Search Results (18)

The metabotropic glutamate receptor type 5 (mGlu5) and adenosine A(2A) receptor form a mutually inhibitory heteromer with the dopamine D2 receptor, where the activation of either mGlu5 or A(2A) leads to reduced D2 signaling. This study investigated whether a mGlu5-positive allosteric modulator (PAM) or an A(2A) agonist treatment could mitigate sensorimotor gating deficits and alter cyclic AMP response element-binding protein (CREB) levels in a rodent neonatal quinpirole (NQ) model of psychosis. F0 Sprague–Dawley rats were treated with neonatal saline or quinpirole (1 mg/kg) from postnatal day 1 to 21 and bred to produce an F1 generation. F1 offspring underwent prepulse inhibition (PPI) testing from postnatal day 44 to 48 to assess sensorimotor gating. The rats were treated with mGlu5 PAM 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl) benzamide (CDPPB) or A(2A) agonist CGS21680. Rats with at least one NQ-treated parent showed PPI deficits, which were alleviated by both CDPPB and CGS21680. Sex differences were noted across groups, with CGS21680 showing greater efficacy than CDPPB. Additionally, CREB levels were elevated in the nucleus accumbens (NAc), and both CDPPB and CGS21680 reduced CREB expression to control levels. These findings suggest that targeting the adenosinergic and glutamatergic systems alleviates sensorimotor gating deficits and abnormal CREB signaling, both of which are associated with psychosis. Full article

New haloaminopyrazole derivatives differing in the number of pyrazole nuclei 4a–f and 5a–e, respectively, were synthesized and characterized by ¹H-NMR, ¹³C-NMR, IR, UV-Vis, and elemental analysis. The single-crystal X-ray diffraction method was used to describe compounds 4a and 5d. When tested on normal NCTC fibroblasts in vitro, the newly synthesized derivatives were shown to be non-cytotoxic at a dosage of 25 μg/mL. Two compounds 4a and 5d showed a high degree of biocompatibility. From the two series of compounds tested on HEp-2 human cervical carcinoma cells, compound 5d showed a more pronounced antiproliferative effect. Gram-positive strains of Staphylococcus aureus ATCC25923, Enterococcus faecalis ATCC29212, Gram-negative strains of Pseudomonas aeruginosa ATCC27853, and strains of Escherichia coli ATCC25922 were used to test the newly synthesized compounds antibacterial and antibiofilm properties. Among the studied pyrazole compounds, 2 compounds 4a and 5a with fluorine content on the phenyl ring and 4 compounds 4b, 4e, 4f, and 5b with chlorine content on the phenyl ring were noted, which proved to be the most active compared with the two reference drugs, metronidazole and nitrofurantoin. The six compounds showed a broad spectrum of action against all four tested bacterial strains, the most active being compound 4b, with a chlorine atom in the “4” position of the phenyl nucleus and a MIC of 460 μg/mL. Compounds 4a and 5a showed the best antibiofilm activity against the bacterial strain Staphylococcus aureus ATCC25923, with an MBIC of 230 μg/mL. Full article

Aminopyrazoles represent interesting structures in medicinal chemistry, and several derivatives showed biological activity in different therapeutic areas. Previously reported 5-aminopyrazolyl acylhydrazones and amides showed relevant antioxidant and anti-inflammatory activities. To further extend the structure–activity relationships in this class of derivatives, a novel series of pyrazolyl acylhydrazones and amides was designed and prepared through a divergent approach. The novel compounds shared the phenylamino pyrazole nucleus that was differently decorated at positions 1, 3, and 4. The antiproliferative, antiaggregating, and antioxidant properties of the obtained derivatives 10–22 were evaluated in in vitro assays. Derivative 11a showed relevant antitumor properties against selected tumor cell lines (namely, HeLa, MCF7, SKOV3, and SKMEL28) with micromolar IC₅₀ values. In the platelet assay, selected pyrazoles showed higher antioxidant and ROS formation inhibition activity than the reference drugs acetylsalicylic acid and N-acetylcysteine. Furthermore, in vitro radical scavenging screening confirmed the good antioxidant properties of acylhydrazone molecules. Overall, the collected data allowed us to extend the structure–activity relationships of the previously reported compounds and confirmed the pharmaceutical attractiveness of this class of aminopyrazole derivatives. Full article

