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Background: Eosinophilic dermatosis of hematologic malignancy (EDHM) is a rare dermatosis associated with blood tumors.Objective: To characterize the expression of T-cell and B-cell markers and pruritogenic mediators in EDHM skin.Methods: Immunohistochemical and immunofluorescence analysis were performed in 12 skin samples of EDHM, 11 samples of bullous pemphigoid (BP), and 5 samples from healthy controls (HC). Serum levels of interleukin (IL) 4 were analyzed in 11 patients with EDHM, 11 BP patients, and 5 HC by enzyme-linked immunosorbent assay.Results: T-cell markers, including clusters of differentiation (CD) 3, CD4, CD8, and CD5 were significantly overexpressed in EDHM and BP skin compared to HC. A predominance of CD4+ over CD8+ cells and GATA3+ (helper T cell type 2 [Th2] marker) over T-bet+ (Th1 marker) cells were observed. FOXP3 expression was increased but the FOXP3/CD4 ratio was low. B-cell markers were under-represented, without significant differences between the 3 groups. IL-4 and IL-31 were significantly overexpressed in EDHM and BP compared to HC and colocalized with the Th2-associated marker GATA3. Eotaxin-1 was significantly overexpressed in EDHM compared to BP and HC. IL-4 serum concentration was significantly increased in EDHM and BP compared to HC.Limitations: Small sample size; retrospective design.Conclusions: Targeting Th2-related molecules, in particular IL-4, holds promise for EDHM management. [ABSTRACT FROM AUTHOR]

Abstract: The synthesis and antifungal activity of 2-acylhydrazino-5-arylpyrroles 21–62 are described. Pyrrole derivatives 21–62 were evaluated for their antifungal activity towards Candida albicans ATCC 10231 and three Candida non-albicans isolated from clinical specimens. Most of them showed very good antifungal activities against Candidae, having MIC values in the 0.39–3.12μg/mL range and enhanced inhibition potency as compared to that of fluconazole. In addition, some of the most active compounds were tested for cytotoxic activities against breast (MCF-7), lung (H-460), and central nervous system (SF-268) human cancer cell lines with the NCI anticancer drug screen. The activity of pyrroles described in this paper, along with the low toxicity, shows promise for the future development of non-toxic new antimycotic agents. The relationship between functional group variation and biological activity of the evaluated compounds is also discussed. [Copyright &y& Elsevier]

Abstract: As a continuation of our previous work that turned toward the identification of antimycobacterial compounds with innovative structures, two series of pyrazole derivatives were synthesized by parallel solution-phase synthesis and were assayed as inhibitors of Mycobacterium tuberculosis (MTB), which is the causative agent of tuberculosis. One of these compounds showed high activity against MTB (MIC=4μg/mL). The newly synthesized pyrazoles were also computationally investigated to analyze their fit properties to the pharmacophoric model for antitubercular compounds previously built by us and to refine structure–activity relationship analysis. [Copyright &y& Elsevier]

• Benzoxazin-2-one and -3-one derivatives were synthesized and biologically evaluated. • Antimycobacterial evaluation (MIC) and cytotoxicity (IC50) have been reported. • Oxoacetamide-isoniazid analogues were obtained and biologically evaluated. • Compound 8a has been computationally studied. This study examines in depth benzoxazine nucleus for antimycobacterial property. We synthesized some benzoxazin-2-one and benzoxazin-3-one derivatives, which were tested for activity against a panel of Mycobacterium tuberculosis (Mtb) strains, including H37Ra, H37Rv and some resistant strains. Several compounds displayed a high antimycobacterial activity and the three isoniazid analogue derivatives 8a-c exhibited a MIC range of 0.125–0.250 μg/mL (0.37–0.75 μM) against strain H37Ra, therefore lower than the isoniazid reference drug. Two benzoxazin-2-one derivatives, 1c and 5j , together with isoniazid-analogue compound 8a , also revealed low MIC values against resistant strains and proved highly selective for mycobacterial cells, compared to mammalian Vero cells. To predict whether molecule 8a is able to interact with the active site of InhA, we docked it into the crystal structure; indeed, during the molecular dynamic simulation the compound never left the protein pocket. The more active compounds were predicted for ADME properties and all proved to be potentially orally active in humans. [ABSTRACT FROM AUTHOR]

Sixteen 3-(carboxymethyl)rhodanines, and twelve aminothiazoles as rhodanine-mimetics were designed, synthesized and tested as inhibitors of the Zmp1 enzyme from Mycobacterium tuberculosis (Mtb). Almost all rhodanines ( 5a – d , 5f – n , and 7a – b ) exhibited Zmp1 inhibition with IC 50 values in the range 1.3–43.9 µM, whereas only aminothiazoles 12b and 12d proved active with IC 50 values of 41.3 and 35.7 µM, respectively. Structure-activity relationships (SAR) were coupled with molecular modeling studies to highlight structural determinants for Zmp1 inhibition. Moreover, rhodanines 5a and 5c induced 23.4 and 53.8% of Mtb growth inhibition in THP-1 infected cells, respectively, at the non-toxic concentration of 10 µg/ml. This work represents a step forward in targeting Zmp1 by small molecules. [ABSTRACT FROM AUTHOR]

