Exploring the anti-biofilm activity of cinnamic acid derivatives in Candida albicans

Some compounds, characterized by phenylethenyl moiety, such as methyl cinnamate and caffeic acid phenethyl ester, are able to inhibit C. albicans biofilm formation. On these bases, and as a consequence of our previous work, we synthesized a series of cinnamoyl ester and amide derivatives in order to evaluate them for the activity against C. albicans biofilm and planktonically grown cells. The most active compounds 7 and 8 showed ⩾50% biofilm inhibition concentrations (BMIC50) of 2 μg/mL and 4 μg/mL respectively, against C. albicans biofilm formation; otherwise, 7 showed an interesting activity also against mature biofilm, with BMIC50 of 8 μg/m

New N,N-dimethylcarbamate inhibitors of acetylcholinesterase: design synthesis and biological evaluation

A series of N,N-dimethylcarbamates containing a N,N-dibenzylamino moiety was synthesized and tested to evaluate their ability to inhibit Acetylcholinesterase (AChE). The most active compounds 4 and 8, showed 85 and 69% of inhibition at 50 mM, respectively. Furthermore, some basic SAR rules were outlined: an alkyl linker of six methylene units is the best spacer between the carbamoyl and dibenzylamino moieties; electron-withdrawal substituents on aromatics rings of the dibenzylamino group reduce the inhibitory power. Compound 4 produces a slow onset inhibition of AChE and this is not due to the carbamoylation of the enzyme, as demonstrated by the time-dependent inhibition assay of AChE with compound 4 and by MALDI-TOF MS analysis of trypsinized AChE inhibited by compound 4. Instead, compound 4 could act as a slow-binding inhibitor of AChE, probably because of its high conformational freedom due to the linear alkyl chain

Biochemical characterization of a multi-drug resistant HIV-1 subtype AG reverse transcriptase: antagonism of AZT discrimination and excision pathways and sensitivity to RNase H inhibitors

We analyzed a multi-drug resistant (MR) HIV-1 re- verse transcriptase (RT), subcloned from a patient- derived subtype CRF02 AG, harboring 45 amino acid exchanges, amongst them four thymidine analog mutations (TAMs) relevant for high-level AZT (azi- dothymidine) resistance by AZTMP excision (M41L, D67N, T215Y, K219E) as well as four substitutions of the AZTTP discrimination pathway (A62V, V75I, F116Y and Q151M). In addition, K65R, known to an- tagonize AZTMP excision in HIV-1 subtype B was present. Although MR-RT harbored the most signif- icant amino acid exchanges T215Y and Q151M of each pathway, it exclusively used AZTTP discrimi- nation, indicating that the two mechanisms are mu- tually exclusive and that the Q151M pathway is ob- viously preferred since it confers resistance to most nucleoside inhibitors. A derivative was created, ad- ditionally harboring the TAM K70R and the rever- sions M151Q as well as R65K since K65R antago- nizes excision. MR-R65K-K70R-M151Q was compe- tent of AZTMP excision, whereas other combinations thereof with only one or two exchanges still pro- moted discrimination. To tackle the multi-drug resis- tance problem, we tested if the MR-RTs could still be inhibited by RNase H inhibitors. All MR-RTs exhibited similar sensitivity toward RNase H inhibitors be- longing to different inhibitor classes, indicating the importance of developing RNase H inhibitors further as anti-HIV drugs

