New inhibitors of fungal 17β-hydroxysteroid dehydrogenase based on the [1,5]-benzodiazepine scaffold

Figures & data

Figure 1 Reactions catalyzed by 17β-hydroxysteroid dehydrogenases.

Scheme 1 Synthesis of the 1,5-benzodiazepine derivatives. a) CH₂Cl₂, 1 h, rt, then 2 h, 8–12°C; b) EtOH, AcCl, 0°C, then 20 h, reflux; c) nitrobenzoic acid, DPPA, Et₃N, DMF, 0°C, 5 h, then rt overnight; d) 37% HCl, 1 h, 40°C; e) RCOOH, DPPA, Et₃N, DMF, 0°C, 5 h, then rt, overnight; or benzoyl chloride, Et₃N, rt, overnight; or EDC, HOBt, Et₃N, DMF, − 5°C and then rt overnight; f) H₂O, NaOH, rt to 100°C, 2 h; g) cinnamic acid, DPPA, Et₃N, DMF, 0°C, 5 h, then rt overnight; h) 1-methylpiperazine, DMSO, toluene, 12 h, 125°C.

Table I.  1,5-Benzodiazepines as inhibitors of 17β-HSDcl.

Compound	Structure	IC50 (μM) oxidation	IC50 (μM) reduction	Compound	Structure	IC50 (μM) oxidation	IC50 (μM) reduction
4		NI^a	ND^b	7c		4	10
5		44	(17%)^c	7d		19	(27%)^c
6		10	28	8		(16%)^d	ND^b
7a		3	(50%)^c	9		43	(26%)^c
7b		40	ND^b	10		NI^a	ND^b

Results represent the means of three independent experiments. Standard deviations were within ± 10% of the means

^aNI – no inhibition observed

^bND – not done

^c% inhibition at 25 μM inhibitor

^d% inhibition at 100 μM inhibitor.

Figure 2 Superimposition of the computer modeling of compound 7c (in yellow) on the homology-built model of androstenedione and NADPH (both in green) bound to 17β-HSDcl. The highest ranked position of the inhibitor, as calculated by AutoDock 3.0, is presented. For clarity, only the surface of the protein is shown. (See colour online)