Multi-targeting exploration of new 2-aminothiazolyl quinolones: Synthesis, antimicrobial evaluation, interaction with DNA, combination with topoisomerase IV and penetrability into cells

Cheng, Yu; Avula, Srinivasa Rao; Gao, Wei‐Wei; Addla, Dinesh; Tangadanchu, Vijai Kumar Reddy; Zhang, Ling; Lin, Jian-Mei; Zhou, Cheng‐He

doi:10.1016/j.ejmech.2016.10.011

Cited by 67 publications

(18 citation statements)

References 59 publications

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“…However, most compounds developed or isolated thus far exhibit moderate to weak antifungal activity against C. albicans (MIC ranges from 8 to 512 μg/mL) and are inactive against species of Cryptococcus and Aspergillus 17–20 . Thus improving the potency of quinoline-based antifungals and expanding their spectrum of activity is a key component to their development as antifungal agents.…”

Section: Resultsmentioning

confidence: 99%

“…This activity led to the discovery of a series of quinolone scaffold-based compounds that were earlier investigated by our group and found to display moderate anticancer activity (Figure 1) 16 . Quinolones have been investigated primarily as potent antibacterial agents; however, several recent studies have demonstrated that quinolone compounds and natural products can possess antifungal activity 17–21 . In line with the aforementioned, our screening endeavor unmasked the highly potent antifungal activity residing in members of this chemotype family of compounds.…”

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confidence: 99%

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Discovery of a Novel Dibromoquinoline Compound Exhibiting Potent Antifungal and Antivirulence Activity That Targets Metal Ion Homeostasis

et al. 2018

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Globally, invasive fungal infections pose a significant challenge to modern human medicine due to the limited number of antifungal drugs and the rise in resistance to current antifungal agents. The vast majority of invasive fungal infections are caused by species of Candida, Cryptococcus, and Aspergillus. Novel antifungal molecules consisting of unexploited chemical scaffolds with a unique mechanism are a pressing need. The present study identifies a dibromoquinoline compound (4b) with broad-spectrum antifungal activity that inhibits growth of pertinent species of Candida (chiefly C. albicans), Cryptococcus, and Aspergillus at a concentration as low as 0.5 μg/mL. Furthermore, 4b, at a subinhibitory concentration, interfered with expression of two key virulence factors (hyphae and biofilm formation) involved in C. albicans pathogenesis. Three yeast deletion strains (cox17Δ, ssa1Δ, aft2Δ) related to metal ion homeostasis were found to be highly-sensitive to 4b in growth assays indicating the compound exerts its antifungal effect through a unique, previously unexploited mechanism. Supplementing the media with either copper or iron ions reversed the strain sensitivity to 4b further corroborating that the compound targets metal ion homeostasis. 4b’s potent antifungal activity was validated in vivo, as the compound enhanced survival of Caenorhabditis elegans infected with fluconazole-resistant C. albicans. The present study indicates 4b warrants further investigation as a novel antifungal agent.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

Discovery of a Novel Dibromoquinoline Compound Exhibiting Potent Antifungal and Antivirulence Activity That Targets Metal Ion Homeostasis

et al. 2018

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“…The cyclization of the bromoacetyl group at the C-3 position of 170 and 173 with thiourea in ethyl alcohol at 60 • C yielded aralkyl 2-aminothiazolyl quinolones 171 (R 1 = H, F, Cl; R 2 = H, F, Cl; R 3 = H, F, Cl, NO 2 ) and alkyl derivatives 174 (R 4 = n-propyl, n-pentyl, n-heptyl, n-decyl, n-dodecyl, CH 2 C≡CH). The new 2-aminothiazolyl quinolones' in vitro antimicrobial activity could effectively restrain the growth of some tested strains [69]. Antibacterial screening of the synthesized hybrids exhibited that N-1 propargyl modified 2-aminothiazolyl quinolone 174, which presented high antibacterial activities in contrast to the rest of the derivatives against B. typhi.…”

Section: Scheme 35 Synthesis Of Derivative 123a-lmentioning

confidence: 99%

An Overview on Synthetic 2-Aminothiazole-Based Compounds Associated with Four Biological Activities

2021

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Amongst sulfur- and nitrogen-containing heterocyclic compounds, the 2-aminothiazole scaffold is one of the characteristic structures in drug development as this essential revelation has several biological activities abiding it to act as an anticancer, antioxidant, antimicrobial and anti-inflammatory agent, among other things. Additionally, various 2-aminothiazole-based derivatives as medical drugs have been broadly used to remedy different kinds of diseases with high therapeutic influence, which has led to their wide innovations. Owing to their wide scale of biological activities, their structural variations have produced attention amongst medicinal chemists. The present review highlights the recently synthesized 2-aminothiazole-containing compounds in the last thirteen years (2008–2020). The originality of this proposal is based on the synthetic strategies developed to access the novel 2-aminothiazole derivatives (N-substituted, 3-substituted, 4-substituted, multi-substituted, aryl/alkyl substituents or acyl/other substituents). The literature reports many synthetic pathways of these 2-aminothiazoles associated with four different biological activities (anticancer, antioxidant, antimicrobial and anti-inflammatory activities). It is wished that this review will be accommodating for new views in the expedition for rationalistic designs of 2-aminothiazole-based medical synthetic pathways.

