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Antimalarial and Structural Studies of Pyridine-containing Inhibitors of 1-Deoxyxylulose-5-phosphate Reductoisomerase.

ABSTRACT: 1-Deoxy-D-xylulose-5-phosphate reductoisomerase (DXR) in the non-mevalonate isoprene biosynthesis pathway is a target for developing antimalarial drugs. Fosmidomycin, a potent DXR inhibitor, showed safety as well as efficacy against P. falciparum malaria in clinical trials. Based on our previous quantitative structure activity relationship (QSAR) and crystallographic studies, several novel pyridine-containing fosmidomycin derivatives were designed, synthesized and found to be highly potent inhibitors of P. falciparum DXR (PfDXR) having K_i values of 1.9 - 13 nM, with the best one being ~11× more active than fosmidomycin. These compounds also potently block the proliferation of multi-drug resistant P. falciparum with EC₅₀ values as low as 170 nM. A 2.3 Å crystal structure of PfDXR in complex with one of the inhibitors is reported, showing the flexible loop of the protein undergoes conformational changes upon ligand binding and a hydrogen bond and favorable hydrophobic interactions between the pyridine group and PfDXR account for the enhanced activity.

SUBMITTER: Xue J

PROVIDER: S-EPMC3685428 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Antimalarial and Structural Studies of Pyridine-containing Inhibitors of 1-Deoxyxylulose-5-phosphate Reductoisomerase.

Xue Jian J Diao Jiasheng J Cai Guobin G Deng Lisheng L Zheng Baisong B Yao Yuan Y Song Yongcheng Y

ACS medicinal chemistry letters 20130201 2

1-Deoxy-<i>D</i>-xylulose-5-phosphate reductoisomerase (DXR) in the non-mevalonate isoprene biosynthesis pathway is a target for developing antimalarial drugs. Fosmidomycin, a potent DXR inhibitor, showed safety as well as efficacy against <i>P. falciparum</i> malaria in clinical trials. Based on our previous quantitative structure activity relationship (QSAR) and crystallographic studies, several novel pyridine-containing fosmidomycin derivatives were designed, synthesized and found to be highl ...[more]

PMID: 23795240

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Project description:The current study aimed to synthesize seven new metal coordination complexes (Q1-Q7) with potential biomedical applications. Novel mononuclear, polynuclear and mixed-ligand coordination compounds of the elements, cadmium(ii) and silver(i) derived from a pyridine containing ligand (2,4,6-tris-(2-pyridyl)-1,3,5-triazine (TPT)) have been synthesized successfully with the general formulae [Cd(TPT)Cl6]·H2O and [Ag x (TPT) y (L)2(ClO4)](ClO4) z (x = 1,2,3, y = 1,2,3, L = PPh3 or phen, z = 1,2). The structural features were fully characterized using various spectroscopic techniques, such as infrared, ultraviolet-visible spectroscopy, 1D and 2D-NMR (1H, 13C, 31P, 1H-1H COSY and 1H-13C HSQCAD), CHN analysis, molar conductance (Λ), thermogravimetric analysis (TGA), and powder X-ray diffraction analysis. The structure of complex Q6 was also confirmed by single-crystal X-ray analysis. The luminescence and electrochemical properties of complexes, in solution, have been studied. X-ray crystallographic determination of the [Ag(TPT)(PPh3)2]ClO4·EtOH (Q6) complex shows that the Ag+ cation is bonded to one tridentate TPT ligand through NNN set of donor atoms and two triphenylphosphine ligands, giving the Ag+ a distorted trigonal bipyramidal geometry. X-ray powder diffraction analysis showed that metal complexes Q3, Q6 and Q7 display crystalline peaks. The complexes were evaluated for their in vitro antibacterial efficacy against various bacterial and fungal species. The in vitro efficacy against the MCF-7 human breast cancer cell line was assessed to determine the anticancer activities. The tri-nuclear silver complex Q3 shows great potential as a therapeutic candidate for treating breast cancer, since it exhibits a half-maximal inhibition concentration (IC50) of 13.45 ± 0.9 μM. Molecular docking simulations were also carried out to evaluate the interaction strength and properties of the metal complexes with selected cancer and bacteria relevant proteins namely cyclin-dependent kinase 2 (CDK2), cyclin-dependent kinase 6 (CDK6), signal transducer and activator of transcription 3 (STAT3), and beta-lactamases from Escherichia coli and Staphylococcus aureus.

Dataset Information

Antimalarial and Structural Studies of Pyridine-containing Inhibitors of 1-Deoxyxylulose-5-phosphate Reductoisomerase.

Publications

Antimalarial and Structural Studies of Pyridine-containing Inhibitors of 1-Deoxyxylulose-5-phosphate Reductoisomerase.

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