Patent Highlight pubs.acs.org/acsmedchemlett
Inhibitors of DNA Gyrase-GyrB Subunit and/or Topoisomerase IV-ParE Subunit May Treat Infectious Diseases Caused by Antibiotic-Resistant Bacteria Ahmed F. Abdel-Magid* Therachem Research Medilab (India) Pvt. Ltd., Jaipur, India Patent Application Title
Hydroxyalkyl Thiadiazole Derivatives
Patent Application Number
WO 2017/056012 A1
Publication date:
6 April 2017
Priority Application
IN 3119/DEL/2015
Priority date:
30 September 2015
Inventors
Khera, M. K.; Mathur, T.; Sattigeri, J. A.; Masuda, N.; Soneda, T.; Kagoshima, Y.; Konosu, T.; Suzuki, T.; Yamaoka, M.; Itooka, R.
Applicant
Daiichi Sankyo Company, Ltd.; 3-5-l, Nihonbashi Honcho, Chuo-ku, Tokyo 103-S426, Japan
Disease Area
Bacterial infectious diseases
Summary:
Biological Target:
DNA gyrase GyrB subunit and/or topoisomerase IV ParE subunit
The invention in this patent application relates to 2-hydroxyalkyl-1,3,4-thiadiazole derivatives represented generally by formula I. These compounds are inhibitors of DNA gyrase-GyrB subunit and/or topoisomerase IV-ParE subunit and thus may be useful for treating and/or preventing infectious diseases caused by antibiotic resistant bacteria. There are several common Gram-positive bacteria species that cause a variety of infectious diseases in humans. Treatment of many of these infections has become increasingly difficult because of the growing trend by these bacteria to develop resistance against known antibiotics. The following are examples of difficult-to-treat Gram-positive antibiotic-resistant bacteria and the infectious diseases associated with them:
• Methicillin-resistant Staphylococcus aureus (MRSA): This organism causes a wide range of infectious diseases including pimples, impetigo, boils, cellulitis folliculitis, furuncles, carbuncles, scalded skin syndrome, pneumonia, meningitis, osteomyelitis, endocarditis, toxic shock syndrome, and sepsis. S. aureus is also one of the most common causes of hospital-acquired infections. • Penicillin-resistant Streptococcus pneumoniae (PRSP): It causes many types of infections such as community acquired pneumonia, bronchitis, rhinitis, acute sinusitis, otitis media, conjunctivitis, meningitis, bacteremia, sepsis, osteomyelitis, septic arthritis, endocarditis, peritonitis, pericarditis, cellulitis, and brain abscess. • Vancomycin-resistant Enterococcus (VRE): This bacterium can cause urinary tract infections, bacteremia, endocarditis, diverticulitis, and meningitis. • Clostridium: This bacterium causes a dangerous infection known as Clostridium diff icile infection (CDI). CDI-related death has increased due to the spread of the hypervirulent NAP1/027 strain of this bacteria. Existing treatments result in more than 23% recurrence and have limitations against this virulent strain. Treatment limitations also exist with Gram-negative bacteria. For example, Haemophilus inf luenzae is a Gramnegative bacterium that displays some antibiotic resistance. It causes multiple infections including, but not limited to, ear infections, bacteremia, community-acquired respiratory infections, pneumonia, and acute bacterial meningitis. The emergence of hypervirulent antibiotic-resistant strains by different bacteria made it increasingly difficult and expensive to treat many of the bacterial infectious diseases. The problem is compounded by the unavailability of novel antibacterial alternatives to replace the existing classical antibiotics. Therefore, there is a growing and urgent need for the discovery and development of novel more efficacious classes of antibacterial agents that can attack the bacteria through novel mechanisms of action and can be less prone to bacteria resistance. DNA gyrase (topoisomerase II) and topoisomerase IV are two topoisomerase enzymes in bacteria that play essential roles in resolving topological problems of the overwinding or underwinding of the DNA double-helix structure during the DNA replication and transcription. Researchers have focused on the inhibition of these enzymes as a therapeutic target to stop or slow bacterial replication. Their efforts resulted in the discovery of many synthetic topoisomerase inhibitors particularly those targeting the DNA gyrase GyrB subunit. These inhibitors can potentially be developed into antibiotics with this novel mechanism of action to meet the urgent need of effective treatment against infections caused by antibiotic-resistant bacteria. The inventors referred to a number of previous patent applications dealing with DNA gyrase inhibition including one of their own (WO 2009/084614) in which they disclosed the following compound that has a closely related structure to the compounds of formula I in the current patent application. While this compound possessed sufficient in vitro
Received: May 18, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acsmedchemlett.7b00207 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
ACS Medicinal Chemistry Letters
Patent Highlight antibacterial activity and no cytotoxicity, it had low water solubility and was not efficacious in animal models and proved unsuitable for human use.
