Полеміка навколо наукової спадщини Володимира Антоновича в українській історіографії радянської доби

(uk) Проаналізовано стан дослідження наукової спадщини класика української історіографії В.Б. Антоновича в працях істориків різних ідеологічних спрямувань. Указано на відмінності теоретичних узагальнень щодо творчості вченого в національно-державницькій та марксистській науці радянської доби.(ru) Проанализировано состояние исследования научного наследия классика украинской историографии В. Б. Антоновича в работах историков различных идеологических направлений. Подчеркнуты различия теоретических обобщений относительно творчества в национально-государственной и марксистской науке советского периода.(en) The state of investigation of V.B. Antonovich\s scientific activity in the researches of historians of different ideological direction was analyzed. It is pointed out the differences of theoretical generalization about activity of scientist in national state and marxist historical science of Soviet epoch

Особливості трудового виховання і профорієнтації в умовах нової парадигми освіти

(uk) У статті розкривається проблема формування майбутнього учителя-предметника, готового до забезпечення трудового виховання у професійній діяльності у світлі нової освітньої парадигми

Synthesis and evaluation of β-substituted fosmidomycin analogues as inhibitors of 1-deoxy-D-xylulose 5-phosphate reductoisomerase

Blocking the MEP pathway for isoprenoid biosynthesis offers interesting prospects for inhibiting Plasmodia growth. Fosmidomycin (1) and its homologue FR900098 (2) potently inhibit 1-deoxy-D-xylulose-5-phosphate reductoisomerase (Dxr), a key enzyme in this pathway. Although fosmidomycin is a remarkably safe antimalarial agent, low oral absorption, short serum half-life and malaria recrudescence preclude its use in monotherapy. The development of more lipophilic Dxr inhibitors able to passively permeate into cells with improved pharmacokinetic properties could lead to more efficacious agents. Previously, we discovered that analogue 4, featuring a 3,4-dichlorophenyl substituent in α-position of the phosphonate, surpasses fosmidomycin’s potency in inhibiting P. falciparum growth. Here we explored the introduction of aryl or aralkyl substituents at the β-position of the known hydroxamate analogue 3. We studied the effect of introducing substituents in β-position of the hydroxamate analogue 3. While direct addition of a β-aryl moiety resulted in poor P. falciparum Dxr inhibition, longer linkers between the carbon backbone and the phenyl ring were generally associated with better binding to the enzyme. X-ray structures of the parasite Dxr-inhibitor complexes show that the “longer” compounds generate a substantially different flap structure, in which a key tryptophan residue is displaced, and the aromatic group of the ligand lies between the tryptophan and the hydroxamate’s methyl group. Several analogues emerged as highly potent inhibitors of Plasmodium falciparum in vitro growth. In some cases (e.g. for compounds 7b and 7f) good Dxr inhibitory activity failed to translate in good in vitro activity against the parasite, which may be due to inefficient uptake. Compounds 5a-e likewise failed to inhibit EcDxr and MtbDxr while 6c was optimal for inhibition of these enzymes

The Measurement of Territorial Differences in the Information Society

Glutamine synthetase (GS, EC 6.3.1.2; also known as γ-glutamyl:ammonia ligase) catalyzes the ATP-dependent condensation of glutamate and ammonia to form glutamine. The enzyme has essential roles in different tissues and species, which have led to its consideration as a drug or an herbicide target. In this article, we describe studies aimed at the discovery of new antimicrobial agents targeting Mycobacterium tuberculosis, the causative pathogen of tuberculosis. A number of distinct classes of GS inhibitors with an IC50 of micromolar value or better were identified via high-throughput screening. A commercially available purine analogue similar to one of the clusters identified (the diketopurines), 1-[(3,4-dichlorophenyl)methyl]-3,7-dimethyl-8-morpholin-4-yl-purine-2,6-dione, was also shown to inhibit the enzyme, with a measured IC50 of 2.5 ± 0.4 μM. Two X-ray structures are presented: one is a complex of the enzyme with the purine analogue alone (2.55-Å resolution), and the other includes the compound together with methionine sulfoximine phosphate, magnesium and phosphate (2.2-Å resolution). The former represents a relaxed, inactive conformation of the enzyme, while the latter is a taut, active one. These structures show that the compound binds at the same position in the nucleotide site, regardless of the conformational state. The ATP-binding site of the human enzyme differs substantially, explaining why it has an ∼ 60-fold lower affinity for this compound than the bacterial GS. As part of this work, we devised a new synthetic procedure for generating l-(SR)-methionine sulfoximine phosphate from l-(SR)-methionine sulfoximine, which will facilitate future investigations of novel GS inhibitors