1,721,015 research outputs found
Novel strategies in the war against antibiotic resistance
No full textThe global threat of antibiotic resistance is steadily growing. Antibiotic resistancemay involve any class of antibiotic,
including second- and third-line agents that have been considered to date the last-resort drugs to counteract common
infections. We may lose our capability to keep under control many common bacterial infections [1].
Despite this, in the past decade significant research efforts have been made to develop new antibacterial strategies
able to treat multidrug-resistant infections; however, no new therapeutic approach has yet reached the clinic [2,3].
In order to identify new valuable antimicrobial drugs, it is important to consider the main bacterial resistance
mechanisms in both planktonic and sessile forms of life [4]
Eight-membered heterocycles with two heteroatoms in a 1,2-relationship of interest in medicinal chemistry
No full textThis chapter treats 1,2-diheterocines, eight membered heterocyclic systems with two
heteroatoms, N, O and S, in an 1,2 relationship, exhibiting biological properties and
exhaustively covers the literature from 2007 to the end of November 2019.
In this period of time 1,2-diazocine, 1,2-oxazocine, 1,2-dioxocin and 1,5-dithiocin
ring systems had derivatives exhibiting pharmacological activities. No articles on biological
properties have been reported for 1,2-thiazocines and 1,2-oxathiocins.
Besides uncondensed derivatives, 1,2-diheterocines fused with five-, six-, and sevenmembered
carbocycles or heterocycles have been reviewed, as well as bridged
1,2-diheterocines
Synthesis of novel 1,2,4-oxadiazole topsentin analogs with antitumor activity
Get PDFSynthesis of novel 1,2,4-oxadiazole topsentin analogs
with antitumor activit
Biofilm capability of staphylococcus strains isolated from food and the anti-biofilm activity of a chemically synthesized pyrrolomycin
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New Tripentone Analogs with Antiproliferative Activity
Get PDFTripentones represent an interesting class of compounds due to their significant cytotoxicity against different human tumor cells in the submicro-nanomolar range. New tripentone analogs, in which a pyridine moiety replaces the thiophene ring originating the fused azaindole system endowed with anticancer activity viz 8H-thieno[2,3-b]pyrrolizinones, were efficiently synthesized in four steps with fair overall yields (34–57%). All tripentone derivatives were tested in the range of 0.1–100 μM for cytotoxicity against two human tumor cell lines, HCT-116 (human colorectal carcinoma) and MCF-7 (human breast cancer). The most active derivative, with GI50 values of 4.25 µM and 20.73 µM for HCT-116 and MCF-7 cells, respectively, did not affect the viability of Caco-2 differentiated in normal intestinal-like cells, suggesting tumor cells as the main target of its cytotoxic action. The same compound was further investigated in order to study its mode of action. Results showed that it did not exert necrotic effects, while induced a clear shift of viable cells towards early apoptosis. Flow cytometric analysis demonstrated that this compound caused cell cycle alteration, inhibiting its progression in S and G2/M phases
A New Oxadiazole-Based Topsentin Derivative Modulates Cyclin-Dependent Kinase 1 Expression and Exerts Cytotoxic Effects on Pancreatic Cancer Cells
Get PDFPancreatic ductal adenocarcinoma (PDAC) is a highly lethal form of cancer characterized
by drug resistance, urging new therapeutic strategies. In recent years, protein kinases have emerged
as promising pharmacological targets for the treatment of several solid and hematological tumors.
Interestingly, cyclin-dependent kinase 1 (CDK1) is overexpressed in PDAC tissues and has been
correlated to the aggressive nature of these tumors because of its key role in cell cycle progression
and resistance to the induction of apoptosis. For these reasons, CDK1 is one of the main causes
of chemoresistance, representing a promising pharmacological target. In this study, we report the
synthesis of new 1,2,4-oxadiazole compounds and evaluate their ability to inhibit the cell growth of
PATU-T, Hs766T, and HPAF-II cell lines and a primary PDAC cell culture (PDAC3). Compound 6b
was the most active compound, with IC50 values ranging from 5.7 to 10.7 M. Molecular docking
of 6b into the active site of CDK1 showed the ability of the compound to interact effectively with
the adenosine triphosphate binding pocket. Therefore, we assessed its ability to induce apoptosis
(which increased 1.5- and 2-fold in PATU-T and PDAC3 cells, respectively) and to inhibit CDK1
expression, which was reduced to 45% in Hs766T. Lastly, compound 6b passed the ADME prediction,
showing good pharmacokinetic parameters. These data demonstrate that 6b displays cytotoxic
activity, induces apoptosis, and targets CDK1, supporting further studies for the development of
similar compounds against PDAC
Synthesis and biological evaluation of a new class of azole urea compounds as Akt inhibitors with promising anticancer activity in pancreatic cancer models
Get PDFThe PI3K/Akt pathway is crucial in numerous cellular functions such as cell growth, survival proliferation and movement in both normal and cancer cells. It plays also a key role in epithelial-mesenchymal transitions and angiogenesis during the tumorigenesis processes. Since many transformative events in cancer are driven by increased PI3K/Akt pathway signaling, Akt is considered a valuable target for developing new therapies against various tumor types, including pancreatic cancer. This is because the PI3K/AKT/mTOR pathway is a key downstream effector of RAS, and RAS activation is the most prominent genetic alteration in pancreatic cancer. Herein we report the synthesis and the biological evaluation of a new series of azole urea compounds that exhibited promising antiproliferative and antimigratory activities against pancreatic cancer cells through an Akt inhibition mechanism. These effects were demonstrated using a variety of assays, including Sulforhodamine B, cell-cycle, wound-healing, and kinase activity, apotposis and ELISA assays. Additionally, the anticancer properties of the most active compound in the series were confirmed in the 3D spheroid model of PATU-T cells
An overview of recent molecular dynamics applications as medicinal chemistry tools for the undruggable site challenge
Get PDFMolecular Dynamics (MD) has become increasingly popular due to the development of hardware and software solutions
and improvement in algorithms, that allowed researchers to scale up calculations in order to speed up them. MD
simulations are usually used to address protein folding issues or protein-ligand complex stability through energy profile
analysis over time. In recent years, the development of new tools able to deeply explore Potential Energy Surface (PES)
allowed researchers to focus on the dynamic nature of binding recognition process and binding-induced protein
conformational change. Moreover, modern approaches have demonstrated to be effective and reliable in calculating some
kinetic and thermodynamic parameters behind the host-guest recognition process. Starting from all of these
considerations, several efforts have been made in order to integrate MD within the virtual screening process in drug
discovery. Knowledge retrieved from MD can be, in fact, exploited as a starting point to build pharmacophores or docking
constraints in the early stage of the screening campaign as well as to define key features, in order to unravel hidden
binding modes and help the optimisation of the molecular structure of a lead compound. Based on these outcomes,
researchers are nowadays using MD as an invaluable tool to discover and target previously considered undruggable
binding sites, including protein-protein interactions and allosteric sites on protein surface. As a matter of fact, the use of
MD has been recognised as vital in the discovery of selective protein-protein interaction modulators. The use of a dynamic
overview on how the host-guest recognition occurs and of the relative conformational modifications induced, allow
researchers to optimise small molecules and small peptides capable to tightly interact within the cleft between the two
proteins.
In this review we point to present the most recent applications of MD as integrated tool to be used in the rational design
of small molecules or small peptides able to modulate undruggable targets, such as allosteric sites and protein-protein
interactions
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