authorities across the world. In fact, therapeutic options for life- threatening infections are rapidly being ruled out and there is a strong urge to discover and develop potent drugs with innovative mechanisms of action.
In the search for new targets, FtsZ (Filamentous temperature sensitive Z) was identified as a very promising candidate. Functionally a GTP-ase, it plays a crucial role in the bacterial cell division process and is widely and specifically expressed among Prokaryotes.
In recent years, our research group developed and synthesized a class of FtsZ inhibitors with interesting antimicrobial activity against drug-resistant strains and further expanded on their SAR through a series of isosteric, positional or substituent modifications on the heterocyclic scaffold.
The aim of the present communication is to summarize the synthetic pathways and the SAR studies for this class of compounds, characterized by differently substituted heterocycles linked by a methylenoxy-bridge to a 2,6-difluorobenzamide
How to fight antimicrobial resistance: design and synthesis of FTSZ inhibitors as novel potent gram-positive antibiotics
No full textNowadays, antimicrobial resistance is a global threat to public health. This well know plague only recently burst out, prompting to the urgent need of developing efficient antibiotics with innovative mechanisms of action.
In this context, the bacterial divisome turned out to be an interesting and promising target (1). Cell division proteins are indeed crucial for bacteria viability, are widely conserved among several species and are completely absent in eukaryotic cells, thus strengthening the selectivity of the novel antimicrobics. FtsZ (Filamentous temperature sensitive Z) is one of the essential cell division proteins; FtsZ is a tubulin homologue (2) and is the first protein that localizes to the mid-point of the cell and undergoes polymerization in a GTP-dependent manner, bringing to the formation of the Z-ring. It recruits at least ten other cell division proteins, which enable cell constriction, the formation of mesosome and two daughter cells (3).
Recently, we studied and developed FtsZ inhibitors, starting from the most significant results of other research groups and confirming that FtsZ inhibition results in a bactericidal effect.
We prepared 3-Methoxybenzamide (3-MBA) derivatives, structurally similar to the FtsZ inhibitors lead compound: PC190723 (4-6).
Our derivatives (which general structure is depicted above) were designed replacing the thiazolopyridine of PC190723 with differently substituted 1,4-benzodioxane or 1,4-benzoxathiane. We further assessed the Structure Activity Relationship (SAR) of this class, through a series of isosteric, positional or substituent modifications (7-9).
These molecules proved to strongly inhibit S. aureus, E. faecalis and M. tuberculosis viability and to target FtsZ. We specifically performed two different biochemical assays, aimed at studying GTPase and polymerization activities of S. aureus FtsZ, when incubated with our compounds
2-Hydroxymethyl-1,4-dioxane: synthesis, resolution and determination of the absolute configurations of the enantiomers
No full text2-Hydroxymethyl-1, 4-dioxane 3 was resolved via salt formation between its hydrogen phthalate and (R)- or (S)-1-phenylethylamine, selective crystallization of the resultant diastereomeric mixtures and subsequent recovery of its enantiomers by saponification. The progress of the resolution was followed by chiral HPLC and the absolute stereochemistry of the two enantiomers determined by comparison of their specific rotations with that of (R)-3 synthesized from enantiomerically pure (R)-1-O-benzylglycerol. The results of the synthesis of 3 and of its resolution are discussed and compared with those previously obtained for 1,2-isopropylidene glycerol evaluating the consequences of replacement of ispropylidene with an ethylene bridge
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