Synthesis and in vitro Evaluation of Novel Small Molecule Inhibitors of Bacterial Arylamine N‐Acetyltransferases (NATs)

Brooke, Edward W.; Davies, Stephen G.; Mulvaney, Andrew W.; Okada, Minoru; Pompeo, Frédérique; Sim, Edith; Vickers, Richard; Westwood, Isaac M.

doi:10.1002/chin.200343140

Cited by 7 publications

(10 citation statements)

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“…6B) has further potential hydrogen bonding from heterocyclic nitrogen to the backbone oxygen of Gly 129 . In the presence of an acetylated cysteine the substrate would have to be recessed away from the catalytic cysteine, possibly allowing hydrogen bonding with the backbone oxygen of Phe 130 , which has previously been implicated in docking studies (Mushtaq et al 2002; Brooke et al 2003b). This residue also plays another role in π‐stacking interactions with the substrates.…”

Section: Resultsmentioning

confidence: 99%

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Binding of the anti‐tubercular drug isoniazid to the arylamine N‐acetyltransferase protein from Mycobacterium smegmatis

et al. 2005

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Isoniazid is a frontline drug used in the treatment of tuberculosis (TB). Isoniazid is a prodrug, requiring activation in the mycobacterial cell by the catalase/peroxidase activity of the katG gene product. TB kills two million people every year and the situation is getting worse due to the increase in prevalence of HIV/AIDS and emergence of multidrug-resistant strains of TB. Arylamine N-acetyltransferase (NAT) is a drug-metabolizing enzyme (E.C. 2.1.3.5). NAT can acetylate isoniazid, transferring an acetyl group from acetyl coenzyme A onto the terminal nitrogen of the drug, which in its N-acetylated form is therapeutically inactive. The bacterium responsible for TB, Mycobacterium tuberculosis, contains and expresses the gene encoding the NAT protein. Isoniazid binds to the NAT protein from Salmonella typhimurium and we report here the mode of binding of isoniazid in the NAT enzyme from Mycobacterium smegmatis, closely related to the M. tuberculosis and S. typhimurium NAT enzymes. The mode of binding of isoniazid to M. smegmatis NAT has been determined using data collected from two distinct crystal forms. We can say with confidence that the observed mode of binding of isoniazid is not an artifact of the crystallization conditions used. The NAT enzyme is active in mycobacterial cells and we propose that isoniazid binds to the NAT enzyme in these cells. NAT activity in M. tuberculosis is likely therefore to modulate the degree of activation of isoniazid by other enzymes within the mycobacterial cell. The structure of NAT with isoniazid bound will facilitate rational drug design for anti-tubercular therapy.

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Section: Resultsmentioning

confidence: 99%

“…The rate of hydrolysis of acetyl CoA by arylamine N ‐acetyltransferase from M. smegmatis (NAT) was determined in 20 mM Tris‐HCl, pH 8.0, using 5,5′‐dithio‐bis(2‐nitrobenzoic acid) (DTNB) as a colorimetric developing agent (Brooke et al 2003b).…”

Section: Methodsmentioning

confidence: 99%

Binding of the anti‐tubercular drug isoniazid to the arylamine N‐acetyltransferase protein from Mycobacterium smegmatis

et al. 2005

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“…The mycobacterial cell wall is unique because it contains an amycolylarabinogalactan layer bound to the peptidoglycan layer via a rhamnoseeGlc-NAc sugar linker, where the dTDP-rhamnose can be vetreated as a precursor [191,192]. 5-Heterylidene-2,4-thiazolidinedione derivatives 67 are competitive inhibitors of recombinant bacterial arylamine-N-acetyltransferases (NATs) [193], which were designed based on the structure modification of N- [194] (Scheme 35).…”

Section: Antimicrobial Agentsmentioning

confidence: 99%

“…b3-AR Agonists are potential drugs for the treatment of obesity, type II diabetes, frequent urination and related diseases [432]. Related thiazolidinones with a cyanamide (193), hydroxylamine (194) (Scheme 90) or 4-amino-1-benzylpiperidine substituents were generally very potent towards the b3 receptor, however, they were not very selective against both the b2 and b1 receptors. Related benzimidazolones (195) (Scheme 90) displayed a good b3 agonist selectivity profile.…”

Section: Other Types Of Activitymentioning

confidence: 99%

5-Ene-4-thiazolidinones – An efficient tool in medicinal chemistry

Kaminskyy

Kryshchyshyn

Lesyk

2017

European Journal of Medicinal Chemistry

147

133

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The presented review is an attempt to summarize a huge volume of data on 5-ene-4-thiazolidinones being a widely studied class of small molecules used in modern organic and medicinal chemistry. The manuscript covers approaches to the synthesis of 5-ene-4-thiazolidinone derivatives: modification of the C5 position of the basic core; synthesis of the target compounds in the one-pot or multistage reactions or transformation of other related heterocycles. The most prominent pharmacological profiles of 5-ene derivatives of different 4-thiazolidinone subtypes belonging to hit-, lead-compounds, drug-candidates and drugs as well as the most studied targets have been discussed. Currently target compounds (especially 5-en-rhodanines) are assigned as frequent hitters or pan-assay interference compounds (PAINS) within high-throughput screening campaigns. Nevertheless, the crucial impact of the presence/nature of C5 substituent (namely 5-ene) on the pharmacological effects of 5-ene-4-thiazolidinones was confirmed by the numerous listed findings from the original articles. The main directions for active 5-ene-4-thiazolidinones optimization have been shown: i) complication of the fragment in the C5 position; ii) introduction of the substituents in the N3 position (especially fragments with carboxylic group or its derivatives); iii) annealing in complex heterocyclic systems; iv) combination with other pharmacologically attractive fragments within hybrid pharmacophore approach. Moreover, the utilization of 5-ene-4-thiazolidinones in the synthesis of complex compounds with potent pharmacological application is described. The chemical transformations cover mainly the reactions which involve the exocyclic double bond in C5 position of the main core and correspond to the abovementioned direction of the 5-ene-4-thiazolidinone modification.

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“…This is achieved by assuring that the final product contains the maximum proportion of the starting materials and by avoiding the use of harmful solvents or, even better, not using solvents at all. 4-Thiazolidinones exhibit a variety of pharmacological activities, functioning, for example, as antibacterial (2Á5), antifungal (6), antidiabetic (7), antitubercular (8,9), anti-HIV (10,11), antiparasitic (12), hypnotic (13), and anathematic agents (14). Also, 5-arylidene derivatives of 4-thiazolidinones have been found to be better fungistatic agents than the parent 4-thiazolidinones (15,16).…”

mentioning

confidence: 99%

A simple and green procedure for the synthesis of 5-arylidene-4-thiazolidinones by grinding

Metwally

Rateb

Zohdi

2011

Green Chemistry Letters and Reviews

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Synthesis and in vitro Evaluation of Novel Small Molecule Inhibitors of Bacterial Arylamine N‐Acetyltransferases (NATs)

Cited by 7 publications

References 1 publication

Binding of the anti‐tubercular drug isoniazid to the arylamine N‐acetyltransferase protein from Mycobacterium smegmatis

Binding of the anti‐tubercular drug isoniazid to the arylamine N‐acetyltransferase protein from Mycobacterium smegmatis

5-Ene-4-thiazolidinones – An efficient tool in medicinal chemistry

A simple and green procedure for the synthesis of 5-arylidene-4-thiazolidinones by grinding

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