Synthesis, biological evaluation, and molecular docking studies of 2,5-substituted-1,4-benzoquinone as novel urease inhibitors

Zhang, You; Xian, Dong-Mei; Zhang, Mei; Cheng, Xiao-Shan; Li, Xiaofang

doi:10.1016/j.bmc.2012.07.002

Cited by 27 publications

(17 citation statements)

References 19 publications

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“…Molecules like morpholine [4], metronidazole [6], substituted piperidines [7], Barbiturates [8] and benzoquinone derivatives [9] having IC50 values 2.37 µM, 12 µM, 13 µM, 19.38 µM and 27.30 µM respectively. Most of our analogues were found to be more active than the results with those of other studies.…”

Section: Pharmacologymentioning

confidence: 99%

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Inhibition of Urease Enzyme Activity by Urea and Thiourea Derivatives of Dipeptides Conjugated 2, 3-Dichlorophenyl Piperazine

Vardhan

Kumara

Kumar

et al. 2017

Int J Pharm Pharm Sci

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Objective: Studies on enzyme inhibition remain an important area of pharmaceutical research since these studies have led to the discoveries of drugs used in a variety of physiological conditions. In search of novel urease enzyme inhibitors, four dipeptides were synthesized, conjugated to 2,3-dichlorophenyl piperazine analogue and converted into urea/thiourea derivatives. Methods:The peptides were synthesized by solution phase method and conjugated to 2,3-dichlorophenyl piperazine (PZN) using 1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide (EDCI)/hydroxybenzotriazole (HOBt) as a coupling agent and N-methylmorpholine (NMM) as a base. The tertbutyloxycarbonyl (Boc) group was removed using trifluoroacetic acid (TFA), neutralized with NMM and converted to urea and thiourea derivatives using substituted phenyl isocyanates and isothiocyanates respectively. Results:Most of the synthesized analogues were found to be good inhibitors of urease enzyme activity. The conjugates of thiourea with F and Cl substituents at meta or para positions showed predominant urease inhibitory activity. The analogue 23 was nearly 10 fold (2 µM) more potent than the reference standard, 21.0±0.11 µM. Conclusion:The reported activity was correlated with some of the literature reported urease inhibitors and found that our compound 23 was more potent than the existing ones.

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Section: Pharmacologymentioning

confidence: 99%

“…Several classes of molecules have been tested as urease inhibitors ( fig. 1) [4][5][6][7][8][9], but part of them was prevented from using in vivo because of their toxicity or instability. As a consequence agents currently used to inhibit urease have some deleterious side effects.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Urease Enzyme Activity by Urea and Thiourea Derivatives of Dipeptides Conjugated 2, 3-Dichlorophenyl Piperazine

Vardhan

Kumara

Kumar

et al. 2017

Int J Pharm Pharm Sci

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“…Urease (urea amidohydrolase: EC 3.5.1.5) is a nickel‐dependent metalloenzyme. Followed by the spontaneous hydrolysis of the carbamate to ammonia and carbonic acid, it catalyzes the hydrolysis of urea to yield ammonia and carbamate . Urease is broadly distributed in nature among prokaryotes, as well as in eukaryotes, including fungi and plants …”

Section: Introductionmentioning

confidence: 99%

Synthesis, Biological Evaluation and Molecular Docking of Deferasirox and Substituted 1,2,4‐Triazole Derivatives as Novel Potent Urease Inhibitors: Proposing Repositioning Candidate