The compounds of formula I in the current patent application are inhibitors of DNA gyrase-GyrB subunit and/or topoisomerase IV-ParE subunit. However, they contain a key structural feature that distinguishes them from the above compound, that is the presence of hydroxyalkyl substituents at the 2-position of the 1,3,4-thiadiazol ring (group A in formula I). The introduction of the hydroxyalkyl substituents on the thiadiazole ring has significantly improved the physical and biological properties of these compounds. They have good water solubility for potentially better oral bioavailability, possess sufficient in vitro antibacterial activity, and show no cytotoxicity. In addition, they display very good efficacy and safety to be suitable for human use. These compounds may thus potentially be useful for the treatment and/or prevention of infectious diseases caused by antibiotic-resistant bacteria, including but not limited to, community-acquired respiratory infections, hospital-acquired infections, urinary tract infections, and Clostridium dif f icile infections. Important Compound Classes:
Key Structures:
The inventors described the synthesis of 11 examples of formula I including the following compounds:
Biological Assay:
The following assay methods were described:
1. Method for testing inhibitory activity of enzymes 2. Method of testing susceptibility (a) of bacteria (b) of Clostridium diff icile 3. Method of testing cytotoxicity 4. Method of testing solubility in water 5. Method for testing oral bioavailability (BA) in rats and monkeys 6. Method for testing therapeutic effect (a) using mouse lung infection model by Streptococcos pneumoniae (b) using neutropenic mouse thigh or calf muscle infection model (c) using mouse systemic infection model (d) in hamster CDI model B
DOI: 10.1021/acsmedchemlett.7b00207 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
ACS Medicinal Chemistry Letters
Patent Highlight
7. Method of testing susceptibility of P. acnes 8. Method of testing susceptibility of N. gonorrheae Biological Data:
Recent Review Articles:
The minimum inhibitory concentrations (MIC) were determined for the compounds of the invention. The following table contains the data for the above represented examples:
1. Spigaglia, P. Ther. Adv. Infect. Dis. 2016, 3 (1), 23−42. 2. Mesleh, M. F.; Cross, J. B.; Zhang, J.; Kahmann, J.; Andersen, O. A.; Barker, J.; Cheng, R. K.; Felicetti, B.; Wood, M.; Hadfield, A. T.; et al. Bioorg. Med. Chem. Lett. 2016, 26 (4), 1314−1318. 3. Azam, M. A.; Thathan, J.; Jubie, S. Bioorg. Chem. 2015, 62, 41−63.
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4. Ehmann, D. E.; Lahiri, S. D. Curr. Opin. Pharmacol. 2014, 18, 76−83.
AUTHOR INFORMATION
Corresponding Author
*Address: 1383 Jasper Drive, Ambler, Pennsylvania 19002, United States. Tel: 215-913-7202. E-mail:
[email protected]. Notes
The author declares no competing financial interest.
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DOI: 10.1021/acsmedchemlett.7b00207 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
