Dynamic Combinatorial Chemistry to Identify Binders of ThiT, an S‐Component of the Energy‐Coupling Factor Transporter for Thiamine

Monjas, Leticia; Swier, Lotteke J Y M; Setyawati, Inda; Slotboom, Dirk Jan; Hirsch, Anna K. H.

doi:10.1002/cmdc.201700440

Cited by 15 publications

(13 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Among them were: 2-pyridinecarboxylic acid hydrazide (A1), 3-pyridinecarboxylic acid hydrazide (A2), 4-pyridinecarboxylic acid hydrazide (A3), 2-pyridneacetic acid (A4), 3-pyridineacetic acid (A5), and 4-pyridineacetic acid hydrazide (A6). Hydrazide (A1–A3) is available commercially but hydrazide (A4–A6) was obtained by the method described in the literature [ 23 , 24 , 25 ]. The title compounds were obtained in the reaction cyclization of appropriate thiosemicarbazide derivatives (B1–B14) in an alkaline medium.…”

Section: Resultsmentioning

confidence: 99%

“…Zero-point-zero-one mole of the corresponding carboxylic ethyl ester, 0.8 mL of 100% hydrazine hydrate, and 5 mL of anhydrous ethanol were refluxed for 2 h. On cooling, a precipitate appeared which crystallized from ethanol upon drying. Hydrazides A4–A6 were described in the previous paper [ 23 , 24 , 25 ]. Hydrazides A1–A3 were commercially available.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

New Application of 1,2,4-Triazole Derivatives as Antitubercular Agents. Structure, In Vitro Screening and Docking Studies

et al. 2020

View full text Add to dashboard Cite

A series of 1,2,4-triazole derivatives were synthesized and assigned as potential anti-tuberculosis substances. The molecular and crystal structures for the model compounds C1, C12, and C13 were determined using X-ray analysis. The X-ray investigation confirmed the synthesis pathway and the assumed molecular structures for analyzed 1,2,4-triazol-5-thione derivatives. The conformational preferences resulting from rotational degrees of freedom of the 1,2,4-triazole ring substituents were characterized. The lipophilicity (logP) and electronic parameters as the energy of frontier orbitals, dipole moments, NBO net charge distribution on the atoms, and electrostatic potential distribution for all structures were calculated at AM1 and DFT/B3LYP/6-311++G(d,p) level. The in vitro test was done against M. tuberculosis H37Ra, M. phlei, M. smegmatis, and M. timereck. The obtained results clearly confirmed the antituberculosis potential of compound C4, which turned out to be the most active against Mycobacterium H37Ra (MIC = 0.976 μg/mL), Mycobaterium pheli (MIC = 7.81 μg/mL) and Mycobacerium timereck (62.6 μg/mL). Satisfactory results were obtained with compounds C8, C11, C14 versus Myc. H37Ra, Myc. pheli, Myc. timereck (MIC = 31.25−62.5 μg/mL). The molecular docking studies were carried out for all investigated compounds using the Mycobacterium tuberculosis cytochrome P450 CYP121 enzyme as molecular a target connected with antimycobacterial activity.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

New Application of 1,2,4-Triazole Derivatives as Antitubercular Agents. Structure, In Vitro Screening and Docking Studies

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Scheme 1. [29][30][31] [43] [a] DSF = differential scanning fluorimetry, HPLC = high-pressure liquid chromatography, IC 50 = half maximal inhibitory concentration, ITC = isothermal titration calorimetry, K D = dissociation constant, K i = inhibition constant, MIC = minimum inhibitory concentration, MS = mass spectrometry, n.a. Adapted from Van der Vlag and Hirsch.…”

Section: Reversible Reaction Suitable For DCCmentioning

confidence: 99%

“…[29,44] DCC experiments are also possible with a mixture of proteins, but a well-defined sample eases up downstream data analysis and reduces the number of false positives for the desired target. As the equilibrium of the library shifts by the templating effect of the added protein sample, it should consist of the target protein as close to its native state as possible.…”

Section: A Closer Look On the Templating Proteinmentioning

confidence: 99%

Protein‐Templated Dynamic Combinatorial Chemistry: Brief Overview and Experimental Protocol

2019

Self Cite

View full text Add to dashboard Cite

Dynamic combinatorial chemistry (DCC) is a powerful tool to identify bioactive compounds. This efficient technique allows the target to select its own binders and circumvents the need for synthesis and biochemical evaluation of all individual derivatives. An ever‐increasing number of publications report the use of DCC on biologically relevant target proteins. This minireview complements previous reviews by focusing on the experimental protocol and giving detailed examples of essential steps and factors that need to be considered, such as protein stability, buffer composition and cosolvents.

show abstract

“…It has been used to discover synthetic receptors for guest templates as well as ligands for biomacromolecular templates, 3 including proteins such as enzymes, 6−10 lectins, 11 and transporters. 12,13 Although some of these proteins are potential therapeutic targets, examples of biologically active molecules resultant of template-induced molecular amplification from dynamic combinatorial libraries are very rare. 6 One limitation of covalent DCC as a tool for the identification of drug discovery relevant ligands is the limited number of reversible reactions that can be carried out under biomacromolecule-compatible conditions and form bonds that are stable under physiological conditions.…”

mentioning

confidence: 99%

Discovery of a Biologically Active Bromodomain Inhibitor by Target-Directed Dynamic Combinatorial Chemistry

García

Alonso

Serra

et al. 2018

ACS Med. Chem. Lett.

View full text Add to dashboard Cite

Target-directed dynamic combinatorial chemistry (DCC) has emerged as a strategy for the identification of inhibitors of relevant therapeutic targets. In this contribution, we use this strategy for the identification of a high-affinity binder of a parasite target, the Trypanosoma cruzi bromodomain-containing protein TcBDF3. This protein is essential for viability of T. cruzi, the protozoan parasite that causes Chagas disease. A small dynamic library of acylhydrazones was prepared from aldehydes and acylhydrazides at neutral pH in the presence of aniline. The most amplified library member shows (a) high affinity for the template, (b) interesting antiparasitic activity against different parasite forms, and (c) low toxicity against Vero cells. In addition, parasites are rescued from the compound toxicity by TcBDF3 overexpression, suggesting that the toxicity of this compound is due to the TcBDF3 inhibition, i.e., the binding event that initially drives the molecular amplification is reproduced in the parasite, leading to selective toxicity.

show abstract

Dynamic Combinatorial Chemistry to Identify Binders of ThiT, an S‐Component of the Energy‐Coupling Factor Transporter for Thiamine

Cited by 15 publications

References 25 publications

New Application of 1,2,4-Triazole Derivatives as Antitubercular Agents. Structure, In Vitro Screening and Docking Studies

New Application of 1,2,4-Triazole Derivatives as Antitubercular Agents. Structure, In Vitro Screening and Docking Studies

Protein‐Templated Dynamic Combinatorial Chemistry: Brief Overview and Experimental Protocol

Discovery of a Biologically Active Bromodomain Inhibitor by Target-Directed Dynamic Combinatorial Chemistry

Contact Info

Product

Resources

About