Influence of the Occlusion Site

Background: Previous findings suggest that transient myocardial ischemia and reperfusion may elicit changes in the autonomic balance. In this study, a spectral analysis of heart rate variability was used to assess the modifications of sympathovagal balance induced by coronary angioplasty and their relationship with the occlusion site. Methods: We studied 23 patients (17M, 6F, age 58 ± 10 years) with left anterior descending and 19 patients (15M, 4F, age 56 ± 9 years) with right coronary artery stenosis. Spectral analysis of heart rate variability was performed, by autoregressive model, in basal conditions and during each balloon inflation. At least two inflations of 90–120 seconds were performed in each patient. Results: In patients with left anterior descending artery stenosis, the first occlusion induced marked changes in the autonomic balance, which moved toward a sympathetic predominance. The low frequency component of the spectrum and the low-to-high frequency ratio increased from 59 ± 10 normalized units (NU) to 75 ± 10 NU (P < 0.001) and from 2.4 ± 1.4 to 7.3 ± 4.7 (P < 0.001) respectively, while the high frequency component decreased from 30 ± 11 NU to 14 ± 7 NU (P < 0.001). These changes showed a progressive attenuation during repetitive occlusions, and were significantly correlated with the entity of myocardial ischemia assessed by the ST-segment shift measured on the intracoronary electrocardiographic lead. On the contrary, in patients with right coronary artery stenosis the first occlusion was ineffective with regard to the spectral parameters whereas the third occlusion induced a significant increase in the high frequency component (from 31 ± 9 NU to 41 ± 10 NU, P < 0.01) and decrease in the low-to-high frequency ratio (from 2.1 ± 0.9 to 1.3 ± 0.5, P < 0.05) suggesting a vagal activation. The entity of vagal activation was not correlated with the ST-segment shift. Conclusions: Our data indicate that repetitive coronary occlusions induce significant changes in the autonomic balance. The direction and the time course of these changes are related to the occlusion site

HIV-1 integrase inhibitors are substrates for the multidrug transporter MDR1-P-glycoprotein

BACKGROUND: The discovery of diketoacid-containing derivatives as inhibitors of HIV-1 Integrase (IN) (IN inhibitors, IINs) has played a major role in validating this enzyme as an important target for antiretroviral therapy. Since the in vivo efficacy depends on access of these drugs to intracellular sites where HIV-1 replicates, we determined whether the IINs are recognized by the multidrug transporter MDR1-P-glycoprotein (P-gp) thereby reducing their intracellular accumulation. To address the effect of IINs on drug transport, nine quinolonyl diketo acid (DKA) derivatives active on the HIV-1 IN strand transfer (ST) step and with EC50 ranging from 1.83 to >50 μm in cell-based assays were tested for their in vitro interaction with P-gp in the CEM-MDR cell system. IINs were investigated for the inhibition and induction of the P-gp function and expression as well as for multidrug resistance (MDR) reversing ability. RESULTS: The HIV-1 IINs act as genuine P-gp substrates by inhibiting doxorubicin efflux and inducing P-gp functional conformation changes as evaluated by the modulation of UIC2 mAb epitope. Further, IINs chemosensitize MDR cells to vinblastine and induce P-gp expression in drug sensitive revertants of CEM-MDR cells. CONCLUSION: To our knowledge, this is the first demonstration that HIV-1 IINs are P-gp substrates. This biological property may influence the absorption, distribution and elimination of these novels anti HIV-1 compounds

Hypoglycemic activity of curcumin synthetic analogues in alloxan-induced diabetic rats.

The currently available therapies for type 2 diabetes have been unable to achieve normoglycemic status in the majority of patients. The reason may be attributed to the limitations of the drug itself or its side effects. In an effort to develop potent and safe oral antidiabetic agents, we evaluated the in vitro and in vivo hypoglycemic effects of 10 synthetic polyphenolic curcumin analogues on alloxan-induced male diabetic albino rats. In vitro studies showed 7-bis(3,4-dimethoxyphenyl)hepta-1,6-diene-3,5-dione (4) to be the most potential hypoglycemic agent followed by 1,5-bis(4-hydroxy-3-methoxyphenyl)penta-1,4-dien-3-one (10). Structure activity relationship (SAR) of the tested compounds was elucidated and the results were interpreted in terms of in vitro hypoglycemic activities. Furthermore, oral glucose tolerance test (OGTT) with compounds 4, 10 and reference hypoglycemic drug glipizide showed that compound 4 and glipizide had relatively similar effects on the reduction of blood glucose levels within 2 h. Thus, compound 4 might be regarded as a potential hypoglycemic agent being able to reduce glucose concentration both in vitro and in vivo

