Green synthesis, X-ray crystal structure, evaluation as in vitro cytotoxic and antibacterial agents of a new Zn(II) complex containing dipicolinic acid

To study the effects of bicarbonate and magnesium on bone, mild acidosis and/or hypermagnesemia were produced in growing rats by feeding ammonium chloride and/or magnesium sulfate. Bone composition, quantitative histomorphometry, and mineral x-ray diffraction (XRD) characteristics were measured after 6 wk of treatment. The results demonstrated that both acidosis (decreased HCO3) and hypermagnesemia inhibited periosteal bone formation, and, when combined, results were summative; and the previously observed in vitro role of HCO3- and Mg2+ as inhibitors of crystal growth were confirmed in vivo. XRD measurements demonstrated that decreased plasma HCO3 resulted in larger crystals and increased Mg resulted in smaller crystals. However, the combined XRD effects of acidosis and hypermagnesemia resembled acidosis alone. It is postulated that the final composition and crystal structure of bone are strongly influenced by HCO3- and Mg2+, and the effects are mediated by the combined influence on both osteoblastic bone formation and the growth of hydroxyapatite.

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Synergistic Lethality of a Binary Inhibitor ofMycobacterium tuberculosisKasA

mBio ◽

10.1128/mbio.02101-17 ◽

2018 ◽

Vol 9 (6) ◽

Cited By ~ 14

Author(s):

Pradeep Kumar ◽

Glenn C. Capodagli ◽

Divya Awasthi ◽

Riju Shrestha ◽

Karishma Maharaja ◽

...

Keyword(s):

Crystal Structure ◽

Cell Wall ◽

Mycobacterium Tuberculosis ◽

Substrate Binding ◽

Content Type ◽

X Ray ◽

Structure Activity Relationships ◽

Structure Activity ◽

Transcriptional Pattern

ABSTRACTWe report GSK3011724A (DG167) as a binary inhibitor of β-ketoacyl-ACP synthase (KasA) inMycobacterium tuberculosis. Genetic and biochemical studies established KasA as the primary target. The X-ray crystal structure of the KasA-DG167 complex refined to 2.0-Å resolution revealed two interacting DG167 molecules occupying nonidentical sites in the substrate-binding channel of KasA. The binding affinities of KasA to DG167 and its analog, 5g, which binds only once in the substrate-binding channel, were determined, along with the KasA-5g X-ray crystal structure. DG167 strongly augmented thein vitroactivity of isoniazid (INH), leading to synergistic lethality, and also synergized in an acute mouse model ofM. tuberculosisinfection. Synergistic lethality correlated with a unique transcriptional signature, including upregulation of oxidoreductases and downregulation of molecular chaperones. The lead structure-activity relationships (SAR), pharmacokinetic profile, and detailed interactions with the KasA protein that we describe may be applied to evolve a next-generation therapeutic strategy for tuberculosis (TB).IMPORTANCECell wall biosynthesis inhibitors have proven highly effective for treating tuberculosis (TB). We discovered and validated members of the indazole sulfonamide class of small molecules as inhibitors ofMycobacterium tuberculosisKasA—a key component for biosynthesis of the mycolic acid layer of the bacterium’s cell wall and the same pathway as that inhibited by the first-line antitubercular drug isoniazid (INH). One lead compound, DG167, demonstrated synergistic lethality in combination with INH and a transcriptional pattern consistent with bactericidality and loss of persisters. Our results also detail a novel dual-binding mechanism for this compound as well as substantial structure-activity relationships (SAR) that may help in lead optimization activities. Together, these results suggest that KasA inhibition, specifically, that shown by the DG167 series, may be developed into a potent therapy that can synergize with existing antituberculars.

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Synthesis, Crystal Structure, and Biological Activity ofcis/transAmide Rotomers of (Z)-N′-(2-Oxoindolin-3-ylidene)formohydrazide

Journal of Chemistry ◽

10.1155/2014/760434 ◽

2014 ◽

Vol 2014 ◽

pp. 1-7 ◽

Cited By ~ 9

Author(s):

Hatem A. Abdel-Aziz ◽

Hazem A. Ghabbour ◽

Wagdy M. Eldehna ◽

Maha M. Qabeel ◽

Hoong-Kun Fun

Keyword(s):

Crystal Structure ◽

Human Tumor ◽

Cancer Cell Line ◽

Monoclinic Space Group ◽

Moderate Activity ◽

Standard Drug ◽

X Ray ◽

H Nmr ◽

Mcf 7

(Z)-N′-(2-Oxoindolin-3-ylidene)formohydrazide (2) was synthesized by the reaction of (Z)-3-hydrazonoindolin-2-one (1) with formic acid under reflux. The structure of2was characterized by IR, Mass,1H NMR, and X-ray crystal structure determination. Interestingly, compound2appeared in DMSO-d6ascisandtransamide rotomers in 25% and 75%, respectively. The X-ray analysis showed theZgeometrical isomer of2around –C=N– forcisandtransamide rotomers. The crystal of2belongs to monoclinic, space groupP21/c, witha=4.5206(1) Å,b=22.4747(7) Å,c=17.3637(5) Å,β=103.752(1)°,Z=8,V=1713.57(8) Å3,Dc=1.467 Mg m−3,μ=0.11 mm−1,F(000)=784,R=0.047, andwR=0.123for 3798 observed reflections withI>2σ(I). Compound2exhibited a moderate activity in its antimicrobial evaluation againstE. coliandP. aeruginosaand a good activity againstS. aureusclose to that of the standard drug ciprofloxacin. Thein vitroanticancer activity of2was evaluated against two human tumor cell lines, namely, HepG2 hepatocellular carcinoma and MCF-7 breast cancer. HepG2 cancer cell line was more susceptible to compound2than MCF-7.

