Repurposing strategies on pyridazinone-based series by pharmacophore- and structure-driven screening

Figures & data

Table 1. Structures of analogues 1–9.

Compd	R1	R2	R3	R4
1a	C6H4-OCH3 (p)	C6H4-O(CH2)3CH3 (p)	OCH3	H
1b	C6H4-OCH3 (m)	C6H4-O(CH2)3CH3 (p)	OCH3	H
2a	C6H4-OCH3 (p)	Cl	C6H4-O(CH2)3CH3 (p)	H
2b	C6H4-OCH3 (m)	Cl	C6H4-O(CH2)3CH3 (p)	H
3a	CO-NH-C6H4-F (p)	H	H	CH3
3b	CO-NH-C6H4-3,4-methlyenedioxy	H	H	CH3
4a	C6H5	NO2	COCH3	C6H5
4b	C6H4-CN (m)	NO2	COCH3	C6H5
5a	C6H5	Cl	COCH3	C6H5
5b	C6H4-CN (m)	Cl	COCH3	C6H5
6a	C6H5	Br	COCH3	C6H5
6b	C6H4-CN (m)	Br	COCH3	C6H5
7	C6H5	COCH3	NH2	C6H5
8	CO-NH-C6H4-Br (p)	CH2-C6H4-(m)CO-NH-C6H4-Br (p)	H	CH3
9	CO-NH-C6H4-Br (p)	N-(C6H4-OCH3)2 (p)	H	CH3

Table 2. Structures of analogues 10–12.

Compd	R	R1
10a	Ph
11	Ph
10b	Ph
10c	Ph
12	Ph
10d	Ph
10e	Ph
10f	CH3
10g	CH3

Table 3. Structures of analogues 13–21.

Compd	R	R1	R2	R3
13a	Ph	Ph	NH2	CONHC3H7
13c	Ph	Ph	NH2	COOcC6H11
13b	Ph	Ph	NH2
17c	4-F-Ph	Ph	NHCOiC3H7	H
18	Ph	CH2Ph	NH2	CONHtC4H9
19	Ph	H	NH2	COOCH2Ph
20	Ph	CH2Ph	NH2	COOCH2Ph
14a	Ph	CH3	NH2	COCH = CHPh
15a	Ph	CH3	NH2	COCH2CH2Ph
14b	Ph	C3H7	NH2	COCH = CHPh
15b	Ph	C3H7	NH2	COCH2CH2Ph
14c	4-F-Ph	CH3	NH2	COCH = CHPh
15g	Ph	C2H5	NH2
15i	Ph	C3H7	NH2
15h	Ph	C3H7	NH2
15l	Ph	Ph	NH2
15f	Ph	Ph	NH2	COCH2CH2Ph
17b	Ph	Ph	NHCOiC3H7	H
17a	Ph	Ph	NHCOC4H9	H
15e	cC6H11	C3H7	NH2	COCH2CH2Ph
15c	Ph	C4H9	NH2	COCH2CH2Ph
15d	Ph	iC3H7	NH2	COCH2CH2Ph
16b	4-F-Ph	Ph	NH2	H
21a	Ph	CH2CONHnC3H7	H	Ph
21b	Ph	CH2CONHiC3H7	H	Ph
21c	Ph	CH2CONHcC5H9	H	Ph
21d	Ph	CH2CONHnC3H7	Ph	H
21e	Ph	CH2CONHiC3H7	Ph	H

Figure 1. Binding poses of the full molecular series (dark pink) in the active site of 7AAT. The cofactor pyridoxal phosphate is reported in yellow.

Table 4. Docking results for 7AAT.

Lig.	LE	BE[kcal/mol]
1a	0.2162	6.271
2a	0.2274	6.368
3a	0.3363	6.390
5a	0.2813	6.752
7	0.2791	6.699
8	0.2203	7.931
9	0.2156	7.760
10b	0.2583	7.233
10g	0.2792	6.421
11	0.2887	6.930
13a	0.2501	6.503
15a	0.2536	6.339
15f	0.2280	6.840
17a	0.2613	6.795
20	0.2311	7.164
21a	0.2718	7.068
21d	0.2539	6.602
hesperetin	0.3054	6.718
hesperidin	0.1831	7.875

Figure 2. Binding of analogue 3a after 50 ns of MD.

Figure 3. Up, binding energy (BE) of analogue 3a during the MD simulation. Down, root-mean-square deviation of atomic positions (RMSD) of 3a during the MD simulation. Time is expressed in ps.

Figure 4. BOILED-Egg plot. Points located in the BOILED-Egg’s yellow represent the analogues predicted to passively permeate the BBB. Points in the egg white are relative to the analogues predicted to face passive absorption by the gastrointestinal tract. Red dots indicate that the molecules are predicted not to be affected by P-glycoprotein mediated extrusion from the CNS.