Synthesis and evaluation of the antimicrobial activity of novel quinazolinones

Figures & data

Scheme 1 Structure of quinazolinones.

Table I.  Reporter strains used for the anti-quorum sensing (–QS) tests.

Strain	Description	Reference
Agrobacterium tumefasciens NTLR4	pTI cured, traG::lacZ fusion, Gm^r	Cha et al., 1998 [17]
Chromobacterium violaceum CV017	Smr mini-Tn5 Hgr, violacein overproducer	Winson et al., 1994 [22]
Pseudomonas aeruginosa PA01 lasB-gfp(ASV)	lasB::gfp(ASV) fusion,Gm^r	Hentzer et al., 2002 [5]

Scheme 2 Synthesis of 1a from methyl anthranilate.

Scheme 3 Conditions: PTSA (1.1 equiv.), THF, MW, 150°C, 5 min (for 2a–e); NMP, MW, 220°C, 15 min (for 2f).

Table II.  Effects of the quinazolinone derivatives synthesised on growth and quorum sensing of C. violaceum (CV017), A. tumefaciens (NTLR4), and P. aeruginosa [PA01 lasB-gfp(ASV)]. The symbol + indicates the presence of an inhibition halo (see Material & Methods).

	Quinazoline Derivatives
	1a	2a	2b	2c	2d	2e	2f
CV017 growth	+	+	+	+	+	0	0
CV017 quorum sensing	+	+	+	+	+	0	0
NTLR4 growth	0	0	+	0	0	0	0
NTLR4 quorum sensing	0	0	+	0	0	0	0
PA01 growth	0	0	0	0	0	0	0
PA01 quorum sensing	0	0	0	0	0	0	0

Table III.  Effect of the 2b derivative on growth of several Gram-positive and Gram-negative bacteria.

Strains	Origin	Inhibition
Gram-positive
Bacillus cereus ^(*)	Our laboratory	0
Bacillus megatherium	CIP 6620T	0
Bacillus subtilis ^(*)	CIP 5262	0
Enterococcus faecalis	CIP 103214	0
Lactobacillus acidophilus ^(*)	Our laboratory	0
Micrococcus luteus ^(*)	ATCC 4698	0
Staphylococcus aureus ^(*)	ATCC 25923	0
Staphylococcus saprophyticus	Our laboratory	0
Gram-negative
Citrobacter freundii	Our laboratory	0
Enterobacter cloacae	Clinical	0
Escherichia coli	Our laboratory	++
Escherichia coli K12	ATCC 23716	+
Hafnia alvei	CIP 5731T	0
Klebsiella pneumoniae subspecies. Pneumoniae	CIP 53153	0
Proteus mirabilis	Our laboratory	0
Salmonella anatum	CIP 5630	0
Salmonella enterica subspecies. Enterica serotype wien ^(*)	CIP 8122	0
Salmonella enteritidis	Clinical	0
Serratia marcescens	CIP 6755	0
Shigella flexeneri	CIP 5236	0
Shigella sonnei	CIP 5255	++

^(*) Incubated at 30°C instead of 37°C. The symbol +(+) indicates the presence of an inhibition halo (see Material & Methods)

Cha C, Gao P, Chen YC, Shaw PD, Farrand SK. Production of acyl-homoserine lactone quorum-sensing signals by gram-negative plant-associated bacteria. MPMI 1998; 11: 1119–1129

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Winson MK, Bainton NJ, Chhabra SR, Bycroft BW, Salmond GPC, Williams P, Stewart GSAB. Control of N-acyl-l-homoserine lactone-regulated expression of multiple phenotypes in Chromobacterium violaceum, Abstracts of the 94th Annual Meeting of the American Society for Microbiology, Washington, D.C: American Society for Microbiology. 1994;Abstr. H-71; p. 212.

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Hentzer M, Wu H, Andersen JB, Riedel K, Rasmussen TB, Bagge N, Kumar N, Schembri MA, Song Z, Kristoffersen P, Manefield M, Costerton JW, Molin S, Eberl L, Steinberg P, Kjelleberg S, Høiby N, Givskov M. Attenuation of Pseudomonas aeruginosa virulence by quorum sensing inhibitors. EMBO J 2003; 22: 3803–3815

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