Isothiazoloquinolones containing functionalized aromatic hydrocarbons at the 7-position: Synthesis and in vitro activity of a series of potent antibacterial agents with diminished cytotoxicity in human cells

Wiles, Jason A.; Wang, Qiuping; Lucien, Edlaine; Hashimoto, Akihiro; Song, Yun-Jeong; Cheng, Jijun; Marlor, Christopher W.; Ou, Yangsi; Podos, Steven D.; Thanassi, Jane A.; Thoma, Christy L.; Deshpande, Milind; Pucci, Michael J.; Bradbury, Barton J.

doi:10.1016/j.bmcl.2005.11.065

Cited by 45 publications

(21 citation statements)

References 14 publications

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“…ACH-702, an isothiazoloquinolone (ITQ), represents an optimized analog of earlier compounds that were previously reported (9,32,43,44,45) to have reduced protein binding, enhanced inhibition of target enzymes, and improved in vitro and in vivo antibacterial activity. This compound displays potent in vitro antibacterial activity against both Gram-positive and Gram-negative bacteria (Tables 2 to 4), with particular effectiveness against resistant Gram-positive strains, including MRSA (Tables 2 and 5).…”

Section: Discussionmentioning

confidence: 99%

“…In particular, most MRSA clinical isolates became resistant to fluoroquinolones within 5 years of their introduction for clinical use (1). Previously, we described a class of compounds with structural similarities to quinolones, the isothiazoloquinolones (ITQs; subset of heteroaryl isothiazolones), which displayed potent and broad-spectrum antibacterial activity against a variety of important pathogens, including fluoroquinolone-resistant isolates (32,43,44,45). Prototype representatives from this class have been synthesized previously (10,11), but none to date have been successfully developed as antibacterial drugs, for reasons unknown.…”

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confidence: 99%

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In Vitro and In Vivo Profiles of ACH-702, an Isothiazoloquinolone, against Bacterial Pathogens

Pucci

Podos

Thanassi

et al. 2011

Antimicrob Agents Chemother

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ACH-702, a novel isothiazoloquinolone (ITQ), was assessed for antibacterial activity against a panel of Gram-positive and Gram-negative clinical isolates and found to possess broad-spectrum activity, especially against antibiotic-resistant Gram-positive strains, including methicillin-resistant Staphylococcus aureus (MRSA). For Gram-negative bacteria, ACH-702 showed exceptional potency against Haemophilus influenzae, Moraxella catarrhalis, and a Neisseria sp. but was less active against members of the Enterobacteriaceae. Good antibacterial activity was also evident against several anaerobes as well as Legionella pneumophila and Mycoplasma pneumoniae. Excellent bactericidal activity was observed for ACH-702 against several bacterial pathogens in time-kill assays, and postantibiotic effects (PAEs) of >1 h were evident with both laboratory and clinical strains of staphylococci at 10؋ MIC and similar in most cases to those observed for moxifloxacin at the same MIC multiple. In vivo efficacy was demonstrated against S. aureus with murine sepsis and thigh infection models, with decreases in the number of CFU/thigh equal to or greater than those observed after vancomycin treatment. Macromolecular synthesis assays showed specific dose-dependent inhibition of DNA replication in staphylococci, and biochemical analyses indicated potent dual inhibition of two essential DNA replication enzymes: DNA gyrase and topoisomerase IV. Additional biological data in support of an effective dual targeting mechanism of action include the following: low MIC values (<0.25 g/ml) against staphylococcal strains with single mutations in both gyrA and grlA (parC), retention of good antibacterial activity (MICs of <0.5 g/ml) against staphylococcal strains with two mutations in both gyrA and grlA, and low frequencies for the selection of higher-level resistance (<10 ؊10 ). These promising initial data support further study of isothiazoloquinolones as potential clinical candidates.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

In Vitro and In Vivo Profiles of ACH-702, an Isothiazoloquinolone, against Bacterial Pathogens

Pucci

Podos

Thanassi

et al. 2011

Antimicrob Agents Chemother

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“…They can act as antibacterial drugs that effectively inhibit DNA replication and are commonly used in treatment of many infections [5,6]. Studies on the biological properties of quinolone-metal complexes have been focused on the interaction with DNA, antibacterial activity tests on diverse microorganisms, cytotoxicity and potential antitumor activity [7][8][9][10][11][12][13][14][15]. In this context, we have studied the interaction of Zn(II) with ciprofloxacin, in the presence of nitrogen-donor ligands such as bpdmed(A 1 )/mtma(A 2 )/apq(A 3 )/ bpeed(A 4 )/dcnd(A 5 )/dpeda(A 6 ).…”

Section: Introductionmentioning

confidence: 99%

Antibacterial and DNA interaction studies of zinc(II) complexes with quinolone family member, ciprofloxacin

Patel

Chhasatia

Parmar

2010

European Journal of Medicinal Chemistry

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“…Quinolones have a long history of chemical modifications giving rise to new compounds with enhanced antibacterial activity. One example is the recently reported ITQ class (30,31), an underexplored chemotype related to quinolones first described by Chu and coworkers at Abbott in the late 1980s (7,8). ITQs have a substitution in the typical 3-carboxyl group by an isothiazolone ring and have demonstrated good antibacterial activity (28,31).…”

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In Vitro Activity of a New Isothiazoloquinolone, ACH-702, against Mycobacterium tuberculosis and Other Mycobacteria

Molina-Torres

Ocampo‐Candiani

Rendón

et al. 2010

Antimicrob Agents Chemother

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In this work, we describe the activity of ACH-702 against clinical isolates of Mycobacterium tuberculosis and six different nontuberculous mycobacteria. The MIC 50 and MIC 90 of both susceptible and drug-resistant M. tuberculosis strains tested were 0.0625 and 0.125 g/ml, respectively. The MIC 50 and MIC 90 values for Mycobacterium fortuitum isolates were 0.0625 g/ml in both cases; Mycobacterium avium complex isolates showed MIC 50 and MIC 90 values of 0.25 and 4 g/ml, respectively.

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Isothiazoloquinolones containing functionalized aromatic hydrocarbons at the 7-position: Synthesis and in vitro activity of a series of potent antibacterial agents with diminished cytotoxicity in human cells

Cited by 45 publications

References 14 publications

In Vitro and In Vivo Profiles of ACH-702, an Isothiazoloquinolone, against Bacterial Pathogens

In Vitro and In Vivo Profiles of ACH-702, an Isothiazoloquinolone, against Bacterial Pathogens

Antibacterial and DNA interaction studies of zinc(II) complexes with quinolone family member, ciprofloxacin

In Vitro Activity of a New Isothiazoloquinolone, ACH-702, against Mycobacterium tuberculosis and Other Mycobacteria

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