A pyrazole nucleus is an easy-to-prepare scaffold with large therapeutic potential. Consequently, the search for new pyrazole-based compounds is of great interest to the academic community as well as industry. In the last ten years, a large number of papers and reviews on the design, synthesis, and biological evaluation of different classes of pyrazoles and many pyrazole-containing compounds have been published. However, an overview of pyrazole derivatives bearing a free amino group at the 3, 4, or 5 position (namely, 3-aminopyrazoles, 4-aminopyrazoles, and 5-aminopyrazoles, respectively) and their biological properties is still missing, despite the fact that aminopyrazoles are advantageous frameworks able to provide useful ligands for receptors or enzymes, such as p38MAPK, and different kinases, COX and others, as well as targets important for bacterial and virus infections. With the aim to fill this gap, the present review focuses on aminopyrazole-based compounds studied as active agents in different therapeutic areas, with particular attention on the design and structure-activity relationships defined by each class of compounds. In particular, the most relevant results have been obtained for anticancer/anti-inflammatory compounds, as the recent approval of Pirtobrutinib demonstrates. The data reported here are collected from different databases (Scifinder, Web of Science, Scopus, Google Scholar, and Pubmed) using “aminopyrazole” as the keyword. Full article

We previously demonstrated that fatty acid-binding protein 3 null (FABP3^−/−) mice exhibit resistance to nicotine-induced conditioned place preference (CPP). Here, we confirm that the FABP3 inhibitor, MF1 ((4-(2-(1-(2-chlorophenyl)-5-phenyl-1H-pyrazol-3-yl)phenoxy) butanoic acid), successfully reduces nicotine-induced CPP scores in mice. MF1 (0.3 or 1.0 mg/kg) was orally administered 30 min before nicotine, and CPP scores were assessed in the conditioning, withdrawal, and relapse phases. MF1 treatment decreased CPP scores in a dose-dependent manner. Failure of CPP induction by MF1 (1.0 mg/kg, p.o.) was associated with the inhibition of both CaMKII and ERK activation in the nucleus accumbens (NAc) and hippocampal CA1 regions. MF1 treatment reduced nicotine-induced increases in phosphorylated CaMKII and cAMP-response element-binding protein (CREB)-positive cells. Importantly, the increase in dopamine D2 receptor (D2R) levels following chronic nicotine exposure was inhibited by MF1 treatment. Moreover, the quinpirole (QNP)-induced increase in the level of CaMKII and ERK phosphorylation was significantly inhibited by MF1 treatment of cultured NAc slices from wild type (WT) mice; however, QNP treatment had no effect on CaMKII and ERK phosphorylation levels in the NAc of D2R null mice. Taken together, these results show that MF1 treatment suppressed D2R/FABP3 signaling, thereby preventing nicotine-induced CPP induction. Hence, MF1 can be used as a novel drug to block addiction to nicotine and other drugs by inhibiting the dopaminergic system. Full article

Pyrazoloporphyrins (PzPs), which are porphyrin analogues incorporating a pyrazole subunit, are examples of carbaporphyrin-type structures with a carbon atom within the macrocyclic cavity. DFT calculations were used to assess a series of 17 PzP tautomers, nine monoprotonated species and four related diprotonated PzP dications. The geometries of the structures were optimized using M06-2X/6-311++G(d,p), and the relative stabilities computed with the cc-PVTZ functional. Nucleus independent chemical shifts, both NICS(0) and NICS(1)_zz, were calculated, and the anisotropy of the induced current density (AICD) plots were generated for all of the species under investigation. The results for free base PzPs show that fully aromatic PzP tautomers are not significantly more stable than weakly aromatic cross-conjugated species. In addition, strongly aromatic structures with internal CH_2′s are much less stable, a feature that is also seen for protonated PzPs. The degree of planarity for the individual macrocycles does not significantly correlate with the stability of these structures. The results allow significant aromatic conjugation pathways to be identified in many cases, and provide insights into the aromatic properties of this poorly studied system. These investigations also complement experimental results for PzPs and emphasize the need for further studies in this area. Full article

