Synthesis, SAR and molecular docking study of novel non-β-lactam inhibitors of TEM type β-lactamase

Antipin, R. L.; Beshnova, Daria A.; Petrov, Rostislav A.; Shiryaeva, Anna S.; Андреева, И. П.; Grigorenko, G.M.; Rubtsova, M. Yu.; Majouga, Alexander G.; Lamzin, Victor S.; Egorov, A. M.

doi:10.1016/j.bmcl.2017.02.025

Cited by 11 publications

(5 citation statements)

References 27 publications

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“…A new direction involves searching for structural analogues of known βL inhibitors, including allosteric ones. The computational ligand-based in silico screening technique, in combination with molecular docking and experimental studies of βL inhibition, has been applied for the identification of acylated phenoxyaniline and thiourea compounds as novel non-β-lactam inhibitors of TEM-type βLs [11,80]. An analysis of the residues involved in the binding of the inhibitor at the active site of the enzyme showed that some of them are conservative for class A βLs, which can be prospective for inhibitors of these enzymes.…”

Section: Current Approaches For Overcoming the Resistance Conferred Bmentioning

confidence: 99%

The Role of the Ω-Loop in Regulation of the Catalytic Activity of TEM-Type β-Lactamases

et al. 2019

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Bacterial resistance to β-lactams, the most commonly used class of antibiotics, poses a global challenge. This resistance is caused by the production of bacterial enzymes that are termed β-lactamases (βLs). The evolution of serine-class A β-lactamases from penicillin-binding proteins (PBPs) is related to the formation of the Ω-loop at the entrance to the enzyme's active site. In this loop, the Glu166 residue plays a key role in the two-step catalytic cycle of hydrolysis. This residue in TEM-type β-lactamases, together with Asn170, is involved in the formation of a hydrogen bonding network with a water molecule, leading to the deacylation of the acyl-enzyme complex and the hydrolysis of the β-lactam ring of the antibiotic. The activity exhibited by the Ω-loop is attributed to the positioning of its N-terminal residues near the catalytically important residues of the active site. The structure of the Ω-loop of TEM-type β-lactamases is characterized by low mutability, a stable topology, and structural flexibility. All of the revealed features of the Ω-loop, as well as the mechanisms related to its involvement in catalysis, make it a potential target for novel allosteric inhibitors of β-lactamases.Biomolecules 2019, 9, 854 2 of 16 of inhibitors, whose structures are based on the β-lactam ring, is also limited because resistance to them has also developed. Today, a promising trend is to design novel βL inhibitors and simultaneously use them with antibiotics [7,8]. Computer methods involving the in silico search of novel inhibitors has significantly broadened the range of potential inhibitors. However, only a limited number of novel βL inhibitors have been found that are of non-β-lactam nature and are capable of binding close to the enzyme's active site [8][9][10][11]. Because of the relatively low inhibition constants of such inhibitors, this area of research needs to be further developed.Recently, special attention has been paid to studying the role of loops and peptide linkers as flexible elements in the functioning of proteins and enzymes [12,13]. The loops, as secondary structural elements of proteins, are characterized by an enhanced mobility; their role is not solely confined to being connecting units [12]. Furthermore, changes in the amino acid composition of the loops may impart new functions to protein superfamilies. The Ω-loops, a special class of loops with a conformation resembling the Greek letter "omega," are currently attracting specific attention. The loop conformation is ensured by the short-distance fixation of terminal amino acids. Ω-Loops have been observed in 60 proteins [13], some of which have been found to be involved in allosteric regulation during biospecific ligand recognition [14,15]. The structure of serine class A βLs represents a compact, conserved scaffold that consists of secondary structural elements linked by flexible loops. The Ω-loop is located at the bottom of the entrance to the enzyme active site and includes the catalytically important and highly conserved residue Glu166, the m...

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Section: Current Approaches For Overcoming the Resistance Conferred Bmentioning

confidence: 99%

The Role of the Ω-Loop in Regulation of the Catalytic Activity of TEM-Type β-Lactamases

et al. 2019

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“…Furthermore, the presence of the pyrazole nucleus in different structures leads to diversified applications in different areas such as technology, medicine, and agriculture. Furthermore, pyrazole derivatives have arrived an extensive view of researchers through the past few decades due to their highly reactive effects as anti-inflammatory 3 , antiglaucoma 4 , antiviral 5 , antimicrobial 6 , antidiabetic activities 7 . In addition, pyrazole prodrugs have been recorded to maintain significant anticancer activity 8 – 12 .…”

