Antimycobacterial and anticancer activity of newly designed cinnamic acid hydrazides with favorable toxicity profile

A series of twelve novel hybrids of cinnamic acid and thiocarbohydrazones were designed, synthesized in high yield using a simple coupling strategy via acid chlorides, and evaluated for their impact against Mycobacterium tuberculosis (Mtb) and cancer cells survival. Among them, compound 3 demonstrated strong anti-Mtb activity by reducing bacilli survival for>90 % in all three treated Mtb isolates, whereas isoniazid and rifampicin did not. Moreover, compound 3 didn’t affect vitality of HepG-2 cells, implying on advantageous hepatotoxicity profile compared to current therapeutic options for tuberculosis. Compounds 2a and 3b displayed as strong inducers of apoptosis in A549 cells, both activating intrinsic caspase pathway and cell cycle arrest at the G0/G1 phase. Subsequent analyses disclosed differences in their activities, where 3b has ability to induce production of mitochondrial superoxide anions, while 2a significantly inhibited cellular mobility. More importantly, 3b considerably affected viability of HepG-2 and HaCaT cells, whereas 2a had moderate impact only on the later. Molecular modeling studies indicated high permeability and good absorption through the human intestine, and moderate aqueous solubility with poor blood–brain barrier permeability. In summary, our results reveal that novel compounds 3 and 2a represent promising agents for tuberculosis and cancer treatment, respectively, indicating that further investigation needs to be performed to clarify the mechanisms of their anti-Mtb and anticancer activity.     

Acylpyrazolone ligands: Synthesis, structures, metal coordination chemistry and applications

This review summarizes the literature on 4-acyl-5-pyrazolone ligands, their synthesis, characterization and coordination chemistry toward main group, transition, lanthanide and actinide metals and relevant applications of their metal complexes.     

Enthalpies of dilution of aqueous systems containing hexamethylenetetramine and other nonelectrolytes

Enthalpies of dilution of aqueous systems containing hexamethylenetetramine, alone and in ternary system with each of mannitol, myoinositol, cyclohexanol, formamide, dimethylformamide, and trioxane have been determined. The data have been treated in terms of the Savage-Wood additivity principle and first estimates for the pairwise groups interaction enthalpies of N/N, CH₂/N, CHOH/N, COHN/N and –O–/N have been made. The results are discussed in light of all other known group interaction enthalpies. The limitations and utilities of the Savage-Wood principle are reviewed.     

3-[Amino(methylthio)methylene]pentane-2,4-dione in the synthesis of functionalized pyridines

New syntheses of functionalized pyridines from 3-[amino(methylthio)methylene]-2,4-pentanedionevia its boron chelates were proposed. The products of condensation of dimethylformamide dimethylacetal with the latter chelates were converted into 3-acetyl-2-methylthio-4-hydroxypyridine by refluxing in BuOH and into 1-alkyl-3-cyano-2-methyl-4-pyridones by treatment with primary amines.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1118–1121, June, 1995.This study was financially supported by the International Science Foundation (Grant M5Q 000).     

Synthesis and chromatographic enantioresolution of anti-HIV quinolone derivatives

The successful enantioseparation of five 6-desfluoroquinolones with three polysaccharide-based stationary phases (namely, the cellulose-based Chiralpak IB and the two amylose-based Chiralpak AD-H and Lux Amylose-2) is herein described. The investigated species differ for the nature of substituents and/or the position of the stereogenic centre on the quinolone scaffold.The effect on the enantioseparation performance exerted by the different morphology of the cellulose-based and amylose-based polymers, was systematically evaluated for all compounds. In this frame, the impact of alternative alcoholic (ethanol, 2-ethoxyethanol, methanol, 2-propanol) and acidic (acetic, methanesulfonic and trifluoroacetic acid) modifiers as well as of a “non-standard” solvent (chloroform), was investigated in normal phase conditions along with the stereo-electronic peculiarities of the selected polymers. While 7-[4-(1,3-benzothiazol-2-yl)-2-methyl-1-piperazinyl]-1-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (1) was enantioresolved with conventional normal-phase conditions by means of the largely employed amylose-based Chiralpak AD-H column, the recruitment of a bulky alcohol (2-ethoxyethanol) succeeded in the enantioresolution of 6-amino-1-methyl-7-[2-methyl-4-(2-pyridinyl)-1-piperazinyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (2) and 6-amino-1-[1-(hydroxymethyl)propyl]-4-oxo-7-(4-pyridin-2-ylpiperazin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid (3) with the same column. The use of the amylose-based Lux Amylose-2 column, carrying both an electro-withdrawing (chlorine) and an electro-donating (methyl) group on the carbamate residue, allowed to get 6-amino-1-methyl-4-oxo-7-[3-(2-pyridinyl)-1-pyrrolidinyl]-1,4-dihydro-3-quinolinecarboxylic acid hydrochloride (4) enanantioresolved, and 6-amino-1-methyl-4-oxo-7-(3-pyridin-2-ylpiperidin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid (5) enantioseparated.     

