Trithioarsenites [(RS)3As], dithioarsonites [R-As(SR′)2] and thioarsinites [R2As-SR′]: Preparations, chemical, biochemical and biological properties

Contrary to P(V) compounds, As(V) compounds can very easily reduced by thiols to As(III) thiolates that are deemed to play a central role in the metabolism of arsenic and therefore a review on the preparation and properties of the title thiolates can be of interest. The preparation of trithioarsenites, dithioarsonites and thioarsinites involves reactions of a thiol with a proper As(V) or As(III) precursor via 4-centered transition states or a thiolate by SN2 mechanisms. Convenient precursors are the solids As2O3, arsonic and arsinic acids, although for the latter two acids the separation of the product from the co-produced disulfides can be problematic. Only a few crystal structures have been reported and involve only trithioarsenites. From their chemical properties, the hydrolyses, transthiolations and air oxidations are of particular interest from mechanistic and biochemical/biological points of view. Their nucleophilicity towards alkyl halides and acyl derivatives revealed unexpected behavior. Although these molecules have many free electron pairs only three reports were found pertaining to their reaction with metal cations (Hg2+) and metal carbonyls; the mercuric complexes being not characterized. Only a few studies appeared for the action of the title compounds towards enzymes, while the patent literature revealed that they have bactericidal, fungicidal and insecticidal activities for agricultural applications, some have antiparasitic activity on animals and a few are carcinostatic.

MOLECULAR DESIGN OF N-ACYL DERIVATIVES OF 2-(2-OXOPYROLIDIN-1-YL)-ACETAMIDE WITH GABA-ERGIC AND GLUTAMATERGIC ACTIVITIES

The first of the most successfully implemented nootropic drugs in medical practice is piracetam, which should be attributed to cyclic derivatives of gamma-aminobutyric acid. The production of new piracetam derivatives with high nootropic activity is a promising direction in the development of new neuroprotective drugs.The aim of the study is to predict GABA-ergic and glutamatergic activities of N-acyl derivatives of 2-(2-oxopyrolidin-1-yl)- acetamide by a molecular docking method through the energy analysis of interaction of modeled structures with GABAA and AMPA receptors with their subsequent targeted synthesis.Materials and methods. The objects of the research are new N-acyl derivatives of 2-oxo-1-pyrrolidineacetamide and a virtual model of the GABAA receptor of the Homo sapiens organism with the identification code 6D6U and a three-dimensional model of the AMPA-receptor of the Rattus norvegicus organism with the identification code 3LSF from the RCSB PDB database. The simulated compounds were designed in the HyperChem 8.0.8 program. This program was also used to optimize geometry using the force field of molecular mechanics MM+. Molecular docking was carried out using the Molegro Virtual Docker 6.0.1 program. The preparation of N-acyl derivatives of 2-(2-oxopyrrolidin-1-yl)-acetamide was carried out by the interaction of 2-(2-oxopyrrolidin-1-yl)-acetamide with an excess of the corresponding anhydride under conditions of acid catalysis.Results. Based on the results of molecular docking, a high affinity of all simulated compounds for the binding site of GABAA and AMPA receptors can be estimated. According to the predict, the maximum GABA-ergic activity should be expected for (N-[2-(2-oxopyrrolidin-1-yl)-acetyl]-butyramide. N-acyl derivatives of 2-oxo-1-pyrrolidineacetamide form a more stable complex with amino acid residues Arg207, Phe200, Thr202, Tyr97, Tyr157, Tyr205 and Phe65 of the GABAA receptor binding site than the GABA molecule. In terms of the minimum interaction energy, the N-acyl derivatives of 2-(2-oxopyrrolidin-1-yl)- acetamide are superior to a number of known ligands such as GABA, piracetam, anipiracetam, picamilon and pramiracetam. The tested compounds have also shown a high affinity for the binding site of the AMPA receptor. The leader compound is also the compound PirBut, as in the case of the GABAА receptor.Conclusion. Molecular modeling of the ligands interaction with the active binding site of gamma-aminobutyric acid of the GABAA receptor by molecular docking showed that all virtual N-acyl derivatives of 2-oxo-1-pyrrolidineacetamide can exceed a number of nootropic drugs by activity. In the course of molecular design, a method for predicting a glutamatergic activity for 2-pyrrolidone derivatives has been developed. It suggests a significant nootropic activity for N-[2-(2-oxopyrrolidin-1-yl)- acetamide amides.

Bromobenzoylation of Methyl α-D-Mannopyranoside: Synthesis and Spectral Characterization

The widening importance of carbohydrate derivatives as unrivaled potential antimicrobial and therapeutic drugs has attracted attentionto the synthesis of mannopyranoside derivatives. In the present study, regioselective 3-bromobenzoylation of methyl α-D-mannopyranoside (1) was carried out using the direct method and gave the corresponding 6-O-(3-bromobenzoyl) derivative (2) in excellent yield. A number of 2,3,4-tri-O-acyl derivatives (3–10) of this 6-substitution product using a wide variety of acylating agents were also prepared in order to obtain newer derivatives of synthetic and biological importance. The chemical structures of the newly synthesized compounds were ascertained by analyzing their physicochemical, elemental, and spectroscopic data. Additionally, the X-ray powder diffraction (XRD) of these acylated products was studiedfor quantitatively identifying crystalline compounds.Therefore, due to the importance of carbohydrates, it might be useful to develop a good method for the synthesis of carbohydrate-based drugs of the current global situation for health and disease

