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Since April 2020, several paediatric cases were reported with a multisystemic inflammatory syndrome related with SARS-CoV2, called MIS-C. In this case report, we describe a 2-year-old male with end-stage renal disease (ESRD) in renal replacement therapy (RRT) with peritoneal dialysis and severe hypertension affected by a severe SARS-CoV2 related illness characterised by multiorgan failure and need for intensive care, with clinical and instrumental features compatible with MIS-C. Most paediatric patients with kidney disease experience mild SARS-CoV2 disease and to our knowledge, this is the first case of a child with chronic kidney disease suffering from MIS-C. We believe that chronic kidney disease together with dialysis status and severe hypertension play a crucial role on developing severe forms of SARS-CoV2 related disease.

The therapeutic approach to Chronic Myeloid Leukemia (CML) has changed since the advent of the tyrosine kinase inhibitor (TKI) imatinib, which was then followed by the second generation TKIs dasatinib, nilotinib, and, finally, by ponatinib, a third-generation drug. At present, these therapeutic options represent the first-line treatment for adults. Based on clinical experience, imatinb, dasatinib, and nilotinib have been approved for children even though the studies that were concerned with efficacy and safety toward pediatric patients are still awaiting more specific and high-quality data. In this scenario, it is of utmost importance to prospectively validate data extrapolated from adult studies to set a standard therapeutic management for pediatric CML by employing appropriate formulations on the basis of pediatric clinical trials, which allow a careful monitoring of TKI-induced adverse effects especially in growing children exposed to long-term therapy.

The cannabinoid receptor subtype 2 (CB2R) represents an interesting and new therapeutic target for its involvement in the first steps of neurodegeneration as well as in cancer onset and progression. Several studies, focused on different types of tumors, report a promising anticancer activity induced by CB2R agonists due to their ability to reduce inflammation and cell proliferation. Moreover, in neuroinflammation, the stimulation of CB2R, overexpressed in microglial cells, exerts beneficial effects in neurodegenerative disorders. With the aim to overcome current treatment limitations, new drugs can be developed by specifically modulating, together with CB2R, other targets involved in such multifactorial disorders. Building on successful case studies of already developed multitarget strategies involving CB2R, in this Perspective we aim at prompting the scientific community to consider new promising target associations involving HDACs (histone deacetylases) and σ receptors by employing modern approaches based on molecular hybridization, computational polypharmacology, and machine learning algorithms.

hERG is best known as a primary anti-target, the inhibition of which is responsible for serious side effects. A renewed interest in hERG as a desired target, especially in oncology, was sparked because of its role in cellular proliferation and apoptosis. In this study, we survey the most recent advances regarding hERG by focusing on SAR in the attempt to elucidate, at a molecular level, off-target and on-target actions of potential hERG binders, which are highly promiscuous and largely varying in structure. Understanding the rationale behind hERG interactions and the molecular determinants of hERG activity is a real challenge and comprehension of this is of the utmost importance to prioritize compounds in early stages of drug discovery and to minimize cardiotoxicity attrition in preclinical and clinical studies. We report how the understanding of SAR and the informed use of reliable data and models are pivotal to modulate the interplay with hERG channels.

Introduction: Oral rehabilitation with overdenture on implants of upper jaw must be taken into consideration a variety of anatomical and biomechanical issues. It is possible to provide for rehabilitation with two or more implants, in different positions, solidarizing them with a bar. Materials & Methods: The present study involved a patient rehabilitated with 4 Xive implants (Friadent GmbH, Mannheim, Germany) solidarized with a titanium bar crafted with CAD-CAM technology for maximal comfort, precision and structural lightness. Results & Discussion: The follow-up was 54 months, with an implant survival of 100%. Based on our clinical evidence, bars engineered with CAD-CAM technology are promising in terms of precision and comfort despite higher costs.