Many elderly individuals frequently experience cataracts that interfere with vision. After cataract surgery, the left lens epithelial cell (LEC) exhibited fibrosis and posterior capsule opacification (PCO). Sometimes, there is a need for a second surgery; nevertheless, people try other methods, such as a good pharmacological agent, to treat PCO to reduce transforming growth factor-β2 (TGF-β2) amounts to avoid secondary surgery. The aim of the present study was to explore the potential anti-PCO activity of five 2,4-dihydro-3H-pyrazol-3-one (DHPO) derivatives in a TGF-β2-induced fibrogenesis SRA01/04 cell model. The 2-phenyl-5-propyl-DHPO (TSE; no. 2: TSE-2) compound showed the best activity of reduced expression levels of TGF-β2 among five derivatives and therefore was chosen to evaluate the anti-PCO activity and molecular mechanisms on the Sma and mad protein (SMAD) signaling pathway (including TGF-β2, SMADs, and the inhibition of nuclear translocation of SMADs), non-SMAD pathway proteins, including p-extracellular, regulated protein kinases (ERK) 1/2, or p-c-Jun N-terminal kinase (JUN) by Western blotting, PCR, or confocal immunofluorescence analyses. Following treatment with 10 μg/mL of the five compounds, the cells displayed great viability by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTT) assay. In this study, the result of lactate dehydrogenase (LDH) activity measurement did not affect the cytotoxicity of the five compounds. In TGF-β2-induced fibrogenesis in SRA01/04 cells, treatment with the TSE compound decreased the TGF-β2/SMAD signaling genes, including reduced mRNA or expression levels of TGF-β2, SMAD3, and SMAD4, leading to inhibition of TGF-β2-induced fibrogenesis. Our confocal immunofluorescence analyses demonstrated that TSE treatment displays a suppressive effect on SMAD2/3 or SMAD4 translocation to the nucleus. Furthermore, TSE treatment exhibits a reduction in the non-SMAD target gene expression levels of p- c-Jun N-terminal kinase (JUN), p- extracellular, regulated protein kinases (ERK)1/2, p- p38 mitogen-activated protein kinase (p38), p-phosphatidylinositol 3-kinase (PI3K), p-mammalian target of rapamycin complex (mTORC), p-Akt (Ser⁴⁷³), and p-Akt (Thr³⁰⁸). The overall effect of TSE is to reduce the expression levels of collagen I and fibrinogen (FN), thus contributing to antifibrotic effects in cell models mimicking PCO. Our findings reveal the benefits of TSE by regulating TGF-β/SMAD signaling and non-SMAD signaling-related gene proteins to display antifibrotic activity in cells for the possibility of preventing PCO after cataract surgery. Full article

Molecules containing the pyrazole nucleus are widely reported as promising candidates to develop new antimicrobial compounds against multidrug-resistant (MDR) bacteria, where available antibiotics may fail. Recently, aiming at improving the too-high minimum inhibitory concentrations (MICs) of a pyrazole hydrochloride salt (CB1H), CB1H-loaded nanoparticles (CB1H-P7 NPs) were developed using a potent cationic bactericidal macromolecule (P7) as polymer matrix. Here, CB1H-P7 NPs have been successfully tested on several clinical isolates of Gram-positive and Gram-negative species, including relevant MDR strains. CB1H-P7 NPs displayed very low MICs (0.6–4.8 µM), often two-fold lower than those of P7, on 34 out of 36 isolates tested. Upon complexation, the antibacterial effects of pristine CB1H were improved by 2–16.4-fold, and, unexpectedly, also the already potent antibacterial effects of P7 were 2–8 times improved against most of bacteria tested when complexed with CB1H. Time-killing experiments performed on selected species established that CB1H-P7 NPs were bactericidal against Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa. Selectivity indices values up to 2.4, determined by cytotoxicity experiments on human keratinocytes, suggested that CB1H-P7 NPs could be promising for counteracting serious infections sustained by most of the isolates tested in this study. Full article

