Quinazolinone fungal efflux pump inhibitors. Part 2: In vitro structure–activity relationships of (N-methyl-piperazinyl)-containing derivatives

Watkins, William J.; Lemoine, Rémy C.; Chong, Lee S.; Cho, Aesop; Renau, Thomas E.; Kuo, Bonnie; Wong, Vickie; Ludwikow, M.; Garizi, Negar; Iqbal, Nadeem; Barnard, John; Jankowska, Renata; Singh, Rajeshwar; Madsen, D. E.; Lolans, Karen; Lomovskaya, Olga; Oza, Uma; Dudley, Michael N.

doi:10.1016/j.bmcl.2004.07.071

Cited by 14 publications

(7 citation statements)

References 2 publications

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“…(v) N -methylpiperazine (quinazolinone derivative) and milbemycin derivatives (Fig. 3) have been characterized as fungal EPIs that enhance fluconazole efficacy in C. albicans [142, 143]. Attempts to improve the aqueous solubility of screening hits led to the discovery of an analog with improved physical properties and activity against clinically-relevant Candida spp.…”

Section: Fungal Epismentioning

confidence: 99%

Microbial Efflux Pump Inhibition: Tactics and Strategies

Tegos

Haynes²,

Strouse³

et al. 2011

CPD

132

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Traditional antimicrobials are increasingly suffering from the emergence of multidrug resistance among pathogenic microorganisms. To overcome these deficiencies, a range of novel approaches to control microbial infections are under investigation as potential alternative treatments. Multidrug efflux is a key target of these efforts. Efflux mechanisms are broadly recognized as major components of resistance to many classes of chemotherapeutic agents as well as antimicrobials. Efflux occurs due to the activity of membrane transporter proteins widely known as Multidrug Efflux Systems (MES). They are implicated in a variety of physiological roles other than efflux and identifying natural substrates and inhibitors is an active and expanding research discipline. One plausible alternative is the combination of conventional antimicrobial agents/antibiotics with small molecules that block MES known as multidrug efflux pump inhibitors (EPIs). An array of approaches in academic and industrial research settings, varying from high-throughput screening (HTS) ventures to bioassay guided purification and determination, have yielded a number of promising EPIs in a series of pathogenic systems. This synergistic discovery platform has been exploited in translational directions beyond the potentiation of conventional antimicrobial treatments. This venture attempts to highlight different tactical elements of this platform, identifying the need for highly informative and comprehensive EPI-discovery strategies. Advances in assay development genomics, proteomics as well as the accumulation of bioactivity and structural information regarding MES facilitates the basis for a new discovery era. This platform is expanding drastically. A combination of chemogenomics and chemoinformatics approaches will integrate data mining with virtual and physical HTS ventures and populate the chemical-biological interface with a plethora of novel chemotypes. This comprehensive step will expedite the preclinical development of lead EPIs.

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Section: Fungal Epismentioning

confidence: 99%

Microbial Efflux Pump Inhibition: Tactics and Strategies

Tegos

Haynes²,

Strouse³

et al. 2011

CPD

132

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“…The reaction was shown to proceed through the intermediates 59, which were isolated in case the reaction was carried out under the above-mentioned mild conditions. There are reports concerning modification of the position 3 in quinazolinones with 4-methylpiperazine [64] and phenylethyl substituents [65].…”

Section: Chemical Properties and Modificationsmentioning

confidence: 99%

Fluorinated azines and benzazines containing oxygen or sulfur atoms

Носова

Lipunova

Charushin

et al. 2010

Journal of Fluorine Chemistry

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“…A mixture of N-substituted isatoic anhydride 1b (0.05 mol) and paminoacetophenone (6.75 g, 0.05 mol) in glacial acetic acid was heated under reflux for 4 h. After cooling, the reaction mixture was poured into cold water (100 mL) and the separated solid was filtered, dried and crystallized from ethanol/H 2 …”

Section: N-(4-acetylphenyl)-2-(ethylamino)benzamide 2bmentioning

confidence: 99%

“…Furthermore, the novel hydrazinecarbothioamide 6 was synthesized via condensation of thiosemicarbazide and the intermediate 3a by heating the reactants at reflux in ethanol containing a catalytic amount of acetic acid for 2 h. The structure of thioamide 6 was established using IR spectroscopy; it showed the appearance of strong absorption band at m = 3407, 3270, 3198 cm -1 for NH 2 and NH groups as well as 1 H-NMR confirmed the presence of such groups through appearance of the corresponding two singlets at d = 8.34 and 10.216 ppm.…”

Section: Chemistrymentioning

confidence: 99%

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Synthesis of New 2,3‐Dihydroquinazolin‐4(1H)‐one Derivatives for Analgesic and Anti‐inflammatory Evaluation

El‐Sabbagh

Ibrahim

Baraka

et al. 2010

Archiv der Pharmazie

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Starting from isatoic anhydrides, several new 2,3-dihydroquinazolin-4(1H)-one derivatives bearing chalcone or pyrazole or thiazole moieties at the third position were synthesized. The analgesic and anti-inflammatory activities for most compounds were studied at a dose level of 50 mg/kg via the acetic-acid-induced writhing-response method and carrageenan-induced edema method, respectively. The study showed that the chalcones bearing a 4-chlorophenyl group 4c or 4-nitrophenyl group 4b were the most active ones as analgesics. Both chalcone 4c and N-phenyl pyrazole bearing 4-methoxy phenyl group 5b showed a higher anti-inflammatory activity than celecoxib but still lower than that of diclofenac sodium. Moreover, the chalcone 4c has nearly the same ulcerogenic index as the selective cyclooxygenase-2 inhibitor celecoxib.

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Quinazolinone fungal efflux pump inhibitors. Part 2: In vitro structure–activity relationships of (N-methyl-piperazinyl)-containing derivatives

Cited by 14 publications

References 2 publications

Microbial Efflux Pump Inhibition: Tactics and Strategies

Microbial Efflux Pump Inhibition: Tactics and Strategies

Fluorinated azines and benzazines containing oxygen or sulfur atoms

Synthesis of New 2,3‐Dihydroquinazolin‐4(1H)‐one Derivatives for Analgesic and Anti‐inflammatory Evaluation

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