Objective: The purpose of this study is to highlight the evidence of signs and symptoms of craniomandibular disorders (CMD) in patients suffering from fibromyalgia. Materials and Method: The study has been carried out from May 2011 to May 2015, recruiting a sample of fibromyalgia patients at the Department of Neurophysiopathology at the hospital Policlinico in Bari. Among the 150 examined patients, 60 of them have been diagnosed to suffer from fibromyalgia and 27 accepted to be investigated with a gnathologic examination at the Dental School at the University of Bari. Results: 24 patients (88.9%) were women and 3 (11.1%) men; from 26 to 66 years old (average age, 39). 14 patients (51.9%) were affected by primary fibromyalgia, the remaining 13 (48.1%) by secondary fibromyalgia, mainly associated with hypothyroidism (29.6%). VAS average score was about 8 ± 1.85. The frequency of pain was daily in 15 patients (55.6%); twice a week in 10 patients (37.03%) and a few times a month in 2 patients (7.4%). 11 patients (40.7%) attributed the onset of fibromyalgia to a specific instigating event. In addition, from the gnathologic anamnesis, 11 patients (40,7%) reported a painful symptom in the head-neck region, especially in the frontal region, in the neck, in the masseter muscle and ATM. VAS average score was 3.4 ± 2.8, significantly lower than the one referring to the fibromyalgia pain. The gnathological examination found CMD signs and symptoms in 18 patients (66.7%). Concerning the prevalence of CMD, in type I fibromyalgia, myofascial pain was more frequent (5 patients), whereas in type II fibromyalgia, what was more frequent was a dislocation with reduction (3 patients). Conclusion: Based on clinic experience, we can affirm that some patients with CMD report pain in other regions. It is difficult to distinguish the CMD forms directly correlated to fibromyalgia from those engendered by parafunctional activities; hence the need is to resolve the fibromyalgia syndrome adopting a multidisciplinary approach.

The Cannabinoid 2 receptor, CB2R, belonging to the endocannabinoid system, ECS, is involved in the first steps of neurodegeneration and cancer evolution and progression and thus its modulation may be exploited in the therapeutic and diagnostic fields. However, CB2Rs distribution and signaling pathways in physiological and pathological conditions are still controversial mainly because of the lack of reliable diagnostic tools. With the aim to produce green and safe systems to detect CB2R, we designed a series of fluorescent ligands with three different green fluorescent moieties (4-dimethylaminophthalimide, 4-DMAP, 7-nitro-4-yl-aminobenzoxadiazole, NBD, and Fluorescein-thiourea, FTU) linked to the N1-position of the CB2R pharmacophore N-adamantyl-4-oxo-1,4-dihydroquinoline-3-carboxamide through polymethylene chains. Compound 28 emerged for its compromise between good pharmacodynamic properties (CB2R Ki = 130 nM and no affinity vs the other subtype CB1R) and optimal fluorescent spectroscopic properties. Therefore, compound 28 was studied through FACS (saturation and competitive binding studies) and fluorescence microscopy (visualization and competitive binding) in engineered cells (CB2R-HEK293 cells) and in diverse tumour cells. The fluoligand binding assays were successfully set up, and affinity values for the two reference compounds GW405833 and WIN55,212-2, comparable to the values obtained by radioligand binding assays, were obtained. Fluoligand 28 also allowed the detection of the presence and quantification of the CB2R in the same cell lines. The interactions of compound 28 within the CB2R binding site were also investigated by molecular docking simulations, and indications for the improvement of the CB2R affinity of this class of compounds were provided. Overall, the results obtained through these studies propose compound 28 as a safe and green alternative to the commonly used radioligands for in vitro investigations.

We previously demonstrated that some N-biphenylanilides caused cell-cycle arrest at G2/M transition in breast cancer cells. Among them we choose three derivatives, namely PTA34, PTA73 and RS35 for experimentation in solid tumor cell lines, classical Hodgkin Lymphoma (cHL) cell lines and bona fide normal cell lines. Almost all tumor cells were sensitive to compounds in the nanomolar range whereas, they were not cytotoxic to normal ones. Interestingly the compounds caused a strong G2/M phase arrest in cHL cell lines, thus, here we investigated whether they affected the integrity of microtubules in such cells. We found that they induced a long prometaphase arrest, followed by induction of apoptosis which involved mitochondria. PTA73 and RS35 induced the mitotic arrest through the fragmentation of microtubules which prevented the kinethocore-mitotic spindle interaction and the exit from mitosis. PTA34 is instead a tubulin-targeting agent because it inhibited the tubulin polymerization as vinblastine. As such, PTA34 maintained the Cyclin B1-CDK1 regulatory complex activated during the G2/M arrest while inducing the inactivation of Bcl-2 through phosphorylation in Ser70, the degradation of Mcl-1 and a strong activation of BIML and BIMS proapoptotic isoforms. In addition PTA34 exerted an antiangiogenic effect by suppressing microvascular formation.

