Synthesis of new 3-phenylquinazolin-4(3H)-one derivatives as potent antibacterial agents effective against methicillin- and vancomycin-resistant Staphylococcus aureus (MRSA and VRSA)

Article abstract of DOI:10.1016/j.bioorg.2018.08.012

Occurrence of infections due to the drug resistant Staphylococcus aureus is on rise necessitating the need for rapid development of new antibacterial agents. In our present work, a series of new 3-phenylquinazolin-4(3H)-one derivatives were designed, synthesized and evaluated for their antibacterial activity against ESKAP (E. coli, S. aureus, K. pneumoniae, A. baumannii, P. aeroginosa) pathogen panel and pathogenic mycobacterial strains. The study revealed that compounds 4a, 4c, 4e, 4f, 4g, 4i, 4o and 4p exhibited selective and potent inhibitory activity against Staphylococcus aureus with MIC values in the range of 0.125–8 μg/mL. Further, the compounds 4c, 4e and 4g were found to be non toxic to Vero cells (CC₅₀ = >10–>100 μg/mL) and exhibited favourable selectivity index (SI = 40–>200). The compounds 4c, 4e and 4g also showed potent inhibitory activity against various MDR-S. aureus including VRSA. The promising results obtained indicated the potential use of the above series of compounds as promising antibacterial agents for the treatment of multidrug resistant Staphylococcus aureus infections.

Full text of DOI:10.1016/j.bioorg.2018.08.012

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Accepted Manuscript
Synthesis of new 3-phenylquinazolin-4(3H)-one derivatives as potent antibac-
terial agents effective against methicillin- and vancomycin-resistantStaphylo-
coccus aureus(MRSA and VRSA)
Srikanth Gatadi, Jitendra Gour, Grace Kaul, Manjulika Shukla, Arunava
Dasgupta, Ravikumar Akunuri, Richa Tripathi, Y.V. Madhavi, Sidharth Chopra,
Srinivas Nanduri
PII:
S0045-2068(18)30590-X
https://doi.org/10.1016/j.bioorg.2018.08.012
YBIOO 2469
DOI:
Reference:
Bioorganic Chemistry
To appear in:
Received Date:
Revised Date:
Accepted Date:
15 June 2018
14 July 2018
8 August 2018
Please cite this article as: S. Gatadi, J. Gour, G. Kaul, M. Shukla, A. Dasgupta, R. Akunuri, R. Tripathi, Y.V.
Madhavi, S. Chopra, S. Nanduri, Synthesis of new 3-phenylquinazolin-4(3H)-one derivatives as potent antibacterial
agents effective against methicillin- and vancomycin-resistantStaphylococcus aureus(MRSA and VRSA),
Bioorganic Chemistry (2018), doi: https://doi.org/10.1016/j.bioorg.2018.08.012
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Synthesis of new 3-phenylquinazolin-4(3H)-one derivatives as potent antibacterial agents
effective against methicillin- and vancomycin-resistant Staphylococcus aureus (MRSA and
VRSA)
Srikanth Gatadia, Jitendra Goura, Grace Kaul,b Manjulika Shukla,b Arunava Dasgupta,b
Ravikumar Akunuria, Richa Tripathia, Y.V. Madhavia, Sidharth Choprab,*
Srinivas Nanduria,*
aDepartment of Medicinal Chemistry, National Institute of Pharmaceutical Education and
Research (NIPER), Hyderabad 500 037, India
bDivision of Microbiology, CSIR-Central Drug Research Institute, Sitapur Road, Sector 10,
Janakipuram Extension, Lucknow-226031, Uttar Pradesh, India
Abstract:- Occurrence of infections due to the drug resistant Staphylococcus aureus is on rise
necessitating the need for rapid development of new antibacterial agents. In our present work, a
series of new 3-phenylquinazolin-4(3H)-one derivatives were designed, synthesized and
evaluated for their antibacterial activity against ESKAP (E. coli, S. aureus, K. pneumoniae, A.
baumannii, P. aeroginosa) pathogen panel and pathogenic mycobacterial strains. The study
revealed that compounds 4a, 4c, 4e, 4f, 4g, 4i, 4o and 4p exhibited selective and potent
inhibitory activity against Staphylococcus aureus with MIC values in the range of 0.125–8
µg/mL. Further, the compounds 4c, 4e and 4g were found to be non toxic to Vero cells (CC50 =
>10–>100 µg/mL) and exhibited favourable selectivity index (SI = 40–>200 µg/mL). The
compounds 4c, 4e and 4g also showed potent inhibitory activity against various MDR-S. aureus
including VRSA. The promising results obtained indicated the potential use of the above series
of compounds as promising antibacterial agents for the treatment of multidrug resistant
Staphylococcus aureus infections.
Keywords: Quinazolinones, minimum inhibitory concentration, multidrug resistant
Staphylococcus aureus (MDR-S. aureus), Vero cells.

