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

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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“…Good in vitro antibacterial activity was also demonstrated against Mycobacterium and Nocardia sp. (24,34,42).…”

Section: Discussionmentioning

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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“…7-Amino-substituted fluoroquinolone intermediates (3-7) were obtained by refluxing 1 in CH 3 CN, Et 3 N with piperidine, octahydro-1H-isoindole, perhydroisoquinoline, pyrrolidine, and morpholine in 48-89% yields [12]. Subsequently, intermediates 3-5 in DMF, DIPEA were coupled with thiazolidine in the presence of HATU at 70°C for 20-24 h to yield corresponding amides (8)(9)(10) in 54-60% yields [13] (Fig. 2).…”

Section: Chemistrymentioning

confidence: 99%

“…The corresponding acid chloride was treated with thiazolidine in the presence of Et 3 N to yield 42% of compound 2 [11]. Synthesis of 7-amino-substituted thiazolidine amide (8)(9)(10) and N-thiazolyl amide fluoroquinolone derivatives (11)(12)(13)(14) involved a two-step reaction sequence of nucleophilic aromatic substitution followed by acid derivatization to amides (Scheme 1). 7-Amino-substituted fluoroquinolone intermediates (3-7) were obtained by refluxing 1 in CH 3 CN, Et 3 N with piperidine, octahydro-1H-isoindole, perhydroisoquinoline, pyrrolidine, and morpholine in 48-89% yields [12].…”

Section: Chemistrymentioning

confidence: 99%

“…More recently a new ITQ, ACH‐702 (Fig. ) inhibited both DNA gyrase and topoisomerase IV and was demonstrated to have antibacterial activity against quinolone‐resistant pathogens , methicillin‐resistant Staphylococcus aureus (MRSA) , and Mycobacterium tuberculosis . In addition, compounds in ACH‐702 series were described as having a favorable toxicity and pharmacokinetic profile .…”

Section: Introductionmentioning

confidence: 99%

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Synthesis and Evaluation of Thiazolidine Amide and N‐Thiazolyl Amide Fluoroquinolone Derivatives

Garza

Wallace

Fernando

et al. 2017

Archiv der Pharmazie

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In an effort to develop new fluoroquinolones, we synthesized eight compounds and tested them against a panel of bacteria. The design of these compounds was guided by the introduction of the isothiazoloquinolone motif. The three most active compounds in this series, 8-10, demonstrated good antibacterial activity against methicillin-sensitive Staphylococcus aureus and healthcare-acquired methicillin-resistant Staphylococcus aureus (MIC 0.62-6.3 µg/mL). Further, when these three active compounds were tested for their inhibitory effects on bacterial enzymes, compound 9 was the most effective agent exhibiting IC values of 33.9 and 116.5 μM in the S. aureus deoxyribonucleic acid (DNA) gyrase supercoiling and topoisomerase IV decatenation assays, respectively.

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“…Literature examples of 2-thioquinolone derivatives lacking an additional ring structure are limited [83], and only ring-fused structures such as the isothiazoloquinolones and thiazetoquinolones ( Figure 15) and are reported to have potent antibacterial activity [84][85][86]. Furthermore, despite extensive modification of the fluoroquinolone core, little precedent exists for removing the 3-carboxylate due to its assumed requirement for activity [87].…”

Section: Substitutionmentioning

confidence: 99%

Investigating the fluoroquinolone-topoisomerase interaction by use of novel fluoroquinolone and quinazoline analogs

Marks¹

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Thesis Supervisor: Associate Professor Robert J. Kerns were synthesized such that the N-1, C-2, and C-8 positions were substituted with cyclopropyl, thioethyl/thioisopropyl, and methoxy groups, respectively. The compounds were then evaluated for antibiotic activity against three different bacterial strains to evaluate the contribution of the C-2 thioalkyl substituent to antibacterial activity.In a third study, quinazoline-2,4-diones, a new antibiotic class structurally and mechanistically similar to fluoroquinolones, were modified at the C-4 position in an effort to understand the binding interaction between these compounds and the target enzyme. Importantly, the quinazoline-2,4-diones typically retain activity against bacterial cells known to be resistant to fluoroquinolones and are less likely to select for resistant mutants. In this study, the C-4 carbonyl was replaced with either a thiocarbonyl or a hydroxylimine and the new compounds, bearing C-7 substituents common to potent antibiotic fluoroquinolones and quinazolines, were evaluated for activity against bacterial cells.Despite the findings of recently published X-ray crystallography, it was determined that one of the greatest determinants in antibiotic activity of fluoroquinolones is the C-7 substituent. Additionally, there is increasing evidence that the C-2 carbonyl of quinazoline-2,4-diones affords the increase in activity against resistant mutants by creating a unique binding interaction. Collectively, the conclusions reached here add to our understanding of the structure activity relationship of the fluoroquinolone antibiotic class for rapidly killing bacterial cells and overcoming resistant mutants.Abstract Approved: ____________________________________ Thesis Supervisor ____________________________________

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

Cited by 14 publications

References 29 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

Synthesis and Evaluation of Thiazolidine Amide and N‐Thiazolyl Amide Fluoroquinolone Derivatives

Investigating the fluoroquinolone-topoisomerase interaction by use of novel fluoroquinolone and quinazoline analogs

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