Objectives: The frequent finding of craniomandibular disorders (CMD) in burning mouth syndrome (BMS) patients has led the scientific community to hypothesize that the two diseases have common aspects that require further examination. Some authors have evaluated the presence of CMD in patients with BMS. No studies have limited the investigation to denture patients affected by BMS. The aim of the study is to estimate signs and symptoms of Craniomandibular Disorders (CMD) in patients with BMS and to investigate for the existence of a possible association between CMD and BMS in removable denture wearers. Materials and Methods: From April 2010 to March 2012 we enrolled forty-eight patients affected by BMS, of which 24 wearing removable denture and 24 without denture, in accordance with the inclusion/exclusion criteria. A clinical-gnathological evaluation and a prosthodontic examination were performed and the results were compared. Original Research Article Corsalini et al.; BJMMR, 7(6): 529-540, 2015; Article no.BJMMR.2015.359 530 Results and Discussion: Nineteen patients of the sample showed disorders classified as primary signs and symptoms of CMD on the basis of Research Diagnostic Criteria of Temporomandibular Disorders (RDC/TDM), compared with ten patients of the control group. Most common disorders were disc displacement and muscle pain. The chi-square test was statistically significant (p

Objectives: Although there is nowadays wide agreement on bacteria being the main etiologic agents of periodontal disease, their sole presence cannot damage periodontal tissues in all subjects. This suggests that an individual response and an adaptation to a certain quantity of bacterial biofilm can occur without the disease progressing and vice versa. Depression, stress and anxiety have not been confirmed yet as risk conditions but, in some observational studies, they have been identified as potential risk factors of periodontal disease. The current study aims at investigating the role which these psychological disorder have in the onset and progression of advanced stage periodontitis. Materials and methods: The case selection was carried out by means of clinical and radiological periodontal assessment involving a total of 108 subjects, both male and female, aged between 24 and 67. Patients were then divided in two groups of 54 patients each: the first group included patients with severe periodontal disease, the second group was formed by periodontally healthy subjects. Clinical assessment was performed by a sole examiner who selected and divided periodontopathic patients from non-periodontopathic ones. From the current study were excluded: patients with systemic pathologies; smokers; patients taking antidepressant drugs; pregnant women. Results: For what concerns depression, in the group of periodontopathic patients it was found that the 62.5% of them were depressed, against the 38.86% in the group of periodontally healthy subjects. For the other two psychological conditions taken into consideration, anxiety and stress, it emerged a different percentage of subjects with anxiety in the periodontal group (31.48%) against healthy controls (20.37%). Conclusions: For each of the psychological variables considered (depression, anxiety, stress), a significant correlation could be observed with periodontal disease, it can be therefore be suggested that the importance these disturbs have in the onset and progress of the dental disease which supports the existing available data in literature. The innovative aspect of this research was the focus on the assessment of compliance, monitoring the ability of periodontal patients to follow oral hygiene instructions aiming at the improving and keeping their own periodontal condition, even though this takes more time than the control group.

Purpose Fixed retainers are used to stabilize dental elements after orthodontic treatment. Being it a permanent treatment, it is necessary to instruct patients about a constant and continuous monitoring of their periodontal conditions and a correct oral hygiene. The aim of this study was to highlight the possible adverse effects of bonded retainers on parameters correlated to the health conditions of periodontal tissues. Materials and methods We selected 16 patients, under treatment in the Orthodontics Department of University of Bari Dental School, who had undergone a lingual retainer insertion at the end of the orthodontic treatment. The patients were then divided into two groups (Control Group and Study Group) and monitored for 3 and 36 months, respectively. The following indexes were taken into consideration: gingival index (GI), plaque index (PI) and the presence of calculus (Calculus Index, CI), the probing depth and the presence of gingival recession on the six inferior frontal dental elements. Results After the observation was carried out, any of the patients showed periodontal sockets and gingival recession. In the Study Group, only 1 patient had a PI score=3, the 7 left had scores between 0.66 and 2.83. In the Control Group, one patient had score=0, the other ones showed values between 0.5 and 1.66. The mean GI in the Study Group peaked at a score of 2.83, the minimum was 0.66; whereas in the Control Group the maximum value was 2 and the minimum 0.66. The CI in the Group Study was between 1 and 2. In the Control Group it was absent in only 1 patient, whereas in the remaining 7, it had a value between 0.3 and 1. The clinical data were studied by means of the Wilcoxon test. We found a statistically significant difference for what concerns the Plaque Indexes (PI) (P>0.05) and Calculus Indexes (CI) (P>0.1) in both groups, with higher scores in the Study Group, having retainers for 36 months. Any statistically significant difference was calculated for the GI. Conclusions We can therefore conclude that patients with lingual retainers need periodontal hygiene and treatment as to prevent, in the course of time, periodontal damages non-detectable in short-term.