The antimicrobial potency of the pyrazole nucleus is widely reported these days, and pyrazole derivatives represent excellent candidates for meeting the worldwide need for new antimicrobial compounds against multidrug-resistant (MDR) bacteria. Consequently, 3-(4-chlorophenyl)-5-(4-nitrophenylamino)-1H-pyrazole-4-carbonitrile (CR232), recently reported as a weak antiproliferative agent, was considered to this end. To overcome the CR232 water solubility issue and allow for the determination of reliable minimum inhibitory concentration values (MICs), we initially prepared water-soluble and clinically applicable CR232-loaded nanoparticles (CR232-G5K NPs), as previously reported. Here, CR232-G5K NPs have been tested on several clinically isolates of Gram-positive and Gram-negative species, including MDR strains. While for CR232 MICs ≥ 128 µg/mL (376.8 µM) were obtained, very low MICs (0.36–2.89 µM) were observed for CR232-G5K NPs against all of the considered isolates, including colistin-resistant isolates of MDR Pseudomonas aeruginosa and Klebsiella pneumoniae carbapenemases (KPCs)-producing K. pneumoniae (0.72 µM). Additionally, in time–kill experiments, CR232-G5K NPs displayed a rapid bactericidal activity with no significant regrowth after 24 h on all isolates tested, regardless of their difficult-to-treat resistance. Conjecturing a clinical use of CR232-G5K NPs, cytotoxicity experiments on human keratinocytes were performed, determining very favorable selectivity indices. Collectively, due to its physicochemical and biological properties, CR232-G5K NPs could represent a new potent weapon to treat infections sustained by broad spectrum MDR bacteria. Full article

Although the antimicrobial potency of the pyrazole nucleus is widely reported, the antimicrobial effects of the 2-(4-bromo-3,5-diphenyl-pyrazol-1-yl)-ethanol (BBB4), found to be active against several other conditions, have never been investigated. Considering the worldwide need for new antimicrobial agents, we thought it noteworthy to assess the minimum inhibitory concentration (MICs) of BBB4 but, due to its scarce water-solubility, unequivocal determinations were tricky. To obtain more reliable MICs and to obtain a substance also potentially applicable in vivo, we recently prepared water-soluble, BBB4-loaded dendrimer nanoparticles (BBB4-G4K NPs), which proved to have physicochemical properties suitable for clinical application. Here, with the aim of developing a new antibacterial agent based on BBB4, the BBB4-G4K NPs were tested on several strains of different species of the Staphylococcus genus. Very low MICs (1.5–3.0 µM), 15.5–124.3-fold lower than those of the free BBB4, were observed against several isolates of S. aureus and S. epidermidis, the most pathogenic species of this genus, regardless of their resistance patterns to antibiotics. Aiming at hypothesizing a clinical use of BBB4-G4K NPs for staphylococcal skin infections, cytotoxicity experiments on human keratinocytes were performed; it was found that the nano-manipulated BBB4 released from BBB4-G4K NPs (LD₅₀ 138.6 µM) was 2.5-fold less cytotoxic than the untreated BBB4 (55.9 µM). Due to its physicochemical and biological properties, BBB4-G4K NPs could be considered as a promising novel therapeutic option against the very frequent staphylococcal skin infections. Full article

2-(4-Bromo-3,5-diphenyl-pyrazol-1-yl)-ethanol (BBB4) was synthetized and successfully evaluated concerning numerous biological activities, except for antimicrobial and cytotoxic effects. Due to the antimicrobial effects possessed by pyrazole nucleus, which have been widely reported, and the worldwide need for new antimicrobial agents, we thought it would be interesting to test BBB4 and to evaluate its possible antibacterial effects. Nevertheless, since it is water-insoluble, the future clinical application of BBB4 will remain utopic unless water-soluble BBB4 formulations are developed. To this end, before implementing biological evaluations, BBB4 was herein re-synthetized and characterized, and a new water-soluble BBB4-based nano-formulation was developed by its physical entrapment in a biodegradable non-cytotoxic cationic dendrimer (G4K), without recovering harmful solvents as DMSO or surfactants. The obtained BBB4 nanoparticles (BBB4-G4K NPs) showed good drug loading (DL%), satisfying encapsulation efficiency (EE%), and a biphasic quantitative release profile governed by first-order kinetics after 24 h. Additionally, BBB4-G4K was characterized by ATR-FTIR spectroscopy, NMR, SEM, dynamic light scattering analysis (DLS), and potentiometric titration experiments. While, before the nanotechnological manipulation, BBB4 was completely water-insoluble, in the form of BBB4-G4K NPs, its water-solubility resulted in being 105-fold higher than that of the pristine form, thus establishing the feasibility of its clinical application. Full article

