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2-aminothiophene derivatives (2AT) in which the thiophene ring is fused with a cycloalkyl or a N-acylated piperidine ring by positions 5 and 6 and carrying a 3-carbethoxy group were synthesized and their bacterial growth and enzyme inhibitory effects against efflux proteins of Staphylococcus aureus leading to resistance to fluoroquinolones and erythromycin (ERY) were investigated. Compounds that most effectively decreases the minimum inhibitory concentrations (MICs) of ciprofloxacin (CIP) were assayed for their dose and time effects on the accumulation and efflux of ethidium bromide (EtBr) in the SA-1 strain. None of the compounds displayed antibacterial activity however, three derivatives carrying 2-amino, 2-aminoacetyl and 2-aminotrifluoroacetyl group enhanced the activity of CIP and ERY by 8- and 16-fold, respectively, and were able to restore the sensitivity of resistant strains, acting as typical efflux pump inhibitors (EPIs). The 2-aminoacetyl and 2-aminotrifluoroacetyl derivatives and two other piperidinyl 2-aminotrifluoroacetyl derivatives increased EtBr accumulation in a dose- and time-dependent manner, and one of them was also able to inhibit the EtBr efflux. Taken together, these results represent an important advance in the development of new EPIs, and demonstrate that 2AT represent a good scaffold for developing new antibiotic adjuvants.

Treatment of pain and fever remains an important challenge for modern medicine. Non-steroidal anti-inflammatory drugs (NSAIDs) are the pharmacological options most often used, but their frequent use exposes the patient to serious side effects and dangerous drug interactions. In this context, thiophene derivatives are promising therapeutic alternatives. In this study, we evaluated the in vivo and in silico antinociceptive and antipyretic properties of RMD86, a thiophene derivative. At 100 mg/kg, RMD86 induced no significant changes in the motor coordination of mice in the Rotarod test. At 25, 50, and 100 mg/kg RMD86 significantly reduced the number of abdominal contortions induced by acetic acid (antinociceptive activity) in mice when compared to the control. In the formalin test, for the first phase, there was a reduction in licking times at doses of 50 and 100 mg/kg. In the second phase, reduction occurred at all doses. In the hot plate test, RMD86 (at 100 mg/kg) increased latency time in the first 30 min. For antipyretic activity, RMD86, when compared to the reference drug acetaminophen (250 mg/kg), significantly reduced pyrexia at 30, 60, and 120 min, at dosages of 25, 50 and 100 mg/kg. Molecular docking studies revealed that RMD86 presents a greater number of interactions and lower energy values than both the co-crystallized ligand and the reference drug (meloxicam) against COX-1 and COX-2 isoenzymes. The results give evidence of the analgesic and antipyretic properties like NSAIDs suggesting its potential for pain therapy., Antipyretic activity; Antinociceptive activity; 2-amino-thiophene derivative; Molecular docking; Biological sciences; Neuroscience; Behavioral neuroscience; Behavioral test; Nervous system.

Background Acridine derivatives, including amsacrine, have antitumor activity. However, side effects, development of resistance and their low bioavailability, have limited their use. Herein, we described the synthesis, and evaluated the toxicity and antitumor activity of a new amsacrine analogous, the N ′-(2-chloro-6-methoxy-acridin-9-yl)-2-cyano-3-(4-dimethylaminophenyl)-acrilohidrazida (ACS-AZ10). Methods The compound was obtained in a linear pathway where the ASC-Az intermediate was obtained by coupling of 6,9-dichloro-3-methoxy-acridine and 2-ciany-acethohidrazide followed by condensation with the corresponding aldehyde. The toxicity of ACS-AZ10 was evaluated in mice using acute toxicity and micronucleus assays. Ehrlich ascites carcinoma model was used to investigate the antitumor activity and toxicity of ACS-AZ10 (7.5, 15 or 30 mg/kg, i.p.), after nine days of treatment. Cell cycle and angiogenesis were also evaluated. Results The ASC-AZ10 was obtained with satisfactory yields and its structure was confirmed by spectroscopic and spectrometric techniques. On acute toxicity study, ACS-AZ10 (2000 mg/kg, i.p.) induced transient depressant effects on central nervous system. The LD 50 was approximately 2500 mg/kg. ACS-AZ10 (15 or 30 mg/kg) displayed significant antitumor activity considering the tumor weight and volume, cell viability, and total Ehrlich cell count. ACS-AZ10 (7.5 mg/kg) induced an increase in sub-G1 peak, suggesting apoptosis. At 15 mg/kg ACS-AZ10 induced cell cycle arrest in G2/M phase and a reduction in the percentage of cells in G0/G1 and S phases, suggesting a pre-mitotic blockade. ACS-AZ10 reduced the microvessel density, indicating an antiangiogenic effect. Weak hematological, biochemical and histopathological toxicity were observed. The compound doesn’t show genotoxicity in micronucleus assay. Conclusions ACS-AZ10 has potent antitumor activity in vivo along with low toxicity.