10% of elderly patients are functionally dependents and they therefore need permanent assistance. Orodental alterations may evolve into a pathological state in elderly people, which is increasing in the recent decades. The current study analysed institutionalized patients in the district of Bari (Southern Italy), who have been so far monitored. We assessed 125 elderly institutionalized patients. The assessment has been carried out by an assessment questionnaire aiming at evaluating the patient’s psychophysical health status, objective intraoral test and prosthetic rehabilitations. About 90% of enrolled patients reported a good general health status. The main dental problems are due to the complete lack of specific prevention and treatment programs, together with handicap, presence of systemic diseases and medicines taken. The level of oral hygiene is poor and the conditions of the residual dental elements are precarious because of root caries and periodontal problems. Prostheses are usually old (on average 15) and appear scarcely retentive and unstable. We believe in the need for specific interventions aiming at the various issues emerging from the present study, so as to achieve a smaller prevalence of dental loss, periodontal disease and caries. These relatively simple interventions are now lacking because of the non-demand of treatment from patients and for economical reasons.

It has long been considered that the most significant risks for breast cancer are gender and age but, as many other tumors, this cancer has also been undeniably linked to gene mutations. The vast majority of breast cancers in postmenopausal women are estrogen-responsive, a hormone which is biosynthesized from blood-circulating androgens through an aromatization reaction, catalyzed by aromatase (AR). One strategy, therefore, to combat breast cancer, has been to find compounds that can inhibit the activity of aromatase to reduce estrogen levels.The authors provide a broad and updated overview of the general structure-activity relationships and on the latest ligand- and structure-based approaches applied to the discovery of potent, selective and safer breast cancer drugs. Specifically the authors review the most consolidated techniques, based on structure-activity relationships, pharmacophore mapping, rigid and flexible molecular docking, as well as sophisticated and reliable protocols simulating critical biological events.The recently solved X-ray structures of aromatase represent solid milestones to breathe new life into the search of newer chemotypes with reduced risks of cross-reactivity toward other CYPs and safer pharmacological profiles. We anticipate that great benefits will arrive from the wealth of information obtained by integrating genomics, site-directed mutagenesis experiments with protein modeling. Furthermore, we welcome the advent of GPU technology that, in conjunction with dedicated algorithms, grants scientists an unprecedented point of view on physiologically relevant phenomena, occurring on the µs time scale, such as ligand binding/unbinding.

Matrix metalloproteinases (MMPs) are attractive biological targets that play a key role in many physiopathological processes such as degradation of extracellular matrix proteins, release and cleavage of cell-surface receptors, tumour progression, homeostatic regulation and innate immunity. A series of 5-hydroxy, 5-substituted pyrimidine-2,4,6-triones were rationally designed, prepared and tested as inhibitors of gelatinases MMP-2 and MMP-9 and collagenase MMP-8. On one side, the presence of the 5-hydroxyl group, that represents an typical feature of this class of compounds, ensured an attractive pharmacokinetic profile while on the other suitably substituted biaryl molecular fragments, attached to position 5 through a ketomethylene linker, guaranteed favourable interaction in the deep region of the S(1)' enzymatic subsite. This rational design led to the discovery of highly potent MMP inhibitors. In particular, biphenyl derivatives bearing at the para position COCH(3) and OCF(3) substituents permitted to inhibit gelatinases MMP-2 and MMP-9, with IC(50) values as low as 30 nM and 21 nM, respectively, whereas the introduction at the same position of the bulkier SO(2)CH(3) group afforded a potent collagenase MMP-8 inhibitor with an IC(50) value equal to 66 nM. Molecular docking simulations allowed us to elucidate key interactions driving the binding of the top active compounds towards their preferred MMP target.

