Chemical reactivity and antimicrobial activity of N-substituted maleimides

Figures & data

Scheme 1.  Synthesis of neutral maleimides.

Table 1.  Lipophilicity and chemical reactivity of maleimides.

Compound	logP	k (M^−1 s^−1)
		pH 5.0	pH 7.0
1	0.29	80.3	404
2	0.87	3.23	40.9
3	1.58	4.74	69.8
4	1.35	47.2	202
5	1.88	39.7	195
6	2.26	58.3	221
7	2.67	85.0	364
8	1.91	1.11	14.1
9	1.13	1.82	17.1
10	1.11	0.82	10.0
11	−0.11	2.28	25.6
12	−0.46	2.11	16.7

Data include calculated 1-octanol/water partition coefficients (logP) and determined apparent second order velocity constants (k) for the reaction of maleimides with ACME.

Scheme 2.  Reaction of maleimides with ACME.

Table 2.  Antibacterial and antifungal in vitro activity of maleimide compounds and reference antifungals.

Compd.	R	MIC (μg ml^−1)
		C. a.	C. g.	C. t.	S. c.	E. c.	B. s.	S. a.
1	Ethyl	2	4	1	2	8	1	2
2	tert-Butyl	2	4	0.5	2	32	2	2
3	Cyclohexyl	1	1	1	1	64	16	32
4	Benzyl	2	2	1	2	32	2	2
5	2,6-Dimethylphenyl	2	4	2	2	64	8	8
6	2,4,6-Trimethylphenyl	2	1	0.5	1	64	4	2
7	2-tert-Butylphenyl	4	2	1	2	64	16	8
8	4-Bromophenyl	1	2	2	1	128	64	128
9	4-Methoxyphenyl	2	4	2	2	128	64	128
10	4-Nitrophenyl	2	2	1	1	128	64	128
11	N-dimethylaminoethyl	128	128	64	64	128	128	128
12	N-morpholinoethyl	128	128	64	64	128	128	128
	Nystatin	2	2	2	2	NT	NT	NT
	Fluconazole	1	2	2	1	NT	NT	NT

C. a., Candida albicans; C. g., Candida glabrata; C. t., Candida tropicalis; S. c., Saccharomyces cerevisiae; E. c., Escherichia coli; B. s., Bacillus subtilis; S. a., Staphylococcus aureus; NT, not tested.

Figure 1.  Visualisation of the effect of maleimides on morphology of Candida albicans yeast cells. (A–C) Cells stained for chitin with Calcofluor White. (A) Control, (B) cells treated with 1, 5 µg ml⁻¹; (C) cells treated with 7, 5 µg ml⁻¹. (D–F) Cells stained for glucan with aniline blue. (D) Control, (E) cells treated with 1, 5 µg ml⁻¹; (F) cells treated with 7, 5 µg ml⁻¹.

Figure 2.  In vitro inhibition of β(1→3)-glucan synthase activity by maleimides. The assay was performed using the microtitre-based fluorescence method. Values are the means of three independent experiments. Bars represent SD.