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Organic & Biomolecular Chemistry
Page 6 of 7
DOI: 10.1039/C8OB00627J
ARTICLE
Journal Name
Table 4. In vitro antifungal activity screening of the synthesized compounds 10a-j as
1
L. L. Ling, T. Schneider, A. J. Peoples, A. L. Spoering, I. Engels,
B. P. Conlon, A. Mueller, T. F. Schäberle, D. E. Hughes and S.
Epstein, Nature, 2015, 517, 455-459.
inhibition Zones (IZ) in millimetres and minimum inhibitory concentrations (MICs) in μg
−
mL
1
.
2
3
R. J. Fair and Y. Tor, Persp. Med. Chem. 2014, 6, 25.
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D. J. Payne, M. N. Gwynn, D. J. Holmes and D. L. Pompliano,
NT: Not tested, Selectivity indices between brackets, I.Z: inhibition diameter
zones expressed in millimetres, MIC: Minimum inhibitory concentration
expressed in μg/mL. The screening organisms: Mould: Aspergillus fumigatus
4
5
6
(
RCMB 02568), Yeast: Candida albicans (RCMB 05036).
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7
8
9
Conclusions
The synthesis and antimicrobial evaluation of the
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78.
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functionalized
5,7-disubstituted
pyrido[2,3-d]pyrimidine
1
1
derivatives were performed with a microwave assisted
1
synthesis of 10a optimized to produce better yields in shorter
times. Using DMF as the solvent and with 10 mol% of I under
2
microwave radiation for 30 minutes gave the best yield 59% 12 J. M. Blair, M. A. Webber, A. J. Baylay, D. O. Ogbolu and L. J.
Piddock, Nat. Rev. Microbiol. 2015, 13, 42-51.
yield. The compounds were tested in vitro for their
1
3 P. N. Markham and A. A. Neyfakh, Curr. Opini. Microbiol.
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5 K. K. Harris, A. Fay, H.-G. Yan, P. Kunwar, N. D. Socci, N.
Pottabathini, R. R. Juventhala, H. Djaballah and M. S.
antibacterial activity and moderate to excellent activity was
2
4
observed for compounds 10a and 10d-i with MIC = 0.49–7.81
1
1
−1
μg mL (Figure 4). Compounds 10d-e and 10h displayed
−1
potent inhibition of MRSA (MIC =1.95–3.90 μg mL ). Among
the tested compounds, derivatives 10d 10g and 10i exhibited
Glickman, ACS Chem. Biol. 2014, 9, 2572-2583.
16 S. B. Singh, J. W. Phillips and J. Wang, Curr. Opin. Drug
Discov. Develop. 2007, 10, 160-166.
,
−1
the best anti-aspergillus activity (MIC = 1.95 μg mL ) and
compound 10d represent the best obtained against Candia
1
7 P. Fernandes and E. Martens, Biochem. Pharmacol. 2017,
33, 152-163.
excellent in silico pharmacokinetic properties calculation. The 18 A. L. Demain, Chem. Biol. 2011, 18, 939.
−1
albicans (MIC = 1.95 μg mL ). All the compounds showed
1
1
9 WHO report, Antibacterial agents under clinical
development, 2017, WHO/EMP/IAU/2017.11.
0 H. Y. Kim, J. A. Wiles, Q. Wang, G. C. Pais, E. Lucien, A.
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Deshpande, M. J. Pucci and B. J. Bradbury, J. Med. Chem.
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best compounds 10d and 10h will be subjected to a further
cycle of derivatization to explore more about the structure
antimicrobial relationship of this scaffold and to eventually
develop the best derivatives into potentially novel and safe
antimicrobial agents.
2
2
1 Y. Qian, G.-Y. Ma, Y. Yang, K. Cheng, Q.-Z. Zheng, W.-J. Mao,
L. Shi, J. Zhao and H.-L. Zhu, Bioorg. Med. Chem. 2010, 18
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,
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2
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2, 139-170.
,
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4 J. Quiroga, B. Insuasty, A. Sanchez, M. Nogueras and H.
Meier, J. Het. Chem. 1992, 29, 1045-1048.
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,
3
2
6 M. Fares, R. A. Eladwy, A. Nocentini, S. R. A. El Hadi, H. A.
Ghabbour, A. Abdel-Megeed, W. M. Eldehna, H. A. Abdel-
Aziz and C. T. Supuran, Bioorg. Med. Chem. 2017.
Figure 4. SAR of all the compounds against the tested bacterial and fungi.
2
2
7 C. A. Lipinski, Adv. Drug Deliv. Rev. 2016, 101, 34-41.
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Conflicts of interest
2
9 M. J. Ahsan, J. G. Samy, H. Khalilullah, M. S. Nomani, P.
Saraswat, R. Gaur and A. Singh, Bioorg. Med. Chem. Lett.
There are no conflicts to declare.
2
011, 21, 7246-7250.
3
3
3
0 D. F. Veber, S. R. Johnson, H.-Y. Cheng, B. R. Smith, K. W.
Ward and K. D. Kopple, J. Med. Chem. 2002, 45, 2615-2623.
1 N. C. Desai, G. M. Kotadiya and A. R. Trivedi, Bioorg. Med.
Chem. Lett. 2014, 24, 3126-3130.
Acknowledgements
MF thanks UOW for the University Postgraduate Award and
International Postgraduate Tuition Award scholarships. Patrick
McCosker is highly appreciated for his efforts revising the first
draft of the Manuscript.
References
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