Synthesis and structure-activity relationships of novel 5-(hydroxamic acid)methyl oxazolidinone derivatives as 5-lipoxygenase inhibitors

Figures & data

Figure 1. Chemical structures of 5-lipoxygenase inhibitors and antibacterial agents.

Scheme 1. Synthetic route for the oxazolidinone hydroxamic acid derivatives. (i) DCM/TFA/0 °C r.t.; (ii) DCM/TEA/acetic anhydride/0 °C r.t.; (iii) DMF/NaH/tert-Butyl-N-(tertbutoxycarbonyl)carbamate/0 °C r.t. or 0–60 °C.; (iv) DCM/TFA/0 °C r.t.; (v) DCM/TEA/RCOCl or (RCO)₂O/0 °C r.t.; (vi) MeOH/THF/NaOH/0 °C.

Table 1. Clog P values and in vitro inhibitory activity of oxazolidinone hydroxamates.

Compd. code	Structure of compounds	Clog P values	Human whole blood LTB4 IC50 (CI)* μM	Human monocyte LTC4 IC50 (CI)* μM	Mouse mast cell LTC4 IC50 (CI)* μM	Direct inhibition of 5-LO activity. IC50 (CI)* μM
PH-23		0.7148	3.3 (1.2–9.2)	18.7 (8.9–39.4)	20.7 (13.7–31.2)	>30
PH-199		1.2438	1.4 (0.9–2.3)	8.2 (5.4–12.6)	6.3 (3.1–12.6)	11.8 (0.8–37.8)
PH-204		2.9859	10.7 (5.3–21.8)	>50	21.8 (10.9–43.5)	>30
PH-205		1.5528	2.3 (1.2–4.4)	14.1 (10.0–19.8)	13.8 (8.5–22.6)	3.9 (1.4–11.8)
PH-206		2.4779	7.9 (3.5–17.8)	>50	37.3 (16.8–82.9)	>30
PH-211		1.2988	1.3 (0.8–1.9)	7.5 (5.7–9.8)	8.7 (6.7–11.3)	3.5 (0.6–12.3)
PH-237		4.2239	>50	>50	>50	>30
PH-239		2.1718	3.5 (1.9–6.3)	8.0 (5.8–11.0)	3.1 (1.9–5.2)	4.7 (1.6–14.2)
PH-241		4.3018	2.2 (1.4–3.5)	3.2 (2.0–5.1)	2.8 (2.3–3.4)	3.3 (1.8–6.3)
PH-245		1.6278	3.4 (1.9–6.1)	ND	ND	ND
PH-244		2.1868	5.5 (3.5–8.5)	ND	ND	ND
PH-246		5.5419	1.5 (1.1–2.2)	7.1 (4.1–12.4)	3.3 (2.5–4.3)	21.6 (6.9–62.5)
PH-247		2.8308	2.3 (1.6–3.4)	2.5 (1.8–3.4)	2.9 (2.1–4.0)	3.4 (1.4–5.7)
PH-249		3.3598	0.7 (0.3–1.6)	0.9 (0.7–1.2)	1.3 (1.0–1.8)	1.9 (1.3–2.9)
PH-251		3.8888	1.9 (1.2–3.0)	2.4 (1.8–3.4)	0.2 (0.1–0.5)	1.6 (0.6–2.8)
PH-201		0.2758	38.0 (13.8–70.5)	>50	>50	>30
PH-212		1.1338	>50	32.7 (16.8–63.4)	>50	14.8 (3.2–38.5)
PH-208		2.0589	38.2 (7.5–84.5)	>50	>50	>30
PH-213		0.8739	22.5 (3.2–77.4)	23.3 (11.3–48.0)	>50	7.8 (1.0–38.7)
Zileuton		2.4830	0.7 (0.5–0.9)	0.5 (0.3–0.6)	0.4 (0.2–0.6)	0.8 (0.2–3.2)

*CI = 95% Confidence Interval; ND = not determined.

Figure 2. Effect of compound PH-249 on the viability of isolated human monocytes. Cells were exposed to the test compound or triton-X, as positive control, for 3 h or 24 h, and viability was assessed by the MTT method, n = 3.

Figure 3. In vivo inhibitory effect of compound PH-249 on zymosan-induced peritoneal inflammation in mice. Animals were pre-treated subcutaneously with PH-249, zileuton or vehicle, 30 min before induction of peritoneal inflammation with intraperitoneal injection of 0.2 ml activated zymosan (2 mg/ml). Peritoneal lavage fluids obtained after 2 h were analysed for total LTC₄ content (A) and total cellular content (B). Values are means ± sem, n = 6–7. ###p < 0.001 with respect to PBS plus vehicle; ***p < 0.001; **p < 0.01, with respect to zymosan plus vehicle.