Cyclization of O-benzoyl-β-piperidinopropionamidoximes to form 5-phenyl-3-(β-piperidino)ethyl-1,2,4-oxadiazoles

The reactions of -piperidinopropionamidoxime with substituted benzoyl chlorides afforded O-benzoylation products, which underwent cyclization to form 5-phenyl-3-(-piperidino)ethyl-1,2,4-oxadiazoles upon heating in dimethylformamide in the presence of molecular sieves at 60 °C for 1—2.5 h. Heating of O-benzoyl--piperidinopropionamidoxime in dimethylformamide in the presence of K₂CO₃ at 85 °C for 4 h afforded a mixture of 5-phenyl-3-(-piperidino)ethyl-1,2,4-oxadiazole, benzoic acid, and N-(-piperidino)ethylurea.     

Effects of aprotic solvents on the stability of metal‐free superoxide dismutase probed by native electrospray ionization–ion mobility–mass spectrometry

Considering that aprotic solvents are often used as cosolvents in investigating the interactions between small molecules and proteins, we assessed the effects of five aprotic solvents represented by dimethylformamide (DMF) on the structure stabilities of metal‐free SOD1 (apo‐SOD1) by native electrospray ionization–ion mobility–mass spectrometry (ESI‐IM‐MS). These aprotic solvents include DMF, 1,3‐dimethyl‐2‐imidazolidinone (DMI), dimethyl sulfoxide (DMSO), acetonitrile (ACN), and tetrahydrofuran (THF). Results indicated that DMI, DMSO, and DMF at low percentage concentration could reduce the average charge and the dimer dissociation of apo‐SOD1. By contrast, ACN and THF at low concentration have no similar effect. DMF was selected as a representative solvent to further investigate the detailed effects on the structure stability of apo‐SOD1 by using collision‐induced dissociation and unfolding. The results reveal that the addition of minimal DMF to an aqueous protein solution can protect against the unfolding and dissociation of dimer, even under destabilizing conditions (such as low pH or high cone voltage). When the different percentage concentrations of DMF were added, the average collision cross section of apo‐SOD1 showed that apo‐SOD1 became compacted when the DMF concentration increased from 0% to 1% and eventually started extending when increased from 1% to 20%. The results indicated that DMF has similar effects to DMSO in native mass spectrometry (MS) and it can also be used as a cosolvent besides DMSO in investigating the stabilities of proteins and the interactions between small molecules and proteins.     

Preparation of Polymer Nanofibers Containing Silver Nanoparticles by Using Poly(N‐vinylpyrrolidone)

Summary: Poly(N‐vinylpyrrolidone) (PVP) was used in two methods to prepare polymer nanofibers containing Ag nanoparticles. The first method involved electrospinning the PVP nanofibers containing Ag nanoparticles directly from the PVP solutions containing the Ag nanoparticles. N,N‐Dimethylformamide was used as a solvent for the PVP as well as a reducing agent for the Ag⁺ ions in the PVP solutions. In the second method, poly(vinyl alcohol) (PVA) aqueous solutions were electrospun with 5 wt.‐% of the PVP containing Ag nanoparticles. The Ag nanoparticles were evenly distributed in the PVA nanofibers. PVP containing Ag nanoparticles could be used to introduce Ag nanoparticles to other polymer nanofibers that are miscible with PVP.

TEM image of a PVA nanofiber electrospun with 5 wt.‐% of the PVP containing Ag nanoparticles.     

Substitution of Hydroxyl Groups by Deuterium in the Electrochemical Reduction of Methanesulfonates

Abstract

The electrochemical reduction of dodecyl methanesulfonate (ROMs; R = n-C₁₂H₂₅ ^?, Ms = CH₃SO₂ ^?) as model compound was studied in deuterated media. This reaction could be of potential use in syntheses of partially deuterated compounds by conversion of C?OH-groups into C?D-bonds in the presence of other reactive groups. In order to obtain detailed information about the origin of the introduced hydrogen all individual components (solvent, supporting electrolyte, substrate) of the reaction system were deuterium labelled in the model reaction. The experiments indicate, that this reduction does not proceed along a uniform pathway. Dodecyl anions play the dominating role in the reaction mechanism. Deuterium is transferred into the product dodecane-d ₁ from all components of the reaction mixture in the order of their relative proton acidities Ms-d ₃ > Bu₄N⁺-d ₃₆ > DMF-d ₇ > R-1,1-d ₂-OMs.

In the presence of D²O a hydrogen isotope exchange was found with the methyl group of MsO^?, catalyzed by electrogenerated bases.