Biological evaluation of isothiazoloquinolones containing aromatic heterocycles at the 7-position: In vitro activity of a series of potent antibacterial agents that are effective against methicillin-resistant Staphylococcus aureus

Wiles, Jason A.; Song, Yun-Jeong; Wang, Qiuping; Lucien, Edlaine; Hashimoto, Akihiro; 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.2005.11.064

Cited by 26 publications

(19 citation statements)

References 9 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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“…The most commonly used tetraalkoxydiboron was bis(pinacolato)diboron (B 2 Pin 2 , 9). [54][55][56][57][58][59][60][61][62] Other tetraalkoxydiboron compounds such as (neopentylglycolato)diboron (10) were also reported. 63 Dialkoxyhydroborane compounds like (pinacolato)-hydroborane (HBPin, 11) are occasionally reported as well.…”

Section: Synthesis Of Pyridinylboronic Acids and Esters By Palladium-mentioning

confidence: 99%

Recent progress in the synthesis of pyridinylboronic acids and esters

Liu¹,

Milo²,

Lai

2013

Arkivoc

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Recent progress in the synthesis of (un)substituted pyridinylboronic acids and esters is reviewed. Five approaches to the synthesis of (un)substituted pyridinylboronic acids and esters are summarized: (1) halogen-metal exchange (HMe) and borylation, (2) metal-hydrogen exchange via directed ortho-metallation (DoM) followed by borylation, (3) palladium-catalyzed crosscoupling of halopyridines with tetraalkoxydiborane or dialkoxyhydroborane (4) iridium or rhodium catalyzed C-H or C-F borylation, and (5) exchange / borylation 2.1.1. The general procedure of halogen-metal (Li or Mg) exchange / borylation 2.1.2. The selectivity of halogen-metal (Li or Mg) exchange / borylation 2.1.3. The synthesis of 2-pyridinylboronic acids and esters by halogen-organometal (Li or Mg) exchange / borylation 2.1.4. The synthesis of pyridinediboronic acids via halogen-organotin (Sn) exchange / borylation 2.2. The synthesis of pyridinylboronic acids and esters by directed ortho-metalation (DoM) / borylation 2.2.1. The general procedure of directed ortho-metalation (DoM) / borylation 2.2.2. The selectivity of directed ortho-metalation (DoM) / borylation 2.3. The synthesis of pyridinylboronic acids and esters by palladium-catalyzed cross-coupling of halopyridines with tetraalkoxydiboron or dialkoxyhydroborane 2.4. The synthesis of pyridinylboronic acids and esters by iridium-or rhodium-catalyzed

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“…These ITQs target bacterial replication and are potent inhibitors of both DNA gyrase and topoisomerase IV (5). A lead ITQ compound, ACH-702, has demonstrated potent antibacterial activity against a number of medically relevant bacteria, including drug-resistant strains such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) (21,28,31). In the present work, we studied the antibacterial activity of ACH-702 against clinical isolates of Mycobacterium tuberculosis, including drug-resistant isolates, and additional isolates of nontuberculous mycobacteria (NTM).…”

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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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Biological evaluation of isothiazoloquinolones containing aromatic heterocycles at the 7-position: In vitro activity of a series of potent antibacterial agents that are effective against methicillin-resistant Staphylococcus aureus

Cited by 26 publications

References 9 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

Recent progress in the synthesis of pyridinylboronic acids and esters

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

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