3-Aryl-4-acyloxyethoxyfuran-2(5H)-ones as inhibitors of tyrosyl-tRNA synthetase: Synthesis, molecular docking and antibacterial evaluation

Wang, Xudong; Deng, Rui-Cheng; Dong, Jing-Jun; Peng, Zhiyuan; Gao, Xiaoming; Li, Shu-Ting; Lin, Wan-Qiang; Lu, Chunlei; Xiao, Zhu‐Ping; Zhu, Hai‐Liang

doi:10.1016/j.bmc.2013.06.066

Cited by 18 publications

(8 citation statements)

References 22 publications

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“…The comparison of binding energies of 5g (−9.52 kcal/mol) with 5ap (−8.63 kcal/mol) and d40 (−5.8 kcal/mol) that were previously published by Xiao revealed that it binds to TyrRs more potent than 5ap and d40 with lower binding energies so our modeling results exhibited that it can be a potent inhibitor of TyrRs. Compound 5g can be considered for further modification for finding a potent antimicrobial agent with a broad spectrum.…”

Section: Resultssupporting

confidence: 66%

“… After that, Xiao et al found that some furan‐2(5 H )‐ones are potent inhibitors against TyrRS and showed excellent antibacterial activity against S. aureus. Xiao et al also synthesized some new TyrRS inhibitors based on the N 2‐(arylacetyl)glycinanilide scaffold, which encourages us to synthesize and evaluate the antibacterial activity of a series of substituted sulfonamide‐amide derivatives. According to structure‐based drug design, Xiao et al undertook an additional design for improving the antibacterial activity of TyrRS inhibitors.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis, molecular docking studies, and absorption, distribution, metabolism, and excretion prediction of novel sulfonamide derivatives as antibacterial agents

Mohebali

Nazifi

et al. 2019

J Chinese Chemical Soc

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A series of novel sulfonamide-amide derivatives were synthesized from 3-(2,4 dichlorophenylamino)-3-oxopropane-1-sulfonylchloride and a variety of amines under solvent-free conditions at room temperature. 3-(2,4-dichlorophenylamino)-3-oxopropane-1 sulfonylchloride was synthesized in four steps starting from 2,4-dichloroaniline and chloropropanoic acid in good yield and purity. The synthesized compounds were screened for their in vitro antibacterial activity against Escherichia coli (ATCC 25922) and Staphylococcus aureus (ATCC 29213). Molecular docking of sulfonamide derivatives into S. aureus tyrosyl-tRNA synthetase (TyrRS)-active site was also performed and among these, 5m and 5g tightly fit the active sites that might be inhibitors of TyrRS for further investigations. Also in the silico metabolism profile, drug-like properties and absorption, distribution, metabolism, excretion and toxicity (ADMET) of the title compounds were calculated by the preADMET server. K E Y W O R D S

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Section: Resultssupporting

confidence: 66%

Section: Introductionmentioning

confidence: 99%

Synthesis, molecular docking studies, and absorption, distribution, metabolism, and excretion prediction of novel sulfonamide derivatives as antibacterial agents

Mohebali

Nazifi

et al. 2019

J Chinese Chemical Soc

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“…Fifty-two furan-2(5H)-one tyrosyl-tRNA synthase inhibitors were collected from papers published by a certain research group 5 , 9 . The biological data of the compounds and their structures were showed in Table 1 .…”

Section: Methodsmentioning

confidence: 99%

“…In this study, they were used to extract the structural features favored for tyrosyl-tRNA synthase inhibitors based on the skeleton of furan-2(5H)-one. The best model, which was developed from a dataset consisted of a 44 molecule training set and a 8 molecule test set, have been validated appropriately, and 10 novel compounds designed on the basis of the model have been predicted better activity than compound 15, the most active molecule in the literatures 5 , 9 . Therefore, the established 3D-QSAR models of fifty-two molecules by CoMFA and CoMSIA could not only give the key structure requirements for the antimicrobial activity but also serve as a helpful guidance in design of novel antibiotics, especially for the control of drug-resistant superbugs.…”

Section: Introductionmentioning

confidence: 99%

New molecular insights into the tyrosyl-tRNA synthase inhibitors: CoMFA, CoMSIA analyses and molecular docking studies

