Discovery of WQ-3810: Design, synthesis, and evaluation of 7-(3-alkylaminoazetidin-1-yl)fluoro-quinolones as orally active antibacterial agents

Itoh, Kenji; Kuramoto, Yoji; Amano, Hiroko; Kazamori, Daichi; Yazaki, Akira

doi:10.1016/j.ejmech.2015.08.015

Cited by 25 publications

(17 citation statements)

References 24 publications

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“…Of these seven predictions, two predictions were reported as potent activity, three predictions were reported as moderate activity, and two predictions were reported as inactive. Activity values of PubChem CID-122195336 (DNA gyrase; IC 50 = 0.17 µM; Itoh et al, 2015) and PubChem CID-122195337 (DNA gyrase; IC 50 = 0.41 µM; Itoh et al, 2015) were reported as potent activity; binfloxacin (topoisomerase IV subunit A; IC 50 = 10 µM; Gaulton et al, 2017), ecenofloxacin (topoisomerase IV subunit A; IC 50 = 10 µM; Gaulton et al, 2017), and irloxacin (topoisomerase IV subunit A; IC 50 = 10 µM; Gaulton et al, 2017) were reported as moderate activity; and PD 118362 (DNA gyrase; IC 50 = 66.75 µM; Domagala et al, 1988) and PD 111834 (DNA gyrase; IC 50 = 201 µM; Domagala et al, 1986) were reported as inactive.…”

Section: Resultsmentioning

confidence: 99%

Reliable Target Prediction of Bioactive Molecules Based on Chemical Similarity Without Employing Statistical Methods

et al. 2019

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The prediction of biological targets of bioactive molecules from machine-readable materials can be routinely performed by computational target prediction tools (CTPTs). However, the prediction of biological targets of bioactive molecules from non-digital materials (e.g., printed or handwritten documents) has not been possible due to the complex nature of bioactive molecules and impossibility of employing computations. Improving the target prediction accuracy is the most important challenge for computational target prediction. A minimum structure is identified for each group of neighbor molecules in the proposed method. Each group of neighbor molecules represents a distinct structural class of molecules with the same function in relation to the target. The minimum structure is employed as a query to search for molecules that perfectly satisfy the minimum structure of what is guessed crucial for the targeted activity. The proposed method is based on chemical similarity, but only molecules that perfectly satisfy the minimum structure are considered. Structurally related bioactive molecules found with the same minimum structure were considered as neighbor molecules of the query molecule. The known target of the neighbor molecule is used as a reference for predicting the target of the neighbor molecule with an unknown target. A lot of information is needed to identify the minimum structure, because it is necessary to know which part(s) of the bioactive molecule determines the precise target or targets responsible for the observed phenotype. Therefore, the predicted target based on the minimum structure without employing the statistical significance is considered as a reliable prediction. Since only molecules that perfectly (and not partly) satisfy the minimum structure are considered, the minimum structure can be used without similarity calculations in non-digital materials and with similarity calculations (perfect similarity) in machine-readable materials. Nine tools (PASS online, PPB, SEA, TargetHunter, PharmMapper, ChemProt, HitPick, SuperPred, and SPiDER), which can be used for computational target prediction, are compared with the proposed method for 550 target predictions. The proposed method, SEA, PPB, and PASS online, showed the best quality and quantity for the accurate predictions.

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Section: Resultsmentioning

confidence: 99%

Reliable Target Prediction of Bioactive Molecules Based on Chemical Similarity Without Employing Statistical Methods

et al. 2019

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“…It was found that introduction of alkyl groups (C0–C4) into 7‐(3‐alkylaminoazetidin‐1‐yl)fluoroquinolones resulted in increasing of lipophilicity and hence oral absorption by enhancing the membrane permeability . This study had demonstrated that WQ‐3810 57 was highly active against quinolone‐resistant pathogens with MIC values between 0.010 and 0.2 μg/mL which was higher than that of levofloxacin against the tested strains of Gram‐negative bacteria with a good pharmacokinetic profile as well as a low potential for side effects …”

Section: Recent Advances Of Quinolone Antibacterial Agentsmentioning

confidence: 93%

Recent updates of fluoroquinolones as antibacterial agents

Ezelarab

Abbas

Hassan

et al. 2018

Archiv der Pharmazie

150

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Fluoroquinolones remain one of the most important kind of antibacterial agents used nowadays. The emergence of more virulent and resistant strains of bacteria by the development of either mutated DNA-binding proteins or efflux pump mechanism for drugs is considered the main problem associated with the therapeutic use of these drugs. This situation participated in pushing researchers to design new fluoroquinolone derivatives, mainly with different substituents at C-7 to withstand these resistant strains of bacteria and to obtain a wider spectrum of activity including activity against anaerobic organisms. Conjugation of fluoroquinolones with substitutions such as 1,2,4-triazoles, alkyl oximes, flavonoids, aryl furans, benzofuroxans, metronidazoles or even other antibiotics such as neomycin-B produced derivatives that have a superior and wider spectrum of activity and better resistance than the classical fluoroquinolone agents. Addition of a hydroxamic acid moiety to fluoroquinolones also increased the activity against Proteus mirabilis, which represents one of the most resistant strains of bacteria in urinary tract infections. This review aims to highlight the recent updates made for fluoroquinolones for broadening the spectrum of activity to become active not only against resistant strains of bacteria but also against anaerobic pathogens.

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“…Highly substituted piperazines can be expected to increase antimicrobial activity probably by enhancing lipophilicity of molecule . Mainly, piperazine nucleus constitutes an active part of fluoroquinolone class antibacterial drugs such as ciprofloxacin, enoxacine, pefloxacine, fleroxacine, ofloxacine, and grepafloxacine . In some of our previous studies, some 1,2,4‐triazole‐ N ‐substituted piperazine conjugates have been obtained as antibacterial and/or antifungal agents .…”

Section: Introductionmentioning

confidence: 99%

Microwave‐Assisted Synthesis, Antioxidant, and Antimicrobial Evaluation of Piperazine‐Azole‐Fluoroquinolone Based 1,2,4‐Triazole Derivatives

Ozdemir

Demirbaş

Demırbas

et al. 2018

Journal of Heterocyclic Chem

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Azole derivatives (10a–f) obtained starting from 1‐(4‐fluorohenyl)piperazine were converted to the corresponding Mannich bases (7a–d, 12a,b, and 16a,b) containing β‐lactame or flouroquinolone core via a one‐pot three‐component reaction. The synthesis of conazole analogues was carried out starting from triazole by three steps. Reactions were carried out under conventional‐mediated and microwave‐mediated conditions. All the newly synthesized compounds were screened for their antimicrobial, antioxidant activity, and most of them displayed good–moderate activity.

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Discovery of WQ-3810: Design, synthesis, and evaluation of 7-(3-alkylaminoazetidin-1-yl)fluoro-quinolones as orally active antibacterial agents

Cited by 25 publications

References 24 publications

Reliable Target Prediction of Bioactive Molecules Based on Chemical Similarity Without Employing Statistical Methods

Reliable Target Prediction of Bioactive Molecules Based on Chemical Similarity Without Employing Statistical Methods

Recent updates of fluoroquinolones as antibacterial agents

Microwave‐Assisted Synthesis, Antioxidant, and Antimicrobial Evaluation of Piperazine‐Azole‐Fluoroquinolone Based 1,2,4‐Triazole Derivatives

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