BM635 is the hit compound of a promising anti-TB compound class. Herein we report systematic variations around the central pyrrole core of BM635 and we describe the design, synthesis, biological evaluation, pharmacokinetic analysis, as well as in vivo TB mouse efficacy studies of novel BM635 analogues that show improved physicochemical properties. This hit-to-lead campaign led to the identification of a new analogue, 4-((1-isopropyl-5-(4-isopropylphenyl)-2-methyl-1H-pyrrol-3-yl)methyl)morpholine ( 17 ), that shows excellent activity (MIC = 0.15 μM; SI = 133) against drug-sensitive Mycobacterium tuberculosis strains, as well as efficacy in a murine model of TB infection. [ABSTRACT FROM AUTHOR]

Mycobacterium tuberculosis (Mtb) protein tyrosine phosphatases A and B (PtpA and PtpB) have been recognized as potential molecular targets for the development of new therapeutic strategies against tuberculosis (TB). In this context, we have recently reported that the naturally occurring Diels-Alder-type adduct Kuwanol E is an inhibitor of PtpB ( K i = 1.6 ± 0.1 μM). Here, we describe additional Diels-Alder-type adducts isolated from Morus nigra roots bark that inhibit PtpB at sub-micromolar concentrations. The two most potent compounds, namely Kuwanon G and Kuwanon H, showed K i values of 0.39 ± 0.27 and 0.20 ± 0.01 μM, respectively, and interacted with the active site of the enzyme as suggested by kinetics and mass spectrometry studies. Molecular docking coupled with intrinsic fluorescence analysis and isothermal titration calorimetry (ITC) further characterized the interaction of these promising PtpB inhibitors. Notably, in an Mtb survival assay inside macrophages, Kuwanon G showed inhibition of Mtb growth by 61.3%. All these results point to the common Diels-Alder-type adduct scaffold, and highlight its relevance for the development of PtpB inhibitors as candidate therapeutics for TB. [ABSTRACT FROM AUTHOR]

Background The activation of oncogenic Wnt/β-catenin pathway in melanoma contributes to a lack of T-cell infiltration. Whether baseline β-catenin expression in the context of tumour-infiltrating lymphocytes (TILs) and programmed death ligand-1 (PD-L1) overexpression correlates with prognosis of metastatic melanoma patients (MMPs) treated with mitogen-activated protein kinase, MAPK inhibitor (MAPKi) monotherapy, however, has not been fully clarified. Patients and methods Sixty-four pre-treatment formalin-fixed and paraffin embedded melanoma samples from MMP treated with a BRAF inhibitor (n = 39) or BRAF and MEK inhibitors (n = 25) were assessed for presence of β-catenin, PD-L1, cluster of differentiation (CD)8, CD103 and forkhead box protein P3 (FOXP3) expression by immunohistochemistry, and results were correlated with clinical outcome. Quantitative assessment of mRNA transcripts associated with Wnt/β-catenin pathway and immune response was performed in 51 patients. Results We found an inverse correlation between tumoural β-catenin expression and the level of CD8, CD103 or forkhead box protein P3 (FOXP3) positivity in the tumour microenvironment (TME). By multivariate analysis, PD-L1 <5% (odds ratio, OR 0.12, 95% confidence interval, CI 0.03–0.53, p = 0.005) and the presence of CD8+ T cells (OR 18.27, 95%CI 2.54–131.52, p = 0.004) were significantly associated with a higher probability of response to MAPKi monotherapy. Responding patients showed a significantly increased expression of mRNA transcripts associated with adaptive immunity and antigen presentation. By multivariate analysis, progression-free survival (PFS) (hazards ratio (HR) = 0.25 95%CI 0.10–0.61, p = 0.002) and overall survival (OS) (HR = 0.24 95%CI 0.09–0.67, p = 0.006) were longer in patients with high density of CD8+ T cells and β-catenin <10% than those without CD8+ T cells infiltration and β-catenin ≥10%. Conclusion Our findings provide evidence that in the context of MAPKi monotherapy, immune subsets in the (TME) and gene signature predict prognosis in MMPs. [ABSTRACT FROM AUTHOR]

The development of new anti-tubercular agents represents a constant challenge mostly due to the insurgency of resistance to the currently available drugs. In this study, a set of 60 molecules were selected by screening the Asinex and the ZINC collections and an in house library by means of in silico ligand-based approaches. Biological assays in Mycobacterium tuberculosis H37Ra ATCC 25177 strain highlighted (±)-1-(4-chlorophenyl)-2-(1 H -imidazol-1-yl)ethyl-4-(3,4-dichlorophenyl)piperazine-1-carboxylate ( 5i ) and 3-(4-chlorophenyl)-5-(2,4-dimethylpyrimidin-5-yl)-2-methylpyrazolo[1.5-a]pyrimidin-7(4 H )-one ( 42 ) as the most potent compounds, having a Minimum Inhibitory Concentration (MIC) of 4 and 2 μg/mL respectively. These molecules represent a good starting point for further optimization of effective anti-TB agents. [ABSTRACT FROM AUTHOR]