Summary Background Proliferation and differentiation of keratinocytes are central processes in tissue regeneration after injury. Chemokines, produced by a wide range of cell types including keratinocytes, play a regulatory role in inflammatory skin diseases. Several studies have shown that an electromagnetic field (EMF) can influence both inflammatory processes and repair mechanisms including wound healing on different tissue models. Objectives To elucidate the effect of extremely low frequency EMF (ELF-EMF) on keratinocyte proliferation and production of chemokines [RANTES, monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1α and interleukin (IL)-8] in order to evaluate a potential therapeutic use of magnetic fields. Methods The human keratinocyte cell line HaCaT was exposed at 1 mT, 50 Hz for different lengths of time and compared with unexposed control cells. Cell growth and viability were evaluated at different exposure times by cell count and trypan blue exclusion. Chemokine production and expression were analysed by enzyme-linked immunosorbent assay (ELISA) and by real-time polymerase chain reaction. Total NF-κB p65 was quantified by ELISA. Results Significantly increased growth rates were observed after 48 h of EMF exposure as compared with control cells, while no difference in cell viabilities were detected. Gene expression and release of RANTES, MCP-1, MIP-1α and IL-8 were significantly reduced after 72 h of exposure. NF-κB levels became almost undetectable after only 1 h of EMF exposure, and were inversely correlated with cell density. Conclusions Our results show that ELF-EMF modulates chemokine production and keratinocyte growth through inhibition of the NF-κB signalling pathway and thus may inhibit inflammatory processes. ELF-EMF could represent an additional therapeutic approach in the treatment of skin injury.

A series of N-terminus benzamides of glycine-based symmetric peptides, linked to m-xylylenediamine and 3,4'-oxydianiline spacers, were prepared and tested as inhibitors of beta-amyloid peptide Abeta(1-40) aggregation in vitro. Compounds with good anti-aggregating activity were detected. Polyphenolic amides showed the highest anti-aggregating activity, with IC(50) values in the micromolar range. Structure-activity relationships suggested that pi-pi stacking and hydrogen-bonding interactions play a key role in the inhibition of Abeta(1-40) self-assembly leading to amyloid fibrils.

Safinamide, (S)-N2-{4-[(3-fluorobenzyl)oxy]benzyl}alaninamide methanesulfonate, which is in phase III clinical trials as an anti-Parkinson drug, and a library of alkanamidic analogues were prepared through an expeditious solid-phase synthesis and evaluated for their monoamine oxidase B (MAO-B) and monoamine oxidase A (MAO-A) inhibitory activity and selectivity. (S)-3-Chlorobenzyloxyalaninamide (8) and (S)-3-chlorobenzyloxyserinamide (13) derivatives proved to be more potent MAO-B inhibitors than safinamide (IC50 = 33 and 43 nM, respectively, vs 98 nM) but with a lower MAO-B selectivity (SI = 3455 and 1967, respectively, vs 5918). The highest MAO-B inhibitory potency (IC50 = 17 nM) and a good selectivity (SI = 2941) were displayed by (R)-21, a tetrahydroisoquinoline analogue of safinamide. Structure-affinity relationships and docking simulations pointed out strong negative steric effects of alpha-aminoamide side chains and para substituents of the benzyloxy groups and favorable hydrophobic interactions of meta substituents. The significantly diverse MAO-B affinities of a number of R and S alpha-aminoamide enantiomers, including the two rigid analogues (21) of safinamide, indicated likely enantioselective interactions at the enzymatic binding sites.

Diseases triggered by an abnormally high level of cortisol (hypercortisolism), such as the Cushing's and metabolic syndromes, could be successfully tackled by inhibitors of CYP11B1, a steroidal cytochrome P450 enzyme that catalyzes the last hydroxylation step of the cortisol biosynthesis. Structural optimization of 7-(benzyloxy)-4-(1H-imidazol-1-ylmethyl)-2H-chromen-2-one 2, a selective aromatase inhibitor, afforded the 4-(1H-imidazol-1-ylmethyl)-7-{[3-(trifluoromethoxy)benzyl]oxy}-2H-chromen-2-one 7, with improved inhibitory potency at human CYP11B1 (IC50 = 5 nM) and an enhanced selectivity over human CYP11B2 (SIB = 25) compared to lead compound 2 (IC50 = 72 nM, SIB = 4.0) and metyrapone (IC50 = 15 nM, SIB = 4.8), a non-selective drug used in the therapy of the Cushing's syndrome. Structure–activity relationship studies allowed the design and optimization of a novel series of potent and selective compounds, that can be regarded as open analogues of 2H-chromen-2-one derivatives. Compound 23, 2-(1H-imidazol-1-yl)-1-(4-{[3(trifluoromethoxy)benzyl]oxy}phenyl) ethanone, was the most interesting inhibitor of the series displaying a high potency at CYP11B1 (IC50 = 15 nM), increased selectivities over CYP11B2 (SIB = 33), CYP19 (SIB = 390) and CYP17 (5% inhibition at 2.5 μM concentration).

