Synthesis and bioactivities of halogen bearing phenolic chalcones and their corresponding bis Mannich bases

Figures & data

Scheme 1. General synthesis of the chalcones and bis Mannich bases. Reagents and conditions: (i) NaOH (10%), EtOH, rt, 24h. (ii) Acetonitrile, paraformaldehyde, amine, 45 min, 120 °C, 200 Watt, 13 barr. R=F (1), Cl (2), Br (3), X= –CH2 (1a, 2a, 3a), –O– (1b, 2b, 3b), –NCH3 (1c, 2c, 3c).

Table 1. The cytotoxicity results of the compounds.

CC50 (μM)
	Tumor cell lines							Nonmalignant cells
	HSC-2		HSC-3		HSC-4		Ave	Ave	HGF	HPLF	Ave
Compound	CC50	SI	CC50	SI	CC50	SI	CC50	SI	CC50	CC50	CC50	PSE	log P
1	5.2	9.2	9.7	4.9	5.8	8.2	6.9	7.5	51.2	44.3	47.8	108.7	3.35
2	2.8	14.5	5.0	8.1	3.1	13.1	3.6	11.9	40.2	40.7	40.5	330.6	3.75
3	3.6	11.2	6.8	5.9	6.6	6.1	5.7	7.7	40.5	39.8	40.2	135.1	4.02
1a	5.3	7.4	7.1	5.5	18.4	2.1	10.3	5.0	39.2	39.0	39.1	48.5	4.70
1b	7.2	7.5	6.7	8.0	11.0	4.9	8.3	6.8	39.6	68.1	53.9	81.9	2.44
1c	8.6	2.2	4.6	4.2	3.1	6.2	5.4	4.2	18.4	19.9	19.2	77.8	2.75
2a	<1.6	11.2	3.0	5.9	<1.6	11.1	<2	9.4	15.2	20.4	17.8	470.0	5.10
2b	<1.6	12.5	1.9	10.5	<1.6	12.5	<1.7	11.8	18.3	21.7	20.0	694.1	2.84
2c	5.5	2.6	3.8	3.7	2.2	6.4	3.8	4.2	6.3	21.8	14.1	110.5	3.15
3a	2.8	7.4	<1.6	12.9	2.5	8.2	2.3	9.5	17.9	23.2	20.6	413.0	5.37
3b	<1.6	12.3	<1.6	12.3	2.0	9.8	1.7	11.5	18.5	20.7	19.6	676.5	3.11
3c	<1.6	5.4	<1.6	5.4	2.7	3.2	2	4.7	8.0	9.1	8.6	235.0	3.42
Average	3.9	8.4	4.4	7.1	4.9	7.4	4.4	7.6	25.5	29.8	27.7	271.2	–
Melphalan	8.5	18.8	5.6	28.5	11.9	13.4	8.7	20.2	140	179	159.5	348.3	–
5-FU	15.2	65.8	41.7	24.0	133.3	7.5	63.4	>32.4	>1000	>1000	>1000	>51.2	–

The CC₅₀ value refers to the concentration of compounds in micromoles which kill 50% of the cells. The SI value indicates the selective index, i.e. the quotient of the averaged CC₅₀ value for nonmalignant cells (HGF and HPLF) divided by CC₅₀ value for a specific tumor cell line (either HSC-2, HSC-3 or HSC-4). The PSE value indicates the potency selectivity expression which is the product of the averaged CC₅₀ value and the averaged SI value for all three cell lines. log P values were calculated by Chem Draw Ultra 12.0 Software (Perkin Elmer, Waltham, MA).

Table 2. Inhibitory effects of the compounds synthesized on hCAI and II isoenzymes.

	Inhibition %
Compound No.	hCA I	hCA II	Selectivity for hCA I
1	34	17	2.0
2	30	11	2.7
3	43	9	4.8
1a	31	6	5.2
1b	26	16	1.6
1c	26	16	1.6
2a	29	19	1.5
2b	30	20	1.5
2c	28	13	2.2
3a	28	25	1.1
3b	29	17	1.7
3c	25	17	1.5
AZA	86	96	0.9

Acetazolamide (AZA) was used as a reference compound. Inhibitor concentration was 10⁻⁵ M for all compounds.