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“…[81] Density functional theory (DFT) calculations were performed using the B3LYP hybrid functional for the most active 3-(pyrazol-3-yl)imino-2oxoindoline derivatives 8b, 9a, 9c, and 10a according to reported methods using Gaussian 09 software. [82,83] As represented in Figure 7, the DFT calculation was used to determine the frontier orbitals HOMO (highest occupied orbitals) and LUMO (lowest unoccupied orbitals), and therefore determine the energy gaps (ΔE) that are significant in defining the reactivity of the tested derivatives. The four derivatives showed energy gaps (ΔE) ranging between 2.67 and 2.87 eV and low-lying LUMOs.…”

Section: Dft Calculationmentioning

confidence: 99%

“…Simultaneously, the DFT calculation and MEP were obtained through Gaussian 09 software after optimizing the synthesized derivatives with DFT calculations using the B3LYP hybrid functional and standard 6-31G(d) basis set according to the reported method. [82,83,97] (all details and figures are represented in the Supporting Information file. )…”

Section: Computational Studymentioning

confidence: 99%

Design, synthesis, molecular modeling, and antimicrobial potential of novel 3‐[(1H‐pyrazol‐3‐yl)imino]indolin‐2‐one derivatives as DNA gyrase inhibitors

Ammar

Salem

Abu-Elghait

2021

Archiv der Pharmazie

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A series of 3-[(1H-pyrazol-3-yl)imino]indolin-2-one derivatives were designed using the molecular hybridization method, characterized using different spectroscopic techniques, and evaluated for their in vitro antimicrobial activity. Most of the target compounds demonstrated good to moderate antimicrobial activity compared with ciprofloxacin and fluconazole. Four compounds (8b, 9a, 9c, and 10a) showed encouraging results, with minimal inhibitory concentration (MIC) values (53.45-258.32 µM) comparable to those of norfloxacin (100.31-200.63 µM) and ciprofloxacin (48.33-96.68 µM). Noticeably, the four derivatives revealed excellent bactericidal and fungicidal activities, except for the bacteriostatic potential of compounds 8b and 9a against Escherichia coli and Staphylococcus aureus, respectively. The time-killing kinetic study against S. aureus confirmed the efficacy of these derivatives. Furthermore, two of the four promising derivatives, 9a and 10a, could prevent the formation of biofilms of S. aureus without affecting the bacterial growth at low concentrations. A combination study with seven commercial antibiotics against the multidrug-resistant bacterium P. aeruginosa showed a notable reduction in the antibiotic MIC values, represented mainly through a synergistic or additive effect. The enzymatic assay implied that the most active derivatives had inhibition potency against DNA gyrase comparable to that of ciprofloxacin. Molecular docking and density functional theory calculations were performed to explore the binding mode and study the reactivity of the promising compounds.3-(pyrazol-3-yl)imino-2-oxoindoline derivatives, antibiofilm, antimicrobial activity, DFT calculations, DNA gyrase, drug combination, molecular docking, time-killing kinetics | INTRODUCTIONIn recent years, infectious diseases caused by bacterial pathogens have become a main public health problem due to the high occurrence of drug resistance. [1] Additionally, infections caused by multidrug-resistant bacteria are a major health concern worldwide. [2] Particularly important are infections caused by the Gram-positive bacteria Staphylococcus aureus and species of the genus Enterococcus due to the increasing incidence of infections caused by these microorganisms in hospitals and communities and their ability to

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Multi-targeting exploration of new 2-aminothiazolyl quinolones: Synthesis, antimicrobial evaluation, interaction with DNA, combination with topoisomerase IV and penetrability into cells

Cited by 67 publications

References 59 publications

Discovery of a Novel Dibromoquinoline Compound Exhibiting Potent Antifungal and Antivirulence Activity That Targets Metal Ion Homeostasis

Discovery of a Novel Dibromoquinoline Compound Exhibiting Potent Antifungal and Antivirulence Activity That Targets Metal Ion Homeostasis

An Overview on Synthetic 2-Aminothiazole-Based Compounds Associated with Four Biological Activities

Design, synthesis, molecular modeling, and antimicrobial potential of novel 3‐[(1H‐pyrazol‐3‐yl)imino]indolin‐2‐one derivatives as DNA gyrase inhibitors

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