Purpose The main aim of the present study is to present a case of mandibular transposition between lateral incisor and canine in a paediatric patient. Materials and methods A fixed multibracket orthodontic treatment was performed by means of a modified welded arch as to correct the transposition and obtaining a class I functional and symmetrical occlusion, also thanks to the early diagnosis of the eruption anomaly. Results Our case report shows that a satisfactory treatment of mandibular transpositions is obtained when detected at an early stage of the tooth development. Conclusions The main treatment options to be taken into consideration in case of a mandibular transposition are two: correcting the transposition or aligning it leaving the dental elements in their transposed order; in both cases, the follow-ups show a stable condition, maintained without relapses. Several factors, such as age of the patient, occlusion, aesthetics, patient's collaboration, periodontal support and duration of treatment have to be considered as to prevent potential damage to dental elements and support appliances. The choice between the two treatment approaches for mandibular lateral incisor/canine transpositions mainly depends on the time the anomaly is detected.

Introduction: It has long been considered that the most significant risks for breast cancer are gender and age but, as many other tumors, this cancer has also been undeniably linked to gene mutations. The vast majority of breast cancers in postmenopausal women are estrogen-responsive, a hormone which is biosynthesized from blood-circulating androgens through an aromatization reaction, catalyzed by aromatase (AR). One strategy, therefore, to combat breast cancer, has been to find compounds that can inhibit the activity of aromatase to reduce estrogen levels. Areas covered: The authors provide a broad and updated overview of the general structure–activity relationships and on the latest ligand- and structure-based approaches applied to the discovery of potent, selective and safer breast cancer drugs. Specifically the authors review the most consolidated techniques, based on structure–activity relationships, pharmacophore mapping, rigid and flexible molecular docking, as well as sophisticated and reliable pr...

The use of selective inhibitors of monoamine oxidase A (MAO-A) and B (MAO-B) holds a therapeutic relevance in the treatment of depressive disorders and Parkinson's disease (PD), respectively. Here, the discovery of a new class of compounds acting as monoamine oxidase inhibitors (MAO-Is) and bearing a 6'-substituted (E)-2-(benzofuran-3(2H)-ylidene)-N-alkylacetamide skeleton is reported. 6'-Sulfonyloxy derivatives exhibited outstanding affinities to MAO-A (7.0 nMIC5049 nM, much higher than moclobemide) and a pronounced MAO-A/B selectivity. The corresponding 6'-benzyloxy derivatives showed potent MAO-B inhibition and inverted selectivity profile. The rigid E-geometry of the exocyclic double bond allowed a more efficient binding conformation compared to more flexible and less active 2-(1-benzofuran-3-yl)-N-methylacetamide isomers and 4-N-methylcarboxamidomethylcoumarin analogues. Focused structural modifications and docking simulations enabled the identification of key molecular determinants for high affinity toward both MAO isoforms. These novel MAO-Is may represent promising hits for the development of safer therapeutic agents with a potential against depression, PD, and other age-related neurodegenerative pathologies.

Acetylcholinesterase inhibitors (AChEIs) are currently the drugs of choice, although only symptomatic and palliative, for the treatment of Alzheimer’s disease (AD). Donepezil is one of most used AChEIs in AD therapy, acting as a dual binding site, reversible inhibitor of AChE with high selectivity over butyrylcholinesterase (BChE). Through a combined target- and ligand-based approach, a series of coumarin alkylamines matching the structural determinants of donepezil were designed and prepared. 6,7-Dimethoxycoumarin derivatives carrying a protonatable benzylamino group, linked to position 3 by suitable linkers, exhibited fairly good AChE inhibitory activity and a high selectivity over BChE. The inhibitory potency was strongly influenced by the length and shape of the spacer and by the methoxy substituents on the coumarin scaffold. The inhibition mechanism, assessed for the most active compound 13 (IC50 7.6 nM) resulted in a mixed-type, thus confirming its binding at both the catalytic and peripheral binding sites of AChE.

