New quinoxalinone inhibitors targeting secreted phospholipase A2 and α-glucosidase

Figures & data

Scheme 1. 2,3-Substituted-quinoxaline and 1,4-substituted-[1,2,4]triazolo[4,3-a]quinoxalin derivatives.

Figure 1. Chemical structures of series 3, series 4, and quercetin.

Table 1. Inhibitory activity of the title compounds against isoforms of sPLA2 expressed as IC₅₀ (µM)±standard deviation.

	IC50 (µM) Against Phospholipase
Compound	pG-IB	hG-IIA	hG-V	hG-X	hG-XIIA
3a	9.31 ± 0.36	2.48 ± 0.28	1.46 ± 0.47	1.26 ± 0.05	3.04 ± 0.67
3b	10.72 ± 0.67	5.36 ± 0.73	1.12 ± 0.31	2.54 ± 0.42	2.28 ± 0.08
3c	13.33 ± 0.50	3.71 ± 0.27	9.45 ± 0.13	12.48 ± 0.87	6.75 ± 0.17
3d	13.50 ± 1.02	4.50 ± 0.33	5.70 ± 0.27	3.00 ± 0.63	10.50 ± 1.74
3e	10.72 ± 0.92	2.81 ± 0.33	6.28 ± 0.40	4.43 ± 1.03	3.81 ± 0.99
3f	12.40 ± 0.03	1.90 ± 0.30	1.22 ± 0.30	0.33 ± 0.06	0.84 ± 0.07
4a	14.19 ± 1.22	13.05 ± 0.05	11.30 ± 0.08	12.20 ± 0.47	13.25 ± 0.21
4b	13.62 ± 0.70	0.76 ± 0.01	1.53 ± 0.14	1.05 ± 0.08	2.58 ± 0.43
4c	14.78 ± 0.44	1.32 ± 0.16	1.05 ± 0.13	0.61 ± 0.03	0.91 ± 0.05
4d	14.49 ± 0.87	1.81 ± 0.04	3.04 ± 0.57	2.71 ± 0.07	1.41 ± 0.07
4e	16.77 ± 0.93	16.81 ± 0.41	18.63 ± 0.56	17.89 ± 0.94	18.63 ± 1.33
4f	15.97 ± 1.71	17.10 ± 0.41	15.80 ± 0.85	14.36 ± 0.52	15.77 ± 1.29
Oleanolic acid	10.40 ± 1.16	11.50 ± 0.76	16.42 ± 1.53	16.531 ± 1.38	13.14 ± 0.92

All experiments were performed in duplicate.

Table 2. Inhibitory activity of the title compounds against α-glucosidase and α-amylase expressed as IC₅₀ (µM) ± standard deviation.

	IC50 (µM)
Compound	α-Glucosidase	α-Amylase
3a	42.33 ± 3.38	428.93 ± 31.04
3b	14.11 ± 2.08	296.38 ± 26.81
3c	14.18 ± 1.51	300.38 ± 26.32
3d	22.51 ± 2.01	735.36 ± 52.52
3e	9.99 ± 0.18	395.84 ± 35.88
3f	13.93 ± 2.03	492.68 ± 46.20
4a	14.75 ± 2.12	638.56 ± 30.65
4b	22.99 ± 2.83	806.19 ± 91.97
4c	12.91 ± 1.69	1087.43 ± 74.08
4d	12.98 ± 1.20	431.81 ± 34.72
4e	36.52 ± 2.98	1330.65 ± 82
4f	24.29 ± 3.76	413.95 ± 52.68
Quercetin	9.93 ± 0.66	479.75 ± 18.86

All experiments were performed in duplicate.

Figure 2. Binding mode of 3f and 4c to hG-X sPLA2. (A) Compound 3f (magenta) and (C) compound 4c (orange) in the binding pocket of hG-X sPLA2 showing hydrogen bonds, calcium coordination (purple), and interacting residues. (B) Compound 3f (magenta) and (D) compound 4c (orange) in the binding pocket of hG-X sPLA2 showing a lipophilic potential surface of the pocket.

Figure 3. Binding mode of quercetin and 3e to α-glucosidase. (A) Quercetin (orange) and (C) compound 3e (magenta) in the binding pocket of α-glucosidase showing hydrogen bonds and interacting residues. (B) Quercetin (orange) and (D) compound 3e (magenta) in the binding pocket of α-glucosidase showing a lipophilic potential surface of the pocket.