Fan

Peng

et al. 2017

Sci Rep

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Drug resistance caused by excessive and indiscriminate antibiotic usage has become a serious public health problem. The need of finding new antibacterial drugs is more urgent than ever before. Tyrosyl-tRNA synthase was proved to be a potent target in combating drug-resistant bacteria. In silico methodologies including molecular docking and 3D-QSAR were employed to investigate a series of newly reported tyrosyl-tRNA synthase inhibitors of furanone derivatives. Both internal and external cross-validation were conducted to obtain high predictive and satisfactory CoMFA model (q 2 = 0.611, r 2 pred = 0.933, r 2 m = 0.954) and CoMSIA model (q 2 = 0.546, r 2 pred = 0.959, r 2 m = 0.923). Docking results, which correspond with CoMFA/CoMSIA contour maps, gave the information for interactive mode exploration. Ten new molecules designed on the basis of QSAR and docking models have been predicted more potent than the most active compound 3-(4-hydroxyphenyl)-4-(2-morpholinoethoxy)furan-2(5H)-one (15) in the literatures. The results expand our understanding of furanones as inhibitors of tyrosyl-tRNA synthase and could be helpful in rationally designing of new analogs with more potent inhibitory activities.

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“…More specifically, TyrRS belongs to subclass Ic, together with tryptophanyl-tRNA synthetase (TrpRS), and contains an “AIDQ” motif characteristic of the ATP binding site. Progress has been made in inhibiting bacterial TyrRSs both with compounds identified from natural sources, as is the case of SB-219383 [19–21], and with synthetized inhibitors [22–25]. However, there have been no significant advances in experimental work with parasitic TyrRSs as drug targets [10].…”

Section: Introductionmentioning

confidence: 99%

Leishmania donovani tyrosyl-tRNA synthetase structure in complex with a tyrosyl adenylate analog and comparisons with human and protozoan counterparts

et al. 2017

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The crystal structure of Leishmania donovani tyrosyl-tRNA synthetase (LdTyrRS) in complex with a nanobody and the tyrosyl adenylate analog TyrSA was determined at 2.75 Å resolution. Nanobodies are the variable domains of camelid heavy chain-only antibodies. The nanobody makes numerous crystal contacts and in addition reduces the flexibility of a loop of LdTyrRS. TyrSA is engaged in many interactions with active site residues occupying the tyrosine and adenine binding pockets. The LdTyrRS polypeptide chain consists of two pseudo-monomers, each consisting of two domains. Comparing the two independent chains in the asymmetric unit reveals that the two pseudo-monomers of LdTyrRS can bend with respect to each other essentially as rigid bodies. This flexibility might be useful in the positioning of tRNA for catalysis since both pseudo-monomers in the LdTyrRS chain are needed for charging tRNATyr. An “extra pocket” (EP) appears to be present near the adenine binding region of LdTyrRS. Since this pocket is absent in the two human homologous enzymes, the EP provides interesting opportunities for obtaining selective drugs for treating infections caused by L. donovani, a unicellular parasite causing visceral leishmaniasis, or kala azar, which claims 20,000 to 30,000 deaths per year. Sequence and structural comparisons indicate that the EP is a characteristic which also occurs in the active site of several other important pathogenic protozoa. Therefore, the structure of LdTyrRS could inspire the design of compounds useful for treating several different parasitic diseases.

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3-Aryl-4-acyloxyethoxyfuran-2(5H)-ones as inhibitors of tyrosyl-tRNA synthetase: Synthesis, molecular docking and antibacterial evaluation

Cited by 18 publications

References 22 publications

Synthesis, molecular docking studies, and absorption, distribution, metabolism, and excretion prediction of novel sulfonamide derivatives as antibacterial agents

Synthesis, molecular docking studies, and absorption, distribution, metabolism, and excretion prediction of novel sulfonamide derivatives as antibacterial agents

New molecular insights into the tyrosyl-tRNA synthase inhibitors: CoMFA, CoMSIA analyses and molecular docking studies

Leishmania donovani tyrosyl-tRNA synthetase structure in complex with a tyrosyl adenylate analog and comparisons with human and protozoan counterparts

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