Cancer is one of the most urgent problems in medicine. In recent years, cancer is the second leading cause of death globally. In search for more effective and less toxic treatment against cancer, natural products are used as prototypes in the synthesis of new anticancer drugs. The aim of this study was to investigate the in vivo toxicity and the mechanism of antitumor action of 7-isopentenyloxycoumarin (UMB-07), a coumarin derivative with antitumor activity. The toxicity was evaluated in vitro (hemolysis assay), and in vivo (micronucleus and acute toxicity assays). Ehrlich ascites carcinoma model was used to evaluate in vivo antitumor activity of UMB-07 (12.5, 25, or 50 mg/kg, intraperitoneally, i.p.), after 9 days of treatment, as well as toxicity. UMB-07 (2000 μg/mL) induced only 0.8% of hemolysis in peripheral blood erythrocytes of mice. On acute toxicity assay, LD50 (50% lethal dose) was estimated at around 1000 mg/kg (i.p.), and no micronucleated erythrocytes were recorded after UMB-07 (300 mg/kg, i.p.) treatment. UMB-07 (25 and 50 mg/kg) reduced tumor volume and total viable cancer cells. In the mechanism action investigation, no changes were observed on the cell cycle analysis; however, UMB-07 reduced peritumoral microvessels density and CCL2 chemokine levels. In addition, UMB-07 showed weak toxicity on biochemical, hematological, and histological parameters after 9 days of antitumor treatment. The current findings suggest that UMB-07 has low toxicity and exerts antitumor effect by inhibit angiogenesis via CCL2 chemokine decrease.

Made available in DSpace on 2019-10-06T16:45:21Z (GMT). No. of bitstreams: 0 Previous issue date: 2019-11-01 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Financiadora de Estudos e Projetos The search for new drugs with anti-inflammatory properties remains a challenge for modern medicine. Among the various strategies for drug discovery, deriving new chemical entities from known bioactive natural and/or synthetic compounds remains a promising approach. Here, we designed and synthesized CVIB, a codrug developed by association of carvacrol (a phenolic monoterpene) with ibuprofen (a non-steroidal anti-inflammatory drug). In silico pharmacokinetic and physicochemical properties evaluation indicated low aqueous solubility (LogP ≥5.0). Nevertheless, the hybrid presented excellent oral bioavailability, gastrointestinal tract absorption, and low toxicity. CVIB did not present cytotoxicity in peripheral blood mononuclear cells (PBMCs), and promoted a significant reduction in IL-2, IL-10, IL-17, and IFN-γ cytokine levels in vitro. The LD50 was estimated to be approximately 5000 mg/kg. CVIB was stable and detectable in human plasma after 24 h. In vivo anti-inflammatory evaluations revealed that CVIB at 10 and 50 mg/kg i.p. caused a significant decrease in total leukocyte count (p < 0.01) and provoked a significant reduction in IL-1β (p < 0.01). CVIB at 10 mg/kg i.p. efficiently decreased inflammatory parameters better than the physical mixture (carvacrol + ibuprofen 10 mg/kg i.p.). The results suggest that the codrug approach is a good option for drug design and development, creating the possibility of combining NSAIDs with natural products in order to obtain new hybrid drugs may be useful for treatment of inflammatory diseases. Laboratory of Synthesis and Drug Delivery State University of Paraiba Post-Graduation Program in Natural and Synthetic Bioactive Products Federal University of Paraiba Laboratory of Immunomodulation and Novel Therapeutic Approaches Federal University of Pernambuco Laboratory of Neurosciences and Pharmacological Assays (LANEF) University of Sergipe Teaching and Research Management - University Hospital Federal University of Paraiba Department of Antibiotics Center for Biosciences Federal University of Pernambuco Laboratory of Toxicology São Paulo State University (UNESP) School of Pharmaceutical Sciences Health Research and Education Center (NUPADS) Federal University of Mato Grosso Université de Nantes Cibles et Médicaments des Infections et du Cancer IICiMed EA 1155 Laboratory of Toxicology São Paulo State University (UNESP) School of Pharmaceutical Sciences CNPq: 304112/2017-8 CNPq: 306115/2017-4 CNPq: 308590/2017-1

Natural products have an important role as prototypes in the synthesis of new anticancer drugs. Piperine is an alkaloid amide with antitumor activity and significant toxicity. Then, the N-(p-nitrophenyl)acetamide piperinoate (HE-02) was synthesized, and tested for toxicological and antitumor effects. The toxicity was evaluated in vitro (on RAW 264.7 cells and mice erythrocytes) and in vivo (acute toxicity in mice). The Ehrlich ascites carcinoma model was used to evaluate the antitumor activity of HE-02 (6.25, 12.5 or 25 mg/kg, intraperitoneally, i.p.), as well as toxicity. HE-02 induced only 5.01% of hemolysis, and reduced the viability of RAW 264.7 cells by 49.75% at 1000 &micro, g/mL. LD50 (lethal dose 50%) was estimated at around 2000 mg/kg (i.p.). HE-02 reduced Ehrlich tumor cell viability and peritumoral microvessels density. There was an increase of Th1 helper T lymphocytes cytokine profile levels (IL-1&beta, TNF-&alpha, IL-12) and a decrease of Th2 cytokine profile (IL-4, IL-10). Moreover, an increase was observed on reactive oxygen species and nitric oxide production. Weak in vivo toxicological effects were recorded. Our data provide evidence that the piperine analogue HE-02 present low toxicity, and its antitumor effect involves modulation of immune system to a cytotoxic Th1 profile.