Corresponding author. Dr. Srinivas Nanduri, Tel: +91-40-23073740; Fax: +91-40-23073751;

E-mail: nandurisrini92@gmail.com; Dr. Sidharth Chopra, Tel.: +91-522-2771940; Fax: +91-
522-2771941; Email: skchopra007@gmail.com
1

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1.0 Introduction
Increase in antibacterial resistance has become a serious health threat universally [1]. Rise in
infections caused by drug resistant Staphylococcus aureus in recent years has created a critical
need for the discovery and development of new classes of antibacterial agents for treating
infections in both nosocomial and community setting [2]. Methicillin-resistant Staphylococcus
aureus (MRSA) [3] and Vancomycin-resistant variants of MRSA have emerged as the most
recalcitrant bacterial strains for the available chemotherapeutic treatment. These strains
developed resistance to the available therapeutics like methicillin, vancomycin [4], daptomycin
[5], linezolid [6], dalbavancin [7], oritavancin [8], ceftaroline, ceftobiprole [9], and carbapenems,
thus necessitating the need for search for new antibacterial agents with potential to overcome the
resistance mechanisms.
In the exploration of various chemical classes for developing new antibacterial agents, we found
quinazolinone to be a promising scaffold which could be considered as a privileged structure by
virtue of its wide range of biological properties such as anti-inflammatory, anti-HIV, anticancer,
antibacterial, antifungal, anticonvulsant, and analgesic activities [10-16] and also scope to
develop structural diversity. Potent anti-bacterial activity of various quinazolinone derivatives
have been reported by several groups. Zayed et al [17] reported the antibacterial properties of 2-
methylquinazolinone compounds A (Figure 1). Saravanan et al [18] and Xioping et al [19]
reported the antimicrobial potential of quinazolinone compounds B & C respectively. Jadhavar
et al [20] also reported 2-styryl quinazolinones D (Figure 1) as potent antimycobacterial agents.
K.R. Desai et al [21] reported 2-styryl-3,4-dihydroquinazolin-6-yl)-1,3,5-triazin-2-yl)-3-
methylurea derivatives E as potent antibacterial agents (Figure 1). Recently Bouley et al
reported 4(3H)-quinazolinones as potent antibacterial agents with good oral bioavailability [22].
In the current work, we designed and synthesized a number of new 3-phenylquinazolin-4(3H)-
one derivatives and evaluated for their antibacterial and antimycobacterial activity.
<Insert Figure 1 here>
2.0 Results and Discussion
2.1 Chemistry
2

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The new 3-phenylquinazolin-4(3H)-one derivatives 3a-3b and 4a-4r were prepared by the
synthetic procedures outlined in Scheme 1. Suitably substituted anthranilic acids 1 were
converted into 2 by refluxing in acetic anhydride. To the intermediate 2 dissolved in glacial
acetic acid, appropriately substituted aniline was added, and the reaction mixture was refluxed
for 4-5 h to give the intermediate 3. The intermediate 3 was treated with 4-chloro or 4-cyano
benzaldehyde in acetic acid under reflux conditions (16–18 h) to afford the final compounds
(Table 1) in moderate to excellent yields. The structures of the synthesized compounds were
1
confirmed by H NMR, 13C NMR (given in supplementary data, 2) and HRMS (ESI)
spectroscopic techniques.
The structure of compound 4a could be easily inferred since there was a clear singlet of –OH
group at 9.95 ppm and the compounds 4c and 4f showed a clear triplet and a singlet of alkyne –
C≡H at 3.55 and 4.34 ppm respectively in their 1H NMR spectra. Besides, compound 4c showed
a doublet of –OCH2– group at 4.88 ppm. All the newly synthesized compounds showed, similar
characteristic peaks of trans alkene protons –CH=CH– with two doublets in the range of 6.37–
6.56 ppm (up field) and 7.90–8.03 ppm (downfield) with coupling constant J = ~15.6 Hz.
13
Examination of C NMR of compound 4c revealed the characteristic peak of carbonyl group
and nitrile group at 161.5 ppm and 119.0 ppm respectively. The trans alkene –CH=CH– carbons
of compound 4c showed sharp peaks at 116.3, 139.8 ppm. All the other aromatic and aliphatic
1
carbons of synthesized compounds were found to be in the range of 159.1–17.5 ppm. The H
NMR and 13C NMR spectra of all the other newly synthesized compounds (Table 1) were found
to exhibit a similar pattern like 4a, 4c, and 4f. The HRMS (ESI) of all the newly synthesized
compounds showed the characteristic [M+H]+ corresponding to their molecular formula.
<Insert Scheme 1 here>
<Insert Table 1 here>
2.2 In vitro antibacterial activity
2.2.1 Antibiotic Susceptibility Testing against ESKAP pathogen panel
All the newly synthesised 3-phenylquinazolin-4(3H)-one were evaluated for their antibacterial
activity against ESKAP pathogen panel. Minimum Inhibitory Concentration (MIC) was
calculated by performing antibiotic susceptibility testing on the newly synthesized compounds
with reference to standard CLSI guidelines [23]. The concentration of new 3-phenylquinazolin-
4(3H)-one compounds used is in the range of 0.03-64 μg/mL and Levofloxacin was used as a
3