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

Метод проектів у процесі музично-виконавської підготовки майбутнього вчителя музики

(uk) У статті визначається сутність інтегрованого методу художньо-творчих проектів, розкривається його специфіка у процесі музично-виконавської підготовки майбутніх учителів музики.(ru) В статье определяется сущность интегрированного метода художественно-творческих проэктов, раскрывается его специфика в процессе музыкально-исполнительской подготовки будущих учителей музыки

From screen to structure with a harvestable microfluidic device

Microfluidic crystallization using the Crystal Former improves the identification of initial crystallization conditions relative to screening via vapour diffusion

Microseed matrix screening for optimization in protein crystallization: what have we learned?

Since the introduction of MMS in 2004, a number of reports (Obmolova et al., 2010a; Persson et al., 2010; Newman et al., 2011) have confirmed that it is a viable optimization alternative. It can produce high quality crystals from poor starting points that are not amenable to the classical optimization strategies. Here we review some recent developments in our own and others' work with MMS. On the basis of the successes from MMS, we offer recommendations for wider applications of MMS to crystallization problem