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Eur J Med Chem. 2019 Aug 1;175:287-308. doi: 10.1016/j.ejmech.2019.04.067. Epub 2019 Apr 28.

Synthesis and evaluation of new quinazolin-4(3H)-one derivatives as potent antibacterial agents against multidrug resistant Staphylococcus aureus and Mycobacterium tuberculosis.

Author information

1
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, 500037, India.
2
Division of Microbiology, CSIR-Central Drug Research Institute, Sitapur Road, Sector 10, Janakipuram Extension, Lucknow, 226031, Uttar Pradesh, India.
3
Division of Microbiology, CSIR-Central Drug Research Institute, Sitapur Road, Sector 10, Janakipuram Extension, Lucknow, 226031, Uttar Pradesh, India. Electronic address: skchopra007@gmail.com.
4
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, 500037, India. Electronic address: nandurisrini92@gmail.com.

Abstract

Staphylococcus aureus and Mycobacterium tuberculosis are major causative agents responsible for serious nosocomial and community-acquired infections impacting healthcare systems globally. Over several decades, these pathogens have developed resistance to multiple antibiotics significantly affecting morbidity and mortality. Thus, these recalcitrant pathogens are amongst the most formidable microbial pathogens for which international healthcare agencies have mandated active identification and development of new antibacterial agents for chemotherapeutic intervention. In our present work, a series of new quinazolin-4(3H)-one derivatives were designed, synthesized and evaluated for their antibacterial activity against ESKAP pathogens and pathogenic mycobacteria. The experiments revealed that 4'c, 4'e, 4'f and 4'h displayed selective and potent inhibitory activity against Staphylococcus aureus with MIC values ranging from 0.03-0.25 μg/mL. Furthermore, compounds 4'c and 4'e were found to be benign to Vero cells (CC50 = >5 μg/mL) and displayed promising selectivity index (SI) > 167 and > 83.4 respectively. Additionally, 4'c and 4'e demonstrated equipotent MIC against multiple drug-resistant strains of S. aureus including VRSA, concentration dependent bactericidal activity against S. aureus and synergized with FDA approved drugs. Moreover, compound 4'c exhibited more potent activity in reducing the biofilm and exhibited a PAE of ∼2 h at 10X MIC which is comparable to levofloxacin and vancomycin. In vivo efficacy of 4'c in murine neutropenic thigh infection model revealed that 4'c caused a similar reduction in cfu as vancomycin. Gratifyingly, compounds 4d, 4e, 9a, 9b, 14a, 4'e and 4'f also exhibited anti-mycobacterial activity with MIC values in the range of 2-16 μg/mL. In addition, the compounds were found to be less toxic to Vero cells (CC50 = 12.5->100 μg/mL), thus displaying a favourable selectivity index. The interesting results obtained here suggest the potential utilization of these new quinazolin-4(3H)-one derivatives as promising antibacterial agents for treating MDR-Staphylococcal and mycobacterial infections.

KEYWORDS:

50% cytotoxic concentration; ATCC; American type culture collection; CC(50); CLSI; CPCSEA; Clinical laboratory standards institute; Committee for the purpose of control and supervision of experiments on animals; Cu(I)-catalyzed azide-alkyne cycloaddition; CuAAC; FDA; FIC; Food and drug administration; Fractional inhibitory concentration; MDR-SA; MHA; MHB; MIC; MRSA; Methicillin resistant Staphylococcus aureus; Minimum inhibitory concentration; Mueller-hinton agar; Mueller-hinton cation supplemented broth; Multi drug resistant Staphylococcus aureus; Multidrug-resistant Staphylococcus aureus (MDR-S. aureus); PBS; Phosphate buffered saline; Quinazolinones; SA; SI; Selectivity index; Staphylococcus aureus; TSA; Tryptic soy agar; VRSA; Vancomycin resistant Staphylococcus aureus; Vero cells; WHO; World health organisation

PMID:
31096152
DOI:
10.1016/j.ejmech.2019.04.067
[Indexed for MEDLINE]

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