Thiazolopyridone ureas as DNA gyrase B inhibitors: Optimization of antitubercular activity and efficacy

Kale, Ramesh R.; Kale, Manoj; Waterson, David; Raichurkar, Anandkumar; Hameed, Shahul; Manjunatha, M; Reddy, B. Kasi; Malolanarasimhan, Krishnan; Shinde, Vikas; Koushik, Krishna; Jena, Lalit Kumar; Menasinakai, Sreenivasaiah; Humnabadkar, Vaishali; Madhavapeddi, Prashanti; Basavarajappa, Halesha D.; Sharma, Sreevalli; Nandishaiah, Radha; Kumar, Kunal; Ganguly, Samit; Ahuja, Vijay Kamal; Gaonkar, Sheshagiri; Kumar, C. N. Naveen; Ogg, D.; Boriack-Sjodin, P.A.; Sambandamurthy, Vasan K.; Sousa, Sunita M. de; Ghorpade, Sandeep R.

doi:10.1016/j.bmcl.2013.12.080

Cited by 38 publications

(23 citation statements)

References 22 publications

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“…The catalytic subunits (GyrA/ParC) are clinically validated drug targets of the fluoroquinolones, such as moxifloxacin (MXF) (2), while the ATPase subunits (GyrB/ParE) have not been as extensively exploited and may present a new option for treating DR strains of M. tuberculosis (3). Furthermore, several different chemical classes have been described as inhibitors of gyrase B with potent activity against DR bacteria, including M. tuberculosis (4)(5)(6)(7)(8)(9)(10).…”

mentioning

confidence: 99%

A Novel Inhibitor of Gyrase B Is a Potent Drug Candidate for Treatment of Tuberculosis and Nontuberculosis Mycobacterial Infections

Locher

Jones

Hanzelka

et al. 2015

Antimicrob Agents Chemother

101

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dNew drugs to treat drug-resistant tuberculosis are urgently needed. Extensively drug-resistant and probably the totally drugresistant tuberculosis strains are resistant to fluoroquinolones like moxifloxacin, which target gyrase A, and most people infected with these strains die within a year. In this study, we found that a novel aminobenzimidazole, VXc-486, which targets gyrase B, potently inhibits multiple drug-sensitive isolates and drug-resistant isolates of Mycobacterium tuberculosis in vitro (MICs of 0.03 to 0.30 g/ml and 0.08 to 5.48 g/ml, respectively) and reduces mycobacterial burdens in lungs of infected mice in vivo. VXc-486 is active against drug-resistant isolates, has bactericidal activity, and kills intracellular and dormant M. tuberculosis bacteria in a low-oxygen environment. Furthermore, we found that VXc-486 inhibits the growth of multiple strains of Mycobacterium abscessus, Mycobacterium avium complex, and Mycobacterium kansasii (MICs of 0.1 to 2.0 g/ml), as well as that of several strains of Nocardia spp. (MICs of 0.1 to 1.0 g/ml). We made a direct comparison of the parent compound VXc-486 and a phosphate prodrug of VXc-486 and showed that the prodrug of VXc-486 had more potent killing of M. tuberculosis than did VXc-486 in vivo. In combination with other antimycobacterial drugs, the prodrug of VXc-486 sterilized M. tuberculosis infection when combined with rifapentine-pyrazinamide and bedaquiline-pyrazinamide in a relapse infection study in mice. Furthermore, the prodrug of VXc-486 appeared to perform at least as well as the gyrase A inhibitor moxifloxacin. These findings warrant further development of the prodrug of VXc-486 for the treatment of tuberculosis and nontuberculosis mycobacterial infections.

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mentioning

confidence: 99%

A Novel Inhibitor of Gyrase B Is a Potent Drug Candidate for Treatment of Tuberculosis and Nontuberculosis Mycobacterial Infections

Locher

Jones

Hanzelka

et al. 2015

Antimicrob Agents Chemother

101

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“…The orientation of azaindole core was such that the 5-substituent pointed toward Arg 140, which was demonstrated as important for potent inhibition of the target [92,109]. Based on these finding the trans-cinnamic acid 71 was designed, which was predicted to form a salt bridge with Arg 140, exhibited an IC 50 In the year 2009, AstraZeneca [110] has reported a series of imidazopyridazines where the ethyl urea substituent is placed to the six member ring instead of the five member ring.…”

Section: A-hmentioning

confidence: 98%

Dual targeting DNA gyrase B (GyrB) and topoisomerse IV (ParE) inhibitors: A review

Azam

Thathan

Selvaraj

2015

Bioorganic Chemistry

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“…Kale et al. found that tetrazole‐linked thiazolopyridone urea 271 caused inhibition of DNA GyrB ATPase enzyme with IC 50 value of 2 nM, and good activity (MIC = 0.2 μM) against M. tuberculosis . Karabanovich et al.…”

Section: Tetrazolesmentioning

confidence: 99%

New structural classes of antituberculosis agents

Kumar

Patel

Jain

2017

Medicinal Research Reviews

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Tuberculosis (TB), one of the deadliest diseases is shattering the health and socioeconomic status of the society. The emergence of multidrug resistant (MDR) and extremely drug resistant (XDR) strains has provided unprecedented lethal character to TB. The development of MDR and XDR strains of TB results in more deaths, longer duration of therapy, and appearance of the disease in the immunocompromised patients. Because of the development of rapid resistance by Mycobacterium tuberculosis, researchers are confronted with serious challenges in combating TB. For instance, the need for potency and specificity in therapeutic agents approaching clinics, and the increasing demand of low toxicity due to long duration of treatment. Recently, it is proposed that such challenges could be addressed by a shift from contemporary or known classes of drugs to new scaffold-containing or entirely new structural classes of drugs that possibly act on the previously unknown targets, resulting in possibly less instances of resistance development. The exploitation of advances made in the biology of TB in the last and present decades have created opportunities to discover a large number of new structural classes that specifically targets TB by molecular mechanism of action(s) unknown earlier. We have earlier reviewed new structural classes of anti-TB agents up to year 2005. This review covers literature reports of the subsequent 10 years on the discovery of new structural classes of synthetic anti-TB agents. Due to the availability of large number of research reports, we have divided new compounds in 38 structural classes, 368 structures, and 307 references.

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Thiazolopyridone ureas as DNA gyrase B inhibitors: Optimization of antitubercular activity and efficacy

Cited by 38 publications

References 22 publications

A Novel Inhibitor of Gyrase B Is a Potent Drug Candidate for Treatment of Tuberculosis and Nontuberculosis Mycobacterial Infections

A Novel Inhibitor of Gyrase B Is a Potent Drug Candidate for Treatment of Tuberculosis and Nontuberculosis Mycobacterial Infections

Dual targeting DNA gyrase B (GyrB) and topoisomerse IV (ParE) inhibitors: A review

New structural classes of antituberculosis agents

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