The Preparation of Two, Preclinical Amino-quinazolinediones as Antibacterial Agents

Beylin, Vladimir G.; Boyles, David C.; Curran, Timothy T.; Macikenas, Dainius; Parlett, and Roger V.; Vrieze, Derek

doi:10.1021/op7000639

Cited by 30 publications

(11 citation statements)

References 10 publications

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“…PD160793 was a generous gift from John Domagala, Parke-Davis Division of Pfizer Corp. (Ann Arbor MI). PD161148 and additional 8-methoxy quinolones, the 8-methyl-and 8-methoxyquinazoline-2,4-diones, and the pyrido[1,2-c]pyrimidine-1,3-dione were prepared using methods described previously (3,12,20,35,41). All compounds were dissolved to 10 mg/ml in either dimethyl sulfoxide (DMSO) (for diones) or 0.1 N NaOH (for quinolones) prior to use.…”

Section: Methodsmentioning

confidence: 99%

Fluoroquinolone and Quinazolinedione Activities against Wild-Type and Gyrase Mutant Strains of Mycobacterium smegmatis

Malik¹,

Marks

Mustaev

et al. 2011

Antimicrob Agents Chemother

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Quinazolinediones (diones) are fluoroquinolone-like inhibitors of bacterial gyrase and DNA topoisomerase IV. To assess activity against mycobacteria, C-8-methoxy dione derivatives were compared with cognate fluoroquinolones by using cultured Mycobacterium smegmatis. Diones exhibited higher MIC values than fluoroquinolones; however, MICs for fluoroquinolone-resistant gyrA mutants, normalized to the MIC for wild-type cells, were lower. Addition of a 3-amino group to the 2,4-dione core increased relative activity against mutants, while alteration of the 8-methoxy group to a methyl or of the 2,4-dione core to a 1,3-dione core lowered activity against mutants. A GyrA G89C bacterial variant was strikingly susceptible to most of the diones tested; in contrast, low susceptibility to fluoroquinolones was observed. Many of the bacteriostatic differences between diones and fluoroquinolones were explained by interactions at the N terminus of GyrA helix IV revealed by recently published X-ray structures of drug-topoisomerase-DNA complexes. When lethal activity was normalized to the MIC in order to minimize the effects of drug uptake, efflux, and ternary complex formation, a 3-amino-2,4-dione exhibited killing activity comparable to that of a cognate fluoroquinolone. Surprisingly, the lethal activity of the dione was inhibited less by chloramphenicol than that of the cognate fluoroquinolone. This observation adds the 2,4-dione structural motif to the list of structural features known to impart lethality to fluoroquinolone-like compounds in the absence of protein synthesis, a phenomenon that is not explained by X-ray structures of drug-enzyme-DNA complexes.Fluoroquinolones are lethal antibacterial agents that are widely used to control many bacterial infections (23); for some diseases, such as multidrug-resistant tuberculosis, fluoroquinolones are key to successful treatment (4). As with other antimicrobials, fluoroquinolone use is threatened by an increasing prevalence of resistance (1). One way to address the resistance problem is to identify new derivatives that are particularly active with resistant mutants. For example, with some bacterial species, addition of an 8-methoxy substituent increases fluoroquinolone activity against mutants (8,45,46). Other examples include quinazolinediones, which have shown good activity with gyrase resistance mutants selected by fluoroquinolone treatment of Escherichia coli, Staphylococcus aureus, and Streptococcus pneumoniae (11,16,34). We found with E. coli that a quinazoline-2,4-dione was almost as active with gyrase mutants as with wild-type cells (12). How quinazolinediones behave with mycobacteria is unknown.To compare quinolone-like compounds with regard to the likely effects of fluoroquinolone resistance mutations, sets of gyrase mutants are prepared in which the strains are otherwise isogenic. The MIC for the mutant is measured and related to the MIC for the wild type to correct for differences in uptake and efflux. The ratio of the MIC for the mutant to the MIC for the wild type de...

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Section: Methodsmentioning

confidence: 99%

Fluoroquinolone and Quinazolinedione Activities against Wild-Type and Gyrase Mutant Strains of Mycobacterium smegmatis

Malik¹,

Marks

Mustaev

et al. 2011

Antimicrob Agents Chemother

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“…The C-7 variants of 1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione (NH dione) and 3-amino-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione (N-NH 2 dione) were synthesized by substituting (S)-3-aminopyrrolidine, (R)-3-N-Boc-aminomethyl pyrrolidine, (S,S)-cis-octahydropyrrolo [3,4-b]pyridine (3B Pharmachem International Co., Wuhan, People's Republic of China) or 2-ethylpiperazine (Atlantic SciTech Group, Bristol, PA) into the C-7 position of 3-H-or 3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione. De novo synthesis of the requisite quinazoline-2,4-dione intermediates and introduction of the C-7 groups was performed with minor modifications to previously described methods (1,10,32,33). The structure of each compound was characterized by nuclear magnetic resonance and high-resolution mass spectroscopy.…”

