Synthesis and in vitro antifungal evaluation of 2-(2,4-difluorophenyl)-1-[(1H-indol-3-ylmethyl)methylamino]-3-(1H-1,2,4-triazol-1-yl)propan-2-ols

Figures & data

Figure 1.  Structures of some triazoles used in clinic.

Scheme 1.  General structures of synthesized compounds.

Table 1.  In vitro antifungal activity of indol-3-ylmethylamino derivatives.

Compounds	R1	R5	R6	MIC80 values (ng/mL)^a
				Candida albicans CA98001	Aspergillus fumigatus AF98003
5a	Boc	O-CH2-O		> 541.0	na
5b	Boc	H	H	373.0 (± 10.0)	na
5c	Boc	H	F	381.0 (± 51.0)	na
6a	H	O-CH2-O		264.0 (± 17.0)	na
6b	H	H	H	258.0 (± 4.00)	na
6c	H	H	F	199.0 (± 29.0)	na
Fluconazole				190.0 (± 6.0)	—
Itraconazole				—	420.0 (± 40.0)

MIC, minimum inhibitory concentration; na, not active.

^aValues are means of triplicate, standard deviation is given in parentheses (MIC₈₀ > 30000.0 ng/mL).

Scheme 2.  Preparation of targeted compounds 5a-c and 6a-c. Reagents and conditions: (a) (i) POCl₃, DMF, 0°C to 35°C, (ii) NaOH, 100°C; (b) Boc₂O, DMAP, CH₃CN, room temperature, 2 h; (c) 3, NaBH₃CN, AcOH/MeOH 2% v/v, room temperature, 24 h; (d) ZnBr₂, CH₂Cl₂, room temperature, 24 h.

Table 2.  Effect of compound 5c on the sterol composition of Candida albicans CA98001.

Sterols	5c (µg/mL)
	control	0.125	0.25	0.5
Lanosterol	1.8	28.4	42.4	44.6
Eburicol		27.9	35.9	39.0
Zymosterol	traces
Fecosterol	11.2
14-Methylfecosterol		0.5	1.3	1.5
Episterol	1.4
14-Methylepisterol		2.7	5.2	7.5
14-Methyl-3,6-diol			0.1	0.1
Ergosterol	85.6	40.5	15.1	7.3

Sterols of interest were identified by their mass spectrum. The area under curve (AUC) of each peak was used to calculate a ratio: sterol AUC/sum of sterols AUC.

Figure 2.  Proposed binding solution of compound (S)-6b (magenta) in the supposed active site pocket (channel 2) of CYP51-Candida albicans. Hip377 is the protonated form of histidine residue.