Anticancer and immunomodulatory activities of novel 1,8-naphthyridine derivatives

Figures & data

Figure 1.  Structure of reference compound.

Scheme 1.  Synthesis of tested compounds (22–59).

Scheme 2.  Synthesis of tested compounds (60–62).

Table 1.  Functionalised amino acid derivatives (3–18).

Compound No.	R1	Compound No.	R1
3		11
4		12
5		13
6		14
7		15
8		16
9		17
10		18	OC2H5

Table 2.  1,8-Naphthyridine derivatives (22–62).

C. No.	R1	X	C. No.	R1	X
22		H	43		7-Cl
23		H	44		7-Cl
24		H	45		7-Cl
25		H	46		7-Cl
26		H	47		6-F, 7-Cl
27		H	48		6-F, 7-Cl
28		H	49		6-F, 7-Cl
29		H	50		6-F, 7-Cl
30		H	51		6-F, 7-Cl
31		H	52		6-F, 7-Cl
32		H	53		6-F, 7-Cl
33		H	54		6-F, 7-Cl
34		H	55		6-F, 7-Cl
35		7-Cl	56		6-F, 7-Cl
36		7-Cl	57		6-F, 7-Cl
37		7-Cl	58		7-CH3
38		7-Cl	59	OCH2CH3	H
39		7-Cl	60		6-F, 7-pyrrolidine
40		7-Cl	61		6-F, 7-(3”-methylpiperidine)
41		7-Cl	62		6-F, 7-(3”-methylpiperidine)
42		7-Cl

Table 3.  In vitro cytotoxicity of 1,8-Naphthyridine derivatives (22–62).

S. No.	Compound No	IC50 (μM)
		PA-1 (Ovary)	DU-145(Prostate)	KB (Oral)	SW620 (Colon)	HBL100 (Breast)	A549 (Lung)	MIAPaCa (Pancreas)	K-562 (Leukemia)	NIH3T3 (Normal fibroblast)	CHO (Normal ovary)
1.	Doxorubicin	0.63	0.10	3.0	0.08	0.24	0.08	0.15	0.10	0.39	1.0
2.	25*	9.1	2.9	>10	>10	5.9	6.09	9.81	>10	4.79	NA
3.	29**	0.41	>10	3.7	1.4	4.1	3.06	>10	4.4	2.2	NA
4.	35	3.12	>10	>10	6.2	8.99	>10	8.26	6.34	9.76	NA
5.	36	1.19	>10	>10	4.62	4.7	9	8	9.4	5	8.7
6.	38	1.2	6.1	2.6	3.2	6.9	>10	>10	>10	NA	NA
7.	39	3.22	>10	>10	5.27	8.8	>10	8.2	>10	7.3	NA
8.	40	8.1	1.6	>10	>10	>10	>10	>10	>10	NA	NA
9.	41	7.6	>10	>10	>10	>10	>10	9.0	>10	NA	NA
10.	42	2.0	>10	>10	7.8	7.5	>10	7.3	>10	5.5	NA
10.	43	3.49	>10	>10	7.13	4	9	7.6	9.2	1.8	9.7
11.	44	3.33	>10	>10	>10	>10	>10	>10	>10	NA	NA
12.	45	3.95	>10	>10	>10	9.1	>10	9.1	>10	NA	NA
13.	46	2.54	8.56	9.6	4.11	6.60	>10	>10	8.60	5.86	NA
14.	47	3.55	>10	>10	2.79	>10	1.5	0.41	0.77	1.05	NA
15.	48	1.7	>10	7.2	4.4	5.0	6.8	3.8	9.9	3.4	2.2
16.	49	>10	>10	>10	>10	4.33	4.82	1.28	2.50	2.24	NA
17.	51	3.6	6.1	3.5	2.8	8.2	9.9	6.7	>10	7.9	2.4
18.	52	>10	>10	>10	>10	9.26	6.99	3.17	5.39	2.85	NA
19.	53	2.62	3.45	9.12	3.79	3.17	9.53	2.83	8.20	4.86	NA
20.	54	3.1	>10	>10	7.9	8.7	>10	3.3	8.4	4.1	NA
21.	55	4.7	>10	8.42	3.35	5.5	>10	8.1	7	7.6	NA
22.	56	3.1	3.6	7.9	6.3	3.20	2.58	3.50	4.16	5.31	NA
23.	57	>10	>10	>10	>10	5.22	7.49	1.78	4.99	1.69	NA

** Salt

* Precipitation observed during aqueous dilution

Cytotoxicity was assessed by MTT assay as described in Methods. Data shown are IC₅₀ of single independent experiments done in triplicates. If IC₅₀ was not achieved even at the highest concentration tested i.e. 10 μM, it was represented as NA.

Figure 2.  Anti-inflammatory activity as a measure of TNF-α downregulation.

Table 4.  IC₅₀ values for TNF-α modulation by selected 1,8-naphthyridine carboxamide derivatives. Molecules were subjected to screening over a multiple dose concentration range of 0.001 μg/mL to 10 μg /mL.

Molecule Numbers	IC50 value (μg)
41	<0.001
44	<0.001
45	0.31
48	<0.001
50	∼0.001
53	<0.001
54	1.1
55	0.59

Figure 3.  IL-1-β modulation of selected molecules. Dotted line shows IC₅₀ (concentration at which 50% inhibition occurs).

Figure 4.  MIP-1-α modulation of selected molecules. Dotted line shows IC₅₀ (concentration at which 50% inhibition occurs).

Figure 5.  IP-10 modulation of selected molecules. Dotted line shows IC₅₀ (concentration at which 50% inhibition occurs).

Table 5.  Downregulation of IP-10 levels to 50% (IC₅₀) of selected 1,8-naphthyridine derivatives. Molecules were subjected to screening over a multiple dose concentration range of 0.001 μg/mL to 10 μg/mL.

Molecule Number	IC50 value (μg)
55	0.62
45	0.32
54	1.1