Section: Methodsmentioning

confidence: 99%

Use of Gyrase Resistance Mutants To Guide Selection of 8-Methoxy-Quinazoline-2,4-Diones

German

Malik²,

Rosen

et al. 2008

Antimicrob Agents Chemother

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A series of 1-cyclopropyl-8-methoxy-quinazoline-2,4-diones was synthesized and evaluated for lowering the ratio of the antimicrobial MIC in gyrase resistance mutants to that in the gyr ؉ (wild type) using isogenic strains of Escherichia coli. Dione features that lowered this ratio were a 3-amino group and C-7 ring structure (3-aminomethyl pyrrolidinyl < 3-aminopyrrolidinyl < diazobicyclo < 2-ethyl piperazinyl). The wild-type MIC was also lowered. With the most active derivative tested, many gyrA resistance mutant types were as susceptible as, or more susceptible than, wild-type cells. The most active 2,4-dione derivatives were also more active with two quinolone-resistant gyrB mutants than with wild-type cells. With respect to lethality, the most bacteriostatic 2,4-dione killed E. coli at a rate that was affected little by a gyrA resistance mutation, and it exhibited a rate of killing similar to its cognate fluoroquinolone at 10؋ the MIC. Population analysis with wild-type E. coli applied to agar showed that the mutant selection window for the most active 2,4-dione was narrower than that for the cognate fluoroquinolone or for ciprofloxacin. These data illustrate a new approach to guide early-stage antimicrobial selection. Use of antimutant activity (i.e., ratio of the antimicrobial MIC in a mutant strain to the antimicrobial MIC in a wild-type strain) as a structure-function selection criterion can be combined with traditional efforts aimed at lowering antimicrobial MICs against wild-type organisms to more effectively afford lead molecules with activity against both wild-type and mutant cells.Fluoroquinolones are lethal antibacterial agents that are widely used for many bacterial infections; with some diseases, such as multidrug-resistant tuberculosis, they are sometimes considered to be agents of last resort. However, fluoroquinolone use is threatened by an increasing prevalence of resistance, now seen with almost every bacterial species treated. Even highly susceptible species, such as Haemophilus influenzae, Neisseria gonorrhoeae, and Streptococcus agalactiae, are exhibiting quinolone resistance (11,21,35,36). A common strategy to bypass resistance is to seek new derivatives with increased ability to kill wild-type (susceptible) cells. Unfortunately, even highly lethal compounds can leave resistant mutants alive and able to amplify (13). As an alternative, we suggested that the choice of lead compounds in antibiotic discovery be guided toward those that have a very narrow mutant selection window, i.e., the MIC approximates the mutant prevention concentration (MPC), a measure of the mutant subpopulation MIC (5, 40, 41). With some gram-positive pathogens, particularly Streptococcus pneumoniae, this criterion has been approached using dual-targeted fluoroquinolones that have similar activities against both gyrase and DNA topoisomerase IV (8, 22-25, 30, 31). In this situation, the MIC of the less-susceptible target approximates the MPC, which creates a narrow window and restricts the recovery of resistant mutants...

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“…In particular, 2,4,5-trifluorobenzoic acid (1) is a valuable precursor for the synthesis of a variety of fluoroquinolone antibiotics [4][5][6][7][8][9][10][11][12]. Ciprofloxacin (Cipro™), norfloxacin (Noroxin™) and pefloxacin (Peflacine™), which are common antibacterial drugs prescribed clinically, are prepared via routes starting from 2,4,5-trifluorobenzoic acid (Fig.…”

Section: Introductionmentioning

confidence: 99%

The continuous flow synthesis of 2,4,5-trifluorobenzoic acid via sequential Grignard exchange and carboxylation reactions using microreactors

Deng

Shen

Zhao

et al. 2015

Chemical Engineering Journal

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The Preparation of Two, Preclinical Amino-quinazolinediones as Antibacterial Agents

Cited by 30 publications

References 10 publications

Fluoroquinolone and Quinazolinedione Activities against Wild-Type and Gyrase Mutant Strains of Mycobacterium smegmatis

Fluoroquinolone and Quinazolinedione Activities against Wild-Type and Gyrase Mutant Strains of Mycobacterium smegmatis

Use of Gyrase Resistance Mutants To Guide Selection of 8-Methoxy-Quinazoline-2,4-Diones

The continuous flow synthesis of 2,4,5-trifluorobenzoic acid via sequential Grignard exchange and carboxylation reactions using microreactors

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