Synthesis and biological assessment of new pyrimidopyrimidines as inhibitors of breast cancer resistance protein (ABCG2)

International audienc

Enhancement of Antibacterial Activity of Paludifilum halophilum and Identification of N-(1-Carboxy-ethyl)-phthalamic Acid as the Main Bioactive Compound

The aim of this study was to determine the combined effect of fermentation parameters and enhance the production of cellular biomass and antibacterial compounds from Paludifilum halophilum SMBg3 using the response surface methodology (RSM). Eight variables were screened to assess the effects of fermentation parameters on growth and metabolite production by Taguchi experimental design. Among these, the initial pH, temperature, and the percentage of MgSO4·7H2O in the medium were found to be most influential. The Box–Behnken design was applied to derive a statistical model for the optimization of these three fermentation parameters. The optimal parameters were initial pH: 8.3, temperature growth: 44°C, and MgSO4·7H2O: 1.6%, respectively. The maximum yield of biomass and metabolite production were, respectively, 11 mg/mL dry weight and 15.5 mm inhibition zone diameter against Salmonella enterica, which were in agreement with predicted values. The bioactive compounds were separated by the thick-layer chromatography technique and analyzed by GC/MS, NMR (1D and 2D), and Fourier-transform infrared spectroscopy (FT-IR). In addition to several fatty acids, N-(1-carboxy-ethyl)-phthalamic acid was identified as the main antibacterial compound. This element exhibited a potent activity against the ciprofloxacin-resistant Salmonella enterica CIP 8039 and Pseudomonas aeruginosa ATCC 9027 with a minimum inhibitory concentration (MIC) value range of 12.5–25 μg/mL. Results demonstrated that P. halophilum strain SMBg3 is a promising resource for novel antibacterial production due to its high-level yield potential and the capacity for large-scale fermentation

Synthesis and Biological Assessment of PyrimidoTacrines as Promising Agents for Alzheimer's Disease Therapy

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Nontoxic and Neuroprotective β‑Naphthotacrines for Alzheimer’s Disease

The synthesis, toxicity, neuroprotection, and human acetylcholinesterase (hAChE)/ human butyrylcholinesterase (hBuChE) inhibition properties of <i>β-naphthotacrines</i> <b>1</b>–<b>14</b> as new drugs for Alzheimer’s disease (AD) potential treatment, are reported. <i>β-Naphthotacrines</i> <b>1</b>–<b>14</b> showed lower toxicity than tacrine; moreover, at the highest concentration assayed (300 μM) compounds <b>7</b>, <b>10</b> and <b>11</b> displayed 2.25–2.01-fold higher cell viability than tacrine in HepG2 cells. A neuroprotective effect was observed for compounds <b>10</b> and <b>11</b> in a neuronal cortical culture exposed to a combination of oligomycin A/rotenone. An efficient and selective inhibition of hAChE, was only observed for the <i>β-naphthotacrines</i> bearing electron-donating substituents at the aromatic ring, <i>β-naphthotacrine</i> <b>10</b> being the most potent (hAChE: IC₅₀ = 0.083 ± 0.024 μM). Kinetic inhibition analysis clearly demonstrated that <i>β-naphthotacrine</i> <b>10</b> behaves as a mixed-type inhibitor (<i>K</i>_i₂= 0.72 ± 0.06 μM) at high substrate concentrations (0.5–10 μM), while at low concentrations (0.01–0.1 μM) it behaves as a hAChE competitive inhibitor (<i>K</i>_i₁= 0.007 ± 0.001 μM). These findings identified <i>β-naphthotacrine</i> <b>10</b> as a potent and selective hAChE inhibitor in a nanomolar range, with toxicity lower than that of tacrine both in human hepatocytes and rat cortical neurons, with a potent neuroprotective activity and, consequently, an attractive multipotent active molecule of potential application in AD treatment

Nontoxic and neuroprotective β-naphthotacrines for alzheimer's disease

The synthesis, toxicity, neuroprotection, and human acetylcholinesterase (hAChE)/ human butyrylcholinesterase (hBuChE) inhibition properties of β-naphthotacrines1-14 as new drugs for Alzheimer's disease (AD) potential treatment, are reported. β-Naphthotacrines1-14 showed lower toxicity than tacrine; moreover, at the highest concentration assayed (300 μM) compounds 7, 10 and 11 displayed 2.25-2.01-fold higher cell viability than tacrine in HepG2 cells. A neuroprotective effect was observed for compounds 10 and 11 in a neuronal cortical culture exposed to a combination of oligomycin A/rotenone. An efficient and selective inhibition of hAChE, was only observed for the β-naphthotacrines bearing electron-donating substituents at the aromatic ring, β-naphthotacrine10 being the most potent (hAChE: IC50 = 0.083 ± 0.024 μM). Kinetic inhibition analysis clearly demonstrated that β-naphthotacrine10 behaves as a mixed-type inhibitor (K i2= 0.72 ± 0.06 μM) at high substrate concentrations (0.5-10 μM), while at low concentrations (0.01-0.1 μM) it behaves as a hAChE competitive inhibitor (Ki1= 0.007 ± 0.001 μM). These findings identified β-naphthotacrine10 as a potent and selective hAChE inhibitor in a nanomolar range, with toxicity lower than that of tacrine both in human hepatocytes and rat cortical neurons, with a potent neuroprotective activity and, consequently, an attractive multipotent active molecule of potential application in AD treatment.Peer Reviewe