1,721,010 research outputs found
DESIGN AND SYNTHESIS OF NOVEL BIOACTIVE PEPTIDES AND PEPTIDOMIMETICS
Full text linkNowadays there’s a growing interest in biologically active peptides for the development of new therapeutics; however in some cases, they could not directly use as drugs, due to their inherent limitations, such as rapid metabolism and low oral activity. As a result, peptides are modified into peptidomimetics with specific characteristics, in a rational design.
The present PhD project is focused on the synthesis of several peptides and peptidomimetics, structurally different and presenting individual features, properties, targets and pharmaceutical applications. In particular, two are the research studies we’ve developed during the three years, these are the design of novel Carnosine-like derivatives and of new Farnesyl Transferase Inhibitors (FTIs).
Concerning the first topic, we investigated how Carnosine (β-alanyl-L-histidine) structural changes influence its role as scavenger of HNE (4-hydroxy-trans-2,3-nonenal) and other toxic aldehydes.
For this reason we modified the carnosine structure firstly replacing the Hystidinil- portion with different aromatic system, secondly substituting the β-alanyl portion with ten different amino acids, chosen in order to cover exhaustively the available chemical space. Finally we rigidified the whole structure, inserting a 2-oxazolidinone; the entire compound underwent biological evaluation, testing their ability to quench HNE.
As a result, some of the twenty dipeptides showed impressing scavenging activities and great selectivity towards toxic aldehydes, suggesting us that they can represent truly promising candidates for the design of improved carnosine derivatives.
Regarding the second subject, we designed, synthesized and tested several peptidomimetics of the CAAX box, where CAAX is the sequence Cysteine-Valine-Isoleucine-Methionine, able to block the farnesylation of RAS proteins and therefore cell proliferation.
The design started from a nanomolar range FTI, previously synthesized by our group, where the central dipeptide (AA) is replaced with a 4-amino-2-o-tolylbenzoyl spacer and the Cysteine (C) with the residue 2-amino-4-thiazolylacetyl. The synthesis of the novel FTIs followed two separate approaches; at first we kept the aromatic spacer and modified the N-terminal residue with other heterocycles; the unimproved antiproliferative activity suggested us to apply other kind of modification. Therefore we replaced the o-tolyl with six heteroaromatic residues, in addition the synthesized compounds presented, as N- terminal residue, the 2-amino-4-thiazolylacetyl itself or the 1,4-benzodioxan-2-ylmethyl or the 1,4-benzodioxan-2-ylformyl. In all the three series of compounds, the 2-thienyl, 1-naphtyl and the 3-furanyl derivatives showed the highest FTase inhibition, at low micromolar level.
Taken together, our biological activities provide interesting results, confirming that peptides and peptidomimetics should be employed as therapeutics
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 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
Battle against antimicrobial resistance: FtsZ inhibitors as novel potent Gram-positive antibiotics
No full textAntimicrobial resistance is one of the major actual health plagues. Even if it started more than 70 years ago, the problem burst out only in the latest years, prompting to the urgent need of novel efficient antibiotics, showing innovative mechanisms of action.
In this context, the bacterial cell division process turned to be an interesting and promising target, firstly because divisome components are crucial for the viability of bacteria. Moreover, the most important division proteins are widely conserved in bacteria and are absent in eukaryotic cells, strengthening the selectivity of the possible novel antimicrobics.
Among the essential cell division proteins, FtsZ (Filamentous temperature sensitive Z), which is a tubulin homologue, became an attractive target. FtsZ is the first protein that localizes to the mid-point of the cell and it 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.
In the last 10 years several research group studied and developed FtsZ inhibitors, confirming that protein inhibition results in a bactericidal effect. Interesting results were obtained with synthetic small molecules; specifically with 3-Methoxybenzamide (3-MBA) derivatives: the lead compound of this class of antimicrobics is PC190723.
In the attempt to design potent novel antibacterial agents, in the latest years we designed and accomplished several derivatives, firstly replacing the thiazolopyridine of PC190723 with differently substituted 1,4-benzodioxane, bringing in particular to compounds I-III. These molecules proved to be strong inhibitors of S. aureus, E. faecalis and M. tuberculosis viability. Recently we consolidated the Structure Activity Relationship (SAR) of this class, designing a number of analogues of I and III, through a series of isosteric, positional or substituent modifications.
Furthermore, we confirmed the target, performing two different biochemical assays, aimed at studying GTPase and polymerization activities of S. aureus FtsZ, when incubated with our compounds
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
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
Structural analogues of methylphenidate as Parkinson's disease-modifying agents
No full textThe present invention describes compounds of formula (A) for use as Parkinson's disease modifying agents, said formula (A). Surprisingly it has been found that the compounds of the invention can significantly reduce alpha-synuclein aggregation and stimulate the functional interaction between alpha-synuclein and Synapsin III
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