Section: Introductionmentioning

confidence: 99%

Synthesis of novel pyrazolone candidates with studying some biological activities and in-silico studies

Abdellattif,

Hamed,

Elhoseni

et al. 2023

Sci Rep

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Pyranopyrazole derivatives have a vital role in the class of organic compounds because of their broad spectrum of biological and pharmacological importance. Our current goal is the [3 + 3] cycloaddition of benzoyl isothiocyanate and pyrazolone 1 to undergo oxidation cyclization, producing pyrazoloxadiazine 3. The diol 5 was obtained as a condensation of two equivalents of 1 with thiophene-2-carboxaldehyde in acetic acid above the sodium acetate mixture. When the condensation was carried out in piperidine under fusion, unsaturated ketone 4 was obtained. The pyrazolo pyran derivative 11 resulted from the [3 + 3] cycloaddition of 1 and cinnamic acid, while the Pyrone derivative was prepared by acylation of 12 with two equivalents of acetic anhydride. Phthalic anhydride undergoes arylation using zinc chloride as a catalyst. The cyclic keto acid 23 was synthesized by the action of succinic anhydride on 12 in the acetic medium, while the latter reacted with cinnamic acid, leading to pyrazole derivative 24. All of these reactions were through the Michael reaction mechanism. All the tested compounds showed good antimicrobial activity against pathogenic microorganisms; newly synthesized compounds were also screened for their antioxidant activity. Rational studies were carried out by the ABTs method to allow a broader choice of activities. In addition, similar off-compounds were conducted. Molecular docking studies with the CB-Dock server and MD simulations were created with the default settings of the Solution Builder on the CHARMM-GUI server at 150 nm. A good correlation was obtained between the experimental results and the theoretical bioavailability predictions using POM theory.

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“…Bacterial resistance is spreading globally and poses a serious threat to human health (Liscio et al, 2015) β-lactam resistance has accelerated to an uncontrolled rate due to many reasons like increased consumption, poor prescribing strategies, and abuse of the antibiotics to treat minor infections etc (Liscio et al, 2015). The most significant form of resistance is the generation of β-lactamases enzyme by the pathogenic bacteria which destroy the β-lactam ring which is essential for antibacterial activity (Blizzard et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

“…As TEM-class b-lactamase inhibitors, Antipin et al (2017) synthesised new modules of acylated phenoxyanilide and thiourea compounds and tested them for their capacity to block TEM type -lactamase enzyme (Antipin et al, 2017). IID572, a novel broad spectrum BLI of the diazabicyclooctane (DBO) family that was synthesised by Reck et al, 2019, has the ability to revive piperacillin's antibacterial activity against piperacillin/tazobactam-resistant clinical isolates.…”

Section: Introductionmentioning

confidence: 99%

Novel β-lactamase inhibitors and the pursuit of MBL inhibitors to combat antibiotic-resistant bacteria: a review

Saleh¹,

Mahmood²

2023

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Bacterial resistance is spreading internationally and poses a serious threat to humans. β-lactam resistance has enhanced to an uncontrolled rate due to many reasons. The most significant form of resistance is destruction of the ß-lactam ring by a bacterial enzyme named ß-lactamase enzyme which is essential for antibacterial activity. There are currently six β-lactamases inhibitors that can be used clinically in conjugation with the antibiotic in order to protect them from enzymatic attacks. They bind the β-lactamase enzyme thus the β-lactam antibiotic catches the transpeptidase (PBP) which has the responsibility of peptidoglycan synthesis and disables it thus causing cell wall lysis. However, in order to tackle the fast escalating ß-lactam resistance, additional research is needed in order to create novel drugs with broad-spectrum. Herein we represent the recently published works of the β-lactamases inhibitors. Until nowadays there are no clinically approved MBL inhibitors, Efforts should be put to discover and evaluate novel MBLi to impede the spread of pathogenic-resistant bacteria and minimize their global health impact. The scientists realize this fact and emphasize their effort toward MBL inhibitors.

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Synthesis, SAR and molecular docking study of novel non-β-lactam inhibitors of TEM type β-lactamase

Cited by 11 publications

References 27 publications

The Role of the Ω-Loop in Regulation of the Catalytic Activity of TEM-Type β-Lactamases

The Role of the Ω-Loop in Regulation of the Catalytic Activity of TEM-Type β-Lactamases

Synthesis of novel pyrazolone candidates with studying some biological activities and in-silico studies

Novel β-lactamase inhibitors and the pursuit of MBL inhibitors to combat antibiotic-resistant bacteria: a review

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