N 1 -[1-[1-aryl-3-[4-(1 H -imidazol-1-yl)phenyl]-3-oxo]propyl]-pyridine-2-carboxamidrazone derivatives were design, synthesized and tested for their in vitro antimycobacterial activity. The new compounds showed a moderate antimycobacterial activity against the tested strain of Mycobacterium tuberculosis H37Ra and a significant antimycobacterial activity against several mycobacteria other than tuberculosis strains. [ABSTRACT FROM AUTHOR]

Abstract: From the methanol extract of the bulbs of Pancratium illyricum L., three phenanthridine type alkaloids, ungeremine (1), (−)-lycorine (2) and (+)-vittatine (3) were isolated. For the evaluation of their anticancer and antibacterial potential, compounds 1–3 were tested against human (I, IIα) and bacterial (IA, IV) topoisomerases. Our data demonstrated that ungeremine impairs the activity of both, human and bacterial topoisomerases. Remarkably, ungeremine was found to largely increments the DNA cleavage promoted by bacterial topoisomerase IA, a new target in antimicrobial chemotherapy. [Copyright &y& Elsevier]

Abstract: During the search of novel antitubercular drugs related to BM 212, new diarylpyrroles were designed and synthesized on the basis of a structure–activity relationship analysis of many pyrroles previously described by us. Among them, 1-(4-fluorophenyl)-2-ethyl-3-(thiomorpholin-4-yl)methyl-5-(4-methylphenyl)-1H-pyrrole (2b) proved to be particularly active, with a minimum inhibitory concentration (MIC, expressed as μg/mL) and a protection index (PI) better than or comparable to those of reference compounds. Also the remaining compounds were very active, although their MIC and PI were in general lower than those of their parent 2-methyl analogues. [Copyright &y& Elsevier]

Abstract: Two series of novel rigid pyrazolone derivatives were synthesized and evaluated as inhibitors of Mycobacterium tuberculosis (MTB), the causative agent of tuberculosis. Two of these compounds showed a high activity against MTB (MIC=4μg/mL). The newly synthesized pyrazolones were also computationally investigated to analyze if their properties fit the pharmacophoric model for antitubercular compounds previously built by us. The results are in agreement with those reported by us previously for a class of pyrazole analogues and confirm the fundamental role of the p-chlorophenyl moiety at C4 in the antimycobacterial activity. [Copyright &y& Elsevier]

Several arylideneisothiosemicarbazones and arylidenehydrazothiazoles have been synthesised to obtain new antimicrobial agents. Their activity against both bacteria and fungi has been tested and some interesting informations about their biological activity have been obtained. [Copyright &y& Elsevier]

It is known that some derivatives of both thiourea and thiosemicarbazide exhibit potent anti-microbial activity. In order to investigate the effects on the biological properties of structural modifications of such structures, we have synthesised and studied some arylidenisothiosemicarbazones. In this paper we report on the synthesis and structure–activity relationships of some isothiosemicarbazones, where the arylidene group has been replaced with a cycloalkyl group and the sulfur atom has been either differently substituted or enclosed in a thiazole ring. [ABSTRACT FROM AUTHOR]

A major constraint in reducing tuberculosis epidemic is the emergence of strains resistant to one or more of clinically approved antibiotics, which emphasizes the need of novel drugs with novel targets. Genetic knockout strains of Mycobacterium tuberculosis (Mtb) have established that tryptophan (Trp) biosynthesis is essential for the bacterium to survive in vivo and cause disease in animal models. An anthranilate-like compound, 6-FABA , was previously shown to synergize with the host immune response to Mtb infection in vivo. Herein, we present a class of anthranilate-like compounds endowed with good antimycobacterial activity and low cytotoxicity. We show how replacing the carboxylic moiety with a hydrazide led to a significant improvement in both activity and cytotoxicity relative to the parent compound 6-FABA. Several new benzohydrazides (compounds 20 – 31 , 33 , 34 , 36 , 38 and 39) showed good activities against Mtb (0.625 ≤ MIC≤6.25 μM) and demonstrated no detectable cytotoxicity against Vero cell assay (CC 50 ≥ 1360 μM). The target preliminary studies confirmed the hypothesis that this new class of compounds inhibits Trp biosynthesis. Taken together, these findings indicate that fluorophenylbenzohydrazides represent good candidates to be assessed for drug discovery. [Display omitted] • Anthranilate-like compounds showed good antimycobacterial activity. • Hydrazides significantly improved the activity relatively to the parent compound. • 6-Fluorophenylbenzohydrazides possibly inhibit Trp biosynthesis. [ABSTRACT FROM AUTHOR]