Epigenetic regulation is an essential process for the normal functioning of genes. Therefore, targeting epigenetic dysregulation in cancer may be a valid therapeutic approach for the treatment of this severe disease. Histone deacetylases (HDACs) are enzymes involved in the regulation of epigenetic post-translational modifications; because they are overexpressed in many types of cancer, HDACs are valuable targets for the development of new anticancer agents. A large series of 2-aminobenzanilides linked at the 4'-position to α-amino acid amides, arenes, and heteroarenes through a methylene bridge were designed, synthesized, and tested as novel HDAC inhibitors. Several compounds showed IC(50) values in the two-digit nanomolar range in hrHDAC1 inhibition assays, lower than that of the reference compound MS-275. They also showed interesting selectivity profiles, as confirmed by western blot assays.

The socioeconomic burden of multi-factorial pathologies, such as neurodegenerative diseases (NDs), is enormous worldwide. Unfortunately, no proven disease-modifying therapy is available yet and in most cases (e.g., Alzheimer's and Parkinson's disease) the approved drugs exert only palliative and symptomatic effects. Nowadays, an emerging strategy for the discovery of disease-modifying drugs is based on the multi-target directed ligand (MTDL) design, an innovative shift from the traditional approach one-drug-one-target to the more ambitious one-drug-more-targets goal. Herein, we review the discovery strategy, the mechanism of action and the biopharmacological evaluation of multipotent ligands exhibiting monoamine oxidase (MAO) inhibition as the core activity with a potential for the treatment of NDs. In particular, MAO inhibitors exhibiting additional acetylcholinesterase (AChE) or nitric oxide synthase (NOS) inhibition, or ion chelation/antioxidant-radical scavenging/anti-inflammatory/A2A receptor antagonist/APP processing modulating activities have been thoroughly examined.

A large series of piperazin-, piperidin- and tetrahydroisoquinolinamides of 4-(1,3-dialkyl-9-deazaxanthin-8-yl)phenoxyacetic acid were prepared through conventional or multiple parallel syntheses and evaluated for their binding affinity at the recombinant human adenosine receptors, chiefly at the h A 2B and h A 2A receptor subtypes. Several ligands endowed with high binding affinity at h A 2B receptors, excellent selectivity over h A 2A and h A 3 and a significant, but lower, selectivity over h A 1 were identified. Among them, piperazinamide derivatives 23 and 52 , and piperidinamide derivative 69 proved highly potent at h A 2B ( K i = 11, 2 and 5.5 nM, respectively) and selective towards h A 2A ( h A 2A / h A 2B SI = 912, 159 and 630, respectively), h A 3 ( h A 3 / h A 2B SI = > 100, 3090 and >180, respectively) and h A 1 ( h A 1 / h A 2B SI = > 100, 44 and 120, respectively), SI being the selectivity index. A number of selected ligands tested in functional assays in vitro showed very interesting antagonist activities and efficacies at both A 2A and A 2B receptor subtypes, with pA 2 values close to the corresponding p K i s. Structure–affinity and structure–selectivity relationships suggested that the binding potency at the h A 2B receptor may be increased by lipophilic substituents at the N4-position of piperazinamides and that an ortho -methoxy substituent at the 8-phenyl ring and alkyl groups at N1 larger than the ones at N3, in the 9-deazaxanthine ring, may strongly enhance the h A 2A / h A 2B SI.

Over two hundred 1-, 3-, 8-, and 9-substituted-9-deazaxanthines were prepared and evaluated for their binding affinity at the recombinant human adenosine receptors, in particular at the hA(2B) and hA(2A) subtypes. Several ligands endowed with sub-micromolar to low nanomolar binding affinity at hA(2B) receptors, good selectivity over hA(2A) and hA(3), but a relatively poor selectivity over hA(1) were obtained. Good antagonistic potencies and efficacies, with pA(2) values close to the corresponding pK(i)s, were observed in functional assays in vitro performed on a selected series of compounds. 1,3-Dimethyl-8-phenoxy-(N-p-halogenophenyl)-acetamido-9-deazaxanthine derivatives appeared as the most interesting leads, some of them showing outstanding hA(2B) affinities, high selectivity over hA(2A) and hA(3), but low selectivity over hA(1). Structure-affinity relationships suggested that the binding potency at the hA(2B) receptor was mainly modulated by the steric (lipophilic) properties of the substituents at positions 1 and 3 and by the electronic and lipophilic characteristics of the substituents at position 8. A comparison among affinity and selectivity profiles of 9-deazaxanthines with the corresponding xanthines suggested some possible differences in their binding mode.