New Acyl Derivatives of 3-Aminofurazanes and Their Antiplasmodial Activities

An N-acylated furazan-3-amine of a Medicines for Malaria Venture (MMV) project has shown activity against different strains of Plasmodium falciparum. Seventeen new derivatives were prepared and tested in vitro for their activities against blood stages of two strains of Plasmodium falciparum. Several structure–activity relationships were revealed. The activity strongly depended on the nature of the acyl moiety. Only benzamides showed promising activity. The substitution pattern of their phenyl ring affected the activity and the cytotoxicity of compounds. In addition, physicochemical parameters were calculated (log P, log D, ligand efficiency) or determined experimentally (permeability) via a PAMPA. The N-(4-(3,4-diethoxyphenyl)-1,2,5-oxadiazol-3-yl)-3-(trifluoromethyl)benzamide possessed good physicochemical properties and showed high antiplasmodial activity against a chloroquine-sensitive strain (IC50(NF54) = 0.019 µM) and even higher antiplasmodial activity against a multiresistant strain (IC50(K1) = 0.007 µM). Compared to the MMV compound, the permeability and the activity against the multiresistant strain were improved.

Synthesis, Antiproliferative Activity and Radical Scavenging Ability of 5-O-Acyl Derivatives of Quercetin

Quercetin is a flavonoid that is found in many plant materials, including commonly eaten fruits and vegetables. The compound is well known for its wide range of biological activities. In this study, 5-O-acyl derivatives of quercetin were synthesised and assessed for their antiproliferative activity against the HCT116 colon cancer and MDA-MB-231 breast cancer cell lines; and their radical scavenging activity against the 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical cation and 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical species. Four derivatives were found to have improved the antiproliferative activity compared to quercetin whilst retaining radical scavenging activity.

Synthesis of N-acyl Derivatives of Aminocombretastatin A-4 and Study of their Interaction with Tubulin and downregulation of c-Myc

Aims: In search of new promising anti-cancer agents. Background: Six N-acyl derivatives of aminocombretastatin A-4 have been synthesized and evaluated as regards their interaction with tubulin and as c-Myc downregulators. Objective: This study is focused on the synthesis and the biological evaluation of N-acyl derivatives of aminocombretastatin A-4 (CA-4). Docking studies were carried out in order to find out whether the synthetic derivatives could bind to tubulin at the colchicine site in a conformation similar to that of CA-4. The effect of the synthetic derivatives on the proliferation of several cancer cells and on non-cancer cells has been measured. In addition, their effect on tubulin polymerization, on cell cycle distribution, on the microtubule network and on c-Myc expression have also been evaluated. Method: A set of six N-acyl derivatives were achieved by means of a peptide-type coupling of aminocombretastatin A-4 and the corresponding carboxylic acid. The ability of the synthetic compounds to inhibit cell proliferation was measured by MTT assay against three human carcinoma cell lines (colorectal HT-29, lung A549 and breast adenocarcinoma MCF-7) and one non-tumor cell line (HEK-293). Inhibition of tubulin polymerization was evaluated by turbidimetry time-course measurements. The action of the synthetic derivatives on cell cycle distribution was measured by flow cytometry and their effects on the microtubule network was determined by immunofluorescence microscopy. Finally, the downregulation of the synthetic derivatives on c-Myc protein was quantified by ELISA assay while the effect on cMyc gene was measured by RT-qPCR analysis. Results: Derivatives bearing pentanoyl (compound 2), hexanoyl (compound 3), and heptanoyl (compound 4) side chains show antiproliferative activities on the HT-29 line in the low nanomolar range, with values similar to that exhibited by AmCA-4 but far exceeding those of CA-4. Compounds 1 (butanoyl side chain) and 2-3 inhibit tubulin polymerization in vitro in a manner similar to that of CA-4 and AmCA-4 whereas compounds 4, 5 (octanoyl side chain) and 6 (dodecanoyl side chain) may be considered as partial inhibitors of tubulin polymerization. While all derivatives are able to accumulate cells in G2/M phase, compounds with the longest acyl chains (5 and 6) are the least active ones in this particular action. Moreover, compounds 2-3 were the most active ones as c-Myc downregulators. Conclusion: Our studies show that the most active compounds in the disruption of the microtubule network are also the most potent ones in the downregulation of c-Myc expression. Other: Compounds 2 and 3 are good candidates for in vivo studies as they combine the best anti-mitotic and c-Myc downregulation activities at low doses.

Benzobicyclo[3.2.1]octene Derivatives as a New Class of Cholinesterase Inhibitors

A library of amine, oxime, ether, epoxy and acyl derivatives of the benzobicyclo[3.2.1]octene were synthesized and evaluated as inhibitors of both human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The majority of the tested compounds exhibited higher selectivity for BChE. Structural adjustment for AChE seems to have been achieved by acylation, and the furan ring opening of furo-benzobicyclo[3.2.1]octadiene results for compound 51 with the highest AChE affinity (IC50 = 8.3 µM). Interestingly, its analogue, an oxime ether with a benzobicyclo[3.2.1]-skeleton, compound 32 was one of the most potent BChE inhibitors in this study (IC50 = 31 µM), but not as potent as endo-43, an ether derivative of the benzobicyclo[3.2.1]octene with an additional phenyl substituent (IC50 = 17 µM). Therefore, we identified several cholinesterase inhibitors with a potential for further development as potential drugs for the treatment of neurodegenerative diseases.