Ashani

Azizian

Alavijeh

et al. 2020

Chemistry & Biodiversity

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A series of new deferasirox derivatives were synthesized through the reaction of monosubstituted hydrazides with 2-(2-hydroxyphenyl)-4H-benzo[e] [1,3]oxazin-4-one. For the first time, deferasirox and some of its derivatives were evaluated for their in vitro inhibitory activity against Jack bean urease. The potencies of the members of this class of compounds are higher than that of acetohydroxamic acid. Two compounds, bearing tetrazole and hydrazine derivatives (bioisoester of carboxylate group), represented the most potent urease inhibitory activity with IC 50 values of 1.268 and 3.254 μM, respectively. In silico docking studies were performed to delineate possible binding modes of the compounds with the enzyme, urease. Docking analysis suggests that the synthesized compounds were anchored well in the catalytic site and extending to the entrance of binding pocket and thus restrict the mobility of the flap by interacting with its crucial amino acid residues, CME592 and His593. The overall results of urease inhibition have shown that these target compounds can be further optimized and developed as a lead skeleton for the discovery of novel urease inhibitors Figure 1. The structure of DFX and its complexation with iron.Scheme 5. The proposed reaction mechanism for the synthesis of DFX and its analogs 7a -7e. two ionic bonds with two Ni 2 + ions. Also, the binding mode of DFX was depicted in Figure 4b, which revealed that like AHA carboxylate group pointed to the bi-nickel ion center. Besides, DFX formed a π -π Figure 2. The location of JBU active site over C-terminal (αβ) 8 TIM barrel domain (a), close-up representation of the active site, the AHA co-crystallized, and the corresponding re-docked form are represented in green and cyan color, respectively (b).Figure 3. Representation of two different docking poses of compounds relative to bi-nickel center over JBU active site: Compounds with 1,2,4-triazole-N 1 -substituted oriented toward the metal center (a), and compounds with 2-hydroxyphenyl pointed one (b). 3,5bis(2-hydroxyphenyl) moiety, related N 1 -substitution and 1,2,4-triazole ring are shown in red, yellow, and navy, respectively.

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“…For the latter, coenzymes Q is involved in centers of reduction and in the translocation of protons across the inner mitochondrial membrane via quinone/quinol (Q/H 2 Q) redox couple turnover . The ability of 1,4‐benzoquinone related compounds to inhibit H. pylori or Canavalia ensiformis (jack bean) ureases is also important . The inhibition of urease by naphthoquinones and their mechanism of action have been elucidated …”

Section: Introductionmentioning

confidence: 99%

Antiureolytic Activity of Substituted 2,5‐Diaminobenzoquinones

Nain-Pérez

Barbosa

Rodríguez-Hernández

et al. 2019

Chemistry & Biodiversity

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A series of 2,5-bis(alkyl/arylamino)-1,4-benzoquinones (1-12) were investigated in vitro for their potential to inhibit the activity of jack bean urease. Compounds 1 -6, 8, 9, 11 and 12 effectively inhibited the jack bean urease activity by 90.8 % when tested at 5 μM, whereas 7 and 10 had relatively little effect. The IC 50 for most compounds was in the nanomolar range (31.4 nM and 36.0 nM for 2 and 8, respectively). The mechanism of enzyme inhibition shown by 2 and 8 is typical of mixed-type inhibitors, whose affinity for the active site is over 6-and 2-fold higher (K i = 30.0 and 22.8 nM, for 2 and 8, respectively) than that of an allosteric site. Molecular docking studies revealed that both 2 and 8 establish hydrogen bonds with the amino acids residues Asp494, Met588, His593 and Ala636 in the active site of jack bean urease. These results indicate that such aminoquinones are useful leads for the development of more efficient urease inhibitors of wider utility. Scheme 1. Structures of 2,5-bis(alky/arylamino)-1,4-benzoquinones used in this study.

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Synthesis, biological evaluation, and molecular docking studies of 2,5-substituted-1,4-benzoquinone as novel urease inhibitors

Cited by 27 publications

References 19 publications

Inhibition of Urease Enzyme Activity by Urea and Thiourea Derivatives of Dipeptides Conjugated 2, 3-Dichlorophenyl Piperazine

Inhibition of Urease Enzyme Activity by Urea and Thiourea Derivatives of Dipeptides Conjugated 2, 3-Dichlorophenyl Piperazine

Synthesis, Biological Evaluation and Molecular Docking of Deferasirox and Substituted 1,2,4‐Triazole Derivatives as Novel Potent Urease Inhibitors: Proposing Repositioning Candidate

Antiureolytic Activity of Substituted 2,5‐Diaminobenzoquinones

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