Medicinal Chemistry

The synthesis, pharmacological evaluation and molecular modeling of (E)-3-propargylene-1,3-dihydro-2Hindol- 2-ones, targeting both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), are described. In vitro inhibition experiments of AChE and BuChE showed that compound 2, 5 and 12 are able to inhibit the two forms of cholinesterases in the submicromolar range. The most selective inhibitor of EeAChE (acetylcholinesterase, E.C. 3.1.1.7, from Electrophorus electricus) and eqBuChE (butylcholinesterase, E.C. 3.1.1.8, from equine serum) in this series are compound 9 (IC50=0.011 ± 0.018 μM) and compound 14 (IC50=0.12 ± 0.22 μM) respectively. But the substitution at 5- or 6- position of indolones is not generally favored for eqBuChE inhibition. Kinetic studies of the BuChE inhibition suggested that compound 1 and 5 produce a mixed inhibition pattern. The molecular modeling investigation confirmed the result and indicated that π-π stacking interaction is a main contributor to the increase of inhibition efficiency.

4- and 5-substituted benzothiophenes were synthesized as starting scaffold in the construction of benzothieno[b] pyridines. Such structures were designed as potential new inhibitors of BACE 1. Preliminary promising biological data were reported. These molecules represent a starting point for improved chemicals in Alzheimer’s disease treatment. Obtained preliminary results encourage research advance and further developments.

Long non-coding RNAs (lncRNAs) are transcripts of more than 200 nucleotides in length with limited protein coding potential were found to be pervasively transcribed and are associated with tumorigenesis due to their various functions in transcriptional, posttranscriptional and epigenetic mechanisms of gene regulation. lncRNAs are found to be differentially expressed in various cancers and associated with cancer development and progression, revealing their potential for diagnostic and prognostic biomarkers in cancer. In this review, we will summarize the most important lncRNAs, focusing on their diagnostic and prognostic potential in different cancers.

As a natural derivative of bioactive xanthone mangiferin, neomangiferin exhibits a wide spectrum of bioactivities. However, studies have yet to elucidate the metabolic pathways and pharmacokinetics of orally administered neomangiferin in vivo. In this study, a simple and accurate high-performance liquid chromatography/diode array detector method was developed and validated to simultaneously determine neomangiferin and its active metabolite mangiferin in plasma after oral and intravenous administration of neomangiferin to rats. Chromatographic separation was performed in a C18 column by using water containing 0.1% formic acid-acetonitrile (88:12, v/v) at a flow rate of 0.7 mL/min. The calibration curves of neomangiferin and mangiferin in rat plasma were linear at 150-15000 (r=0.9999) and 50-1500 ng/mL (r=0.9994), respectively. The relative standard deviations of intraday and inter-day precision were below 10.7%, and accuracy ranged from 94.0 to 105.5% for both analytes. Experimental results showed that intravenously and orally administered neomangiferin was partly metabolized into mangiferin. Tmax of neomangiferin and mangiferin was low (0.05 h), and the two components were eliminated at t1/2 of 0.95 and 0.73 h, respectively. Similar to that of mangiferin, the oral bioavailability of neomangiferin was also low (about 0.32%). Thirty-three metabolites were detected and absolutely or tentatively identified on the basis of mass spectral fragmentation pattern and elution order or were confirmed by using available reference standards. Our findings suggested that neomangiferin undergoes rapid and extensive phases I and II metabolic processes, such as deglycosylation, dehydroxylation, methylation, glycosylation, glucuronidation, and sulfation, in rats. In general, the pharmacokinetic and metabolic profiles, including poor bioavailability, high absorption and elimination rates, extensive biotransformation, of neomangiferin are similar to those of mangiferin to some degrees.

The interaction between Pb2+ and Keyhole Limpet Hemocyanin (KLH) was investigated by fluorescence, Ultraviolet-visible (UV-Vis) absorption and Circular Dichroism (CD) spectroscopy. The experimental results showed that Pb2+ could quench the intrinsic fluorescence of KLH following static and dynamic quenching process. The number of binding sites n was approximately equal to 1. ΔH<0 and ΔS<0 indicated that a Pb-KLH complex was formed. Furthermore, the data of synchronous fluorescence, UV-Vis and CD spectra suggested that Pb2+ changed the micro-environment and conformation of KLH.

Flavonoid is a polyphenolic antioxidant used to treat free radical mediated tissue damage. So flavonoids are the good targets for treatment of many diseases like cancer, toxicity health hazards, neurodegenaration etc. Drug delivery of flavonoid is the novel approach where dosing and drug toxicity can be minimized. Antioxidant Catechin Hydrate (CH) is choosen to make drug delivery vehicle: nanocapsules either alone or in combination with chelator sodium meta borate (SMB) within biodegradable poly-lactide-co-glycolide (PLGA). Sizes of the prepared particles were determined through scanning and atomic force microscopy where less than 50 nm particle sizes were revealed. Bioavailability in serum study determines that shelf life of CH can be increased with nanocapsule delivery compared to free drug. Results demonstrate the efficacy of Nanocapsulated CH to be a potent vehicle for tissue targeting.