Chronic myeloid leukemia (CML) is a myeloproliferative disorder caused by the Philadelphia-positive chromosome deriving from a translocation between chromosomes 22 and 9. The oncogenic product of this aberrant chromosome is the constitutively active tyrosine kinase BCR-ABL that is responsible for leukemic cell growth, proliferation and survival driven by the dysregulation of a large array of signal transduction pathways. Inhibition of BCR-ABL with tyrosine kinase inhibitors proved to be an efficient therapy of CML in the chronic phase. Unfortunately, the impressive success of BCR-ABL inhibitors as front-line therapy in CML has been tempered by problems of disease persistence or relapse arising from different mechanisms, including mutations in the kinase domain of the enzyme BCRABL and mechanisms independent from BCR-ABL activity. Growing evidence has also suggested a pivotal role of persistent leukemic cancer stem cells, characterized by high self-renewal and pluripotency, in CML maintenance and/or relapse. The present review deals with the most recent advances in this challenging field and focuses on the development of new drugs and therapeutic approaches to eradicate the subtle and dangerous leukemic stem cells responsible for maintaining and sustaining tumor growth.

Fibromyalgia (FM) is a rheumatic disease which affects fibrous tissues and muscles; it is characterized by chronic pain and it is often associated with craniomandibular disorders (CMD). 31 patients were assessed from March 2012 to October 2012 through the administration of specific questionnaires and following neurologic and gnatologic assessment. A relevant corre-lation between FM and CMD emerges from the present study, as 80.6% of our patients report CMD symptoms with high prevalence of myofascial pain (84%). Multivariate regression analysis revealed that the patients in the present study did not differ in score of quality of life questionnaires from patients with fibromyalgia. The neuropathic pain diagnostic question-naire (DN4) scores were positively affected by belonging to group II of Research Diagnostic Criteria of Temporomandibular Disorders (RDC/ TDM) classification, suggesting the possibility of a neuropathic component in chronic pain in this CMD group, as already speculated in our study on the correlation between burning mouth syndrome and CMD and by other au-thors in studies on chronic low back pain. However, further clinic and instrumental studies are needed in order to test this as-sumption.

Chronic myeloid leukemia (CML) is a myeloproliferative disease originating from a constitutively active tyrosine kinase, called BCR-ABL, expressed by an oncogene resulting from a reciprocal translocation between chromosome 9 and chromosome 22, coded as (t[9,22][q34;q11]). Inhibition of BCR-ABL with tyrosine kinase inhibitors (TKI) proved to be an efficient targeted therapy of Philadelphia-positive (Ph+) CML in the chronic phase. This review mainly addresses the synthetic pathways and process chemistry leading to the large scale preparation for pre-clinical demands and clinical supply of the three TKIs approved for Ph+ CML, i.e., imatinib, dasatinib and nilotinib and three more investigational drugs, i.e., bosutinib, ponatinib and bafetinib. Recent progress on the biochemical profiling of the six examined TKIs has been also reported.

The hypothesis of Woolley and Shaw1-3that an altered metabolism of 5-hydroxytryptamine (5-HT), serotonin (Rapport4), or enteramine (Erspamer5) may be of importance in the genesis of a psychiatric disturbance, namely, schizophrenia, has aroused great interest and inspired countless investigations. We do not know whether it is a deficiency or an excess of serotonin that may be responsible for the abnormal brain function. In fact, the role played by serotonin in cerebral physiology has yet to be determined. The possibility that the altered metabolism of an endogenous amine may play a role in the genesis of schizophrenia seems particularly interesting in view of the work of V. M. Buscaino.6For over 35 years this investigator and his school have pointed out that the only unquestionable changes found in schizophrenic patients indicate the existence of an altered metabolism of biological amines, including those derived from the indole nucleus.