Inhibition of Polycomb Repressive Complex2 activity reduces trimethylation of H3K27 and affects development in Arabidopsis seedlings

Background: Polycomb repressive complex 2 (PRC2) is an epigenetic transcriptional repression system, whose catalytic subunit (ENHANCER OF ZESTE HOMOLOG 2, EZH2 in animals) is responsible for trimethylating histone H3 at lysine 27 (H3K27me3). In mammals, gain-of-function mutations as well as overexpression of EZH2 have been associated with several tumors, therefore making this subunit a suitable target for the development of selective inhibitors. Indeed, highly specific small-molecule inhibitors of EZH2 have been reported. In plants, mutations in some PRC2 components lead to embryonic lethality, but no trial with any inhibitor has ever been reported. Results: We show here that the 1,5-bis (3-bromo-4-methoxyphenyl)penta-1,4-dien-3-one compound (RDS 3434), previously reported as an EZH2 inhibitor in human leukemia cells, is active on the Arabidopsis catalytic subunit of PRC2, since treatment with the drug reduces the total amount of H3K27me3 in a dose-dependent fashion. Consistently, we show that the expression level of two PRC2 targets is significantly increased following treatment with the RDS 3434 compound. Finally, we show that impairment of H3K27 trimethylation in Arabidopsis seeds and seedlings affects both seed germination and root growth. Conclusions: Our results provide a useful tool for the plant community in investigating how PRC2 affects transcriptional control in plant development

Design, synthesis and biological evaluation of new pyrimidine derivatives as anticancer agents

BACKGROUND: Anticancer drug resistance is a challenging phenomenon of growing concern which arises from alteration in drug targets. Despite the fast speed of new chemotherapeutic agent design, the increasing prevalence of this phenomenon requires further research and treatment development. Recently, we reported a new aminopyrimidine compound-namely RDS 344-as a potential innovative anticancer agent.METHODS: Herein, we report the design, synthesis, and anti-proliferative activity of new aminopyrimidine derivatives structurally related to RDS 3442 obtained by carrying out substitutions at position 6 of the pyrimidine core and/or on the 2-aniline ring of our hit. The ability to inhibit cell proliferation was evaluated on different types of tumors, glioblastoma, triple-negative breast cancer, oral squamous cell carcinomas and colon cancer plus on human dermal fibroblasts chosen as control of normal cells.RESULTS: The most interesting compound was the N-benzyl counterpart of RDS 3442, namely 2a, that induced a significant decrease in cell viability in all the tested tumor cell lines, with EC50s ranging from 4 and 8 muM, 4-13 times more active of hit.CONCLUSIONS: These data suggest a potential role for this class of molecules as promising tool for new approaches in treating cancers of different histotype

Analytical characterization of an inulin-type fructooligosaccharide from root-tubers of Asphodelus ramosus L

Plant-based systems continue to play a pivotal role in healthcare, and their use has been extensively documented. Asphodelus L. is a genus comprising various herbaceous species, known by the trivial name Asphodelus. These plants have been known since antiquity for both food and therapeutic uses, especially for treating several diseases associated with inflammatory and infectious skin disorders. Phytochemical studies revealed the presence of different constituents, mainly anthraquinones, triterpenoids, phenolic acids, and flavonoids. Although extensive literature has been published on these constituents, a paucity of information has been reported regarding the carbohydrate composition, such as fructans and fructan-like derivatives. The extraction of watersoluble neutral polysaccharides is commonly performed using water extraction, at times assisted by microwaves and ultrasounds. Herein, we reported the investigation of the alkaline extraction of roottubers of Asphodelus ramosus L., analyzing the water-soluble polysaccharides obtained by precipitation from the alkaline extract and its subsequent purification by chromatography. A polysaccharide was isolated by alkaline extraction; the HPTLC study to determine its composition showed fructose as the main monosaccharide. FT-IR analysis showed the presence of an inulin-type structure, and NMR analyses allowed us to conclude that A. ramosus roots contain polysaccharide with an inulin-type fructooligosaccharide with a degree of polymerization of 7-8