Antiepileptic activity study considering the MES model and molecular docking studies were performed for a series of previously synthesized dioxoisoindolin benzene sulfonamide derivatives. The reported molecules were investigated as inhibitors of the zinc metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1), specifically against the hCA I and II isoforms. To get a better insight of these molecules as potential inhibitors we specifically consider the hCA I (Ki values in the range 159 nM to >10000 nM) and hCAII (Ki values in range 1.7 nM to >10000 nM). The most potential molecule explored in the study was 3-(4,5,6,7-tetrachloro-1,3-dioxoisoindolin-2-yl)benzenesulfonamide (Ki=27.7 nM), 3-chloro-4-(4,5,6,7-tetrachloro-1,3-dioxoisoindolin-2-yl)benzenesulfonamide(Ki=4.9 nM) and 4-((4-nitro-1,3-dioxoisoindolin-2-yl)methyl)benzenesulfonamide (Ki=34 nM) respectively with obtained p-value <0.01 in the MES study and showed higher antepileptic activity than acetazolamide (AZM). Moreover a well defined docking score with RMSD value of 1.8 throws light on their effective binding to the active site of both 1AZM and 1ZFQ respectively.

Sirtuins are a family of enzymes, which govern genome regulation, stress response, metabolic homeostasis and lifespan. Among all the discovered human isoforms (SIRT1-7), SIRT1 emerged as a promising molecular target for the treatment of several diseases. The SIRT1 activators have shown beneficial effects in diabetes, obesity, disorders related to aging, cardiovascular and neurodegenerative diseases. On the other hand, SIRT1 inhibition could be applied in anticancer therapy. This review is focused on patents regarding small molecules targeting SIRT1 registered from 2012 to 2015. The chemical formula, the activation and/or inhibition activity and the application of the most active compounds are considered.

Antipsychotic agents, highly benefit for the treatment of a range of psychiatric disorders and act by blocking dopamine receptors in the brain and interfering with dopaminergic transmission. Schizophrenia and mania which are psychosis are treated by antipsychotic drugs. These medicines are classified as typical or atypical antipsychotic drugs. The recently developed drugs which are named 'atypical antipsychotics' are useful in patients that do not respond to treatment with other typical antipsychotics. This review puts emphasis on the recent progress in therapeutically attractive piperazine derivatives being novel atypical antipsychotics that were apporved in 2015. Differences in safety-tolerability, affected receptors, activity, side effects are displayed in this review.

Objective: To determine the value of serum and bile insulin-like growth factor I (IGF-I), interleukin-6 (Il-6) and tumor M2-pyruvate kinase (Tu M2-PK) in distinguishing pancreatobiliary cancers from benign biliary strictures.

Material and methods: The study was performed prospectively on forty jaundiced patients admitted for biliary decompression due to bile duct strictures. Malignant strictures were diagnosed in 22 patients including 15 cases of CCA and 7 cases of pancreatic cancer, and benign biliary strictures in 18 cases. IGF-I, Il-6 and Tu M2-PK were measured in sera and bile by ELISA and compared to serum levels of carbohydrate antigens (CA) 19-9 and carcinoembryonic antigen (CEA).

Results: Serum levels of IGF-I (74.4 vs. 117.0 ng/mL, p=0.03), Il-6 (37.1 vs. 17.0 pg/mL, p=0.04), CA19-9 (5689 vs. 38.9 U/mL, p<0.001) and CEA (27.5 vs. 1.9 ng/mL, p<0.0001) differed significantly between patients with malignant and benign biliary strictures, whereas biliary concentrations of IGF-I and Il-6 and serum and biliary levels of Tu M2-PK were comparable. Biliary IGF-I levels were significantly increased in pancreatic cancer as compared to cholangiocarcinoma and benign biliary strictures groups (966 vs. 137 ng/mL, p=0.03 and 966 vs. 90.6 ng/mL, p=0.01, respectively). The AUC-ROCs for serum IGF-I and serum Il-6 were 0.336 and 0.606, respectively, what was worse than that of CA 19-9 (0.855) and CEA (0.794).

Conclusion: Measurement of serum IGF-I and Il-6 may be helpful in differentiation malignant from benign biliary strictures and biliary IGF-I seems to be a promising marker for distinguishing pancreatic cancer from cholangiocarcinoma and benign biliary occlusions.

In the recent decades, antimicrobial plant products have gained special interest because of the resistance to antibiotics that some micro-organisms have acquired. Aromatic and medicinal plants are an important source of bioactive molecules, especially in volatile extracts, that are considered among the most important antimicrobial agents present in these plants. Volatile components of Artemisia herba-alba Asso essential oil obtained by hydrodistillation growing in Algeria (Djelfacityof south Algeria) were investigated by GC/FID and GC-MS. The major components were found to be camphor (39.5%), chrysanthenone (10.38%), 1,8-cineole (8.6%), α-thujone (7.03%), Borneol (3.35%) and bornyl acetate (2.52%). The essential oil has been tested for antimicrobial activity against Gram-negative and Gram-positive bacteria. Inhibition of growth was tested by the agar diffusion method. The Minimal Inhibitory Concentration (MIC) was determined by the method of agar dilution.