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Azobenzene-based inhibitors of human carbonic anhydrase II

Beilstein Journal of Organic Chemistry ◽

10.3762/bjoc.11.127 ◽

2015 ◽

Vol 11 ◽

pp. 1129-1135 ◽

Cited By ~ 7

Author(s):

Leander Simon Runtsch ◽

David Michael Barber ◽

Peter Mayer ◽

Michael Groll ◽

Dirk Trauner ◽

...

Keyword(s):

Crystal Structure ◽

Catalytic Activity ◽

Carbonic Anhydrase ◽

Drug Class ◽

Carbonic Anhydrase Ii ◽

Carbonic Anhydrases ◽

X Ray ◽

X Ray Crystallography ◽

Human Carbonic Anhydrase

Aryl sulfonamides are a widely used drug class for the inhibition of carbonic anhydrases. In the context of our program of photochromic pharmacophores we were interested in the exploration of azobenzene-containing sulfonamides to block the catalytic activity of human carbonic anhydrase II (hCAII). Herein, we report the synthesis and in vitro evaluation of a small library of nine photochromic sulfonamides towards hCAII. All molecules are azobenzene-4-sulfonamides, which are substituted by different functional groups in the 4´-position and were characterized by X-ray crystallography. We aimed to investigate the influence of electron-donating or electron-withdrawing substituents on the inhibitory constant K i. With the aid of an hCAII crystal structure bound to one of the synthesized azobenzenes, we found that the electronic structure does not strongly affect inhibition. Taken together, all compounds are strong blockers of hCAII with K i = 25–65 nM that are potentially photochromic and thus combine studies from chemical synthesis, crystallography and enzyme kinetics.

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Benzylidene-bis-(4-Hydroxycoumarin) and Benzopyrano-Coumarin Derivatives: Synthesis, 1H/13C-NMR Conformational and X-ray Crystal Structure Studies and In Vitro Antiviral Activity Evaluations

Molecules ◽

10.3390/molecules16076023 ◽

2011 ◽

Vol 16 (7) ◽

pp. 6023-6040 ◽

Cited By ~ 46

Author(s):

Davorka Završnik ◽

Samija Muratović ◽

Damjan Makuc ◽

Janez Plavec ◽

Mario Cetina ◽

...

Keyword(s):

Crystal Structure ◽

Antiviral Activity ◽

13C Nmr ◽

Coumarin Derivatives ◽

X Ray

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Two novel Ag(I) complexes of N-nicotinyl phosphoric triamide derivatives: Synthesis, X-ray crystal structure and in vitro antibacterial and cytotoxicity studies

Inorganica Chimica Acta ◽

10.1016/j.ica.2014.07.029 ◽

2014 ◽

Vol 423 ◽

pp. 107-116 ◽

Cited By ~ 16

Author(s):

Khodayar Gholivand ◽

Foroogh Molaei ◽

Nasrin Oroujzadeh ◽

Rezvan Mobasseri ◽

Hossein Naderi-Manesh

Keyword(s):

Crystal Structure ◽

X Ray ◽

Cytotoxicity Studies ◽

Phosphoric Triamide

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Chromium(III) Complex Obtained from Dipicolinic Acid: Synthesis, Characterization, X-Ray Crystal Structure and Electrochemical Studies

Bulletin of the Korean Chemical Society ◽

10.5012/bkcs.2013.34.10.3093 ◽

2013 ◽

Vol 34 (10) ◽

pp. 3093-3097 ◽

Cited By ~ 7

Author(s):

Khaled Ghasemi ◽

Ali Reza Rezvani ◽

Ibrahim Abdul Razak ◽

Abolghasem Moghimi ◽

Fatemeh Ghasemi ◽

...

Keyword(s):

Crystal Structure ◽

Dipicolinic Acid ◽

Acid Synthesis ◽

Electrochemical Studies ◽

X Ray

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Co-crystal structure of the iMango-III fluorescent RNA aptamer using an X-ray free-electron laser

Acta Crystallographica Section F Structural Biology Communications ◽

10.1107/s2053230x19010136 ◽

2019 ◽

Vol 75 (8) ◽

pp. 547-551 ◽

Cited By ~ 3

Author(s):

Robert J. Trachman ◽

Jason R. Stagno ◽

Chelsie Conrad ◽

Christopher P. Jones ◽

Pontus Fischer ◽

...

Keyword(s):

Crystal Structure ◽

Single Crystal ◽

Free Electron ◽

Free Electron Laser ◽

Structural Model ◽

Data Sets ◽

Data Set ◽

X Ray ◽

Turn On

Turn-on aptamers are in vitro-selected RNAs that bind to conditionally fluorescent small molecules and enhance their fluorescence. Upon binding TO1-biotin, the iMango-III aptamer achieves the largest fluorescence enhancement reported for turn-on aptamers (over 5000-fold). This aptamer was generated by structure-guided engineering and functional reselection of the parental aptamer Mango-III. Structures of both Mango-III and iMango-III have previously been determined by conventional cryocrystallography using synchrotron X-radiation. Using an X-ray free-electron laser (XFEL), the room-temperature iMango-III–TO1-biotin co-crystal structure has now been determined at 3.0 Å resolution. This structural model, which was refined against a data set of ∼1300 diffraction images (each from a single crystal), is largely consistent with the structures determined from single-crystal data sets collected at 100 K. This constitutes a technical benchmark on the way to XFEL pump–probe experiments on fluorescent RNA–small molecule complexes.

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