The pyrazole nucleus and its reduced forms, pyrazolines and pyrazolidine, are privileged scaffolds in medicinal chemistry due to their remarkable biological activities. A huge number of pyrazole derivatives have been studied and reported over time. This review article gives an overview of pyrazole derivatives that contain a styryl (2-arylvinyl) group linked in different positions of the pyrazole backbone. Although there are studies on the synthesis of styrylpyrazoles dating back to the 1970s and even earlier, this type of compound has rarely been studied. This timely review intends to summarize the properties, biological activity, methods of synthesis and transformation of styrylpyrazoles; thus, highlighting the interest and huge potential for application of this kind of compound. Full article

Herein, we report the successful syntheses of scarcely represented indole-based heterocycles which have a structural connection with biologically active natural-like molecules. The selective oxidation of indoline nucleus to indole, hydrolysis of ester and carbamoyl residues followed by decarboxylation with concomitant aromatization of the pyridazine ring starting from tetrahydro-1H-pyridazino[3,4-b]indole derivatives lead to fused indole-pyridazine compounds. On the other hand, non-fused indole-pyrazol-5-one scaffolds are easily prepared by subjecting the same C2,C3-fused indoline tetrahydropyridazines to treatment with trifluoroacetic acid (TFA). These methods feature mild conditions, easy operation, high yields in most cases avoiding the chromatographic purification, and broad substrate scope. Interestingly, the formation of indole linked pyrazol-5-one system serves as a good example of the application of the umpolung strategy in the synthesis of C3-alkylated indoles. Full article

The pyrazole nucleus has long been known as a privileged scaffold in the synthesis of biologically active compounds. Within the numerous pyrazole derivatives developed as potential drugs, this review is focused on molecules characterized by a urea function directly linked to the pyrazole nucleus in a different position. In the last 20 years, the interest of numerous researchers has been especially attracted by pyrazolyl-ureas showing a wide spectrum of biological activities, ranging from the antipathogenic activities (bacteria, plasmodium, toxoplasma, and others) to the anticarcinogenic activities. In particular, in the anticancer field, pyrazolyl-ureas have been shown to interact at the intracellular level on many pathways, in particular on different kinases such as Src, p38-MAPK, TrKa, and others. In addition, some of them evidenced an antiangiogenic potential that deserves to be explored. This review therefore summarizes all these biological data (from 2000 to date), including patented compounds. Full article

Genetic abnormalities have been conventionally considered as hallmarks of cancer. However, recent studies have demonstrated that epigenetic mechanisms are also implicated in the insurgence and development of cancer. Patterns of the epigenetic component include DNA methylation and histone modifications. Acetylation of histones is controlled by histone acetyltransferases (HATs) and histone deacetylases (HDACs). Imbalance of these two enzymatic systems is known to be a key factor in tumor progression. Because HDACs have been found to function incorrectly in cancer, various HDAC inhibitors (HDACIs) are being investigated to act as cancer chemotherapeutics. Herein, we report the synthesis, docking studies and biological activity of a series of hydroxamic acid-based HDACIs bearing an N¹-aryl or N¹-H pyrazole nucleus as surface recognition motif and a cinnamoyl group as a linker to the hydroxamic acid zinc-binding group (ZBG). Some of the tested compounds exhibited inhibitory properties towards HDACs and antiproliferative activity against neuroblastoma SH-SY5Y tumor cell line both at micromolar concentrations. Full article