Synthesis and cytotoxicity studies of novel benzhydrylpiperazine carboxamide and thioamide derivatives

Figures & data

Figure 1. Synthesis of compounds 5a–y and 6a–g.

Table 1. Structural and physical information of compounds 5a–y and 6a–g.

Sample	X	R1	R2	R3	Melting point (°C)	Yield (%)
5a*	O	- H	- H	sec-Butyl	198.4	68
5b	O	- H	- H	tert-Butyl	192.4	62
5c	O	- H	- H	Isopropyl	220.4	94
5d	O	- H	- H	Ethyl	208.9	84
5e	O	- H	- H	2,6-Dichlorophenyl	234.6	88
5f	O	- H	- H	2-Benzylphenyl	192.1	89
5g*	O	- H	- H	Ethylacetato	150.0	69
5h*	O	- H	- H	Allyl	213.6	96
5i	O	- F	- F	sec-Butyl	157.7	54
5j	O	- F	- F	tert-Butyl	162.4	82
5k	O	- F	- F	Butyl	132.9	45
5l	O	- F	- F	Ethyl	175	83
5m	O	- F	- F	Isopropyl	169.9	92
5n	O	- F	- F	Ethylacetato	152.3	20
5o	O	- F	- F	4-Bromophenyl	210.9	67
5p	O	- Cl	- H	sec-Butyl	>300 (dec.)	62
5q	O	- Cl	- H	tert-Butyl	190.3	36
5r	O	- Cl	- H	Ethyl	288.6 (dec.)	17
5s	O	- Cl	- H	Isopropyl	198.6	34
5t	O	- Cl	- H	Allyl	172.7	27
5u	O	- Cl	- H	2,6-Dichlorophenyl	224.6	38
5v	O	- Cl	- H	2-Phenylethyl	147.8	49
5w	O	- Cl	- H	4-Bromophenyl	195.5	37
5x	O	- Cl	- H	2-Benzylphenyl	174.6	44
5y	O	- Cl	- H	4-Cyanophenyl	196.8	26
6a	S	- F	- F	tert-Butyl	176.8	14
6b	S	- F	- F	Cyclohexyl	198.2	50
6c	S	- Cl	- H	Ethyl	150.6	15
6d	S	- Cl	- H	Isopropyl	252.4 (dec.)	39
6e	S	- Cl	- H	Allyl	139.4	10
6f	S	- Cl	- H	Benzyl	157.2	23
6g	S	- Cl	- H	Butyl	125.5	20

(*) 5a, CAS No: 1071382-92-7; 5g, CAS No: 1350123-57-7; 5h, CAS No: 1349487-56-4.

Table 2. Cytotoxic activity data for compounds 5a–y and 6a–g.

	Cancer cell line GI50 (μM)
Sample	HUH-7	R^2	MCF-7	R^2	HCT-116	R^2
5a	NI*	–	NI	–	NI	–
5b	NI	–	NI	–	1.01	0.78
5c	NI	–	NI	–	NI	–
5d	NI	–	25.7	0.86	NI	–
5e	NI	–	NI	–	NI	–
5f	NI	–	NI	–	NI	–
5g	NI	–	NI	–	NI	–
5h	NI	–	10.91	0.78	NI	–
5i	13.85	0.94	NI	0.79	24.48	0.77
5j	29.96	0.88	NI	0.77	28.4	0.85
5k	13.39	0.91	19.03	0.84	16.24	0.86
5l	34.84	0.79	NI	0.64	17.98	0.88
5m	36.57	0.79	45.23	0.76	20.94	0.91
5n	NI	–	36.14	0.55	NI	–
5o	9.46	0.98	8.68	0.85	8.87	0.97
5p	13.03	0.98	11.39	0.71	9.33	0.95
5q	10.88	0.93	8.77	0.98	9.33	0.94
5r	20.92	0.92	60.24	0.24	10.78	0.99
5s	15.36	0.86	13.16	0.74	17.12	0.95
5t	16.29	0.96	9.12	0.77	10.14	0.99
5u	6.44	0.97	6.14	0.93	8.93	0.96
5v	13.18	0.97	8.51	0.93	5.72	0.98
5w	8.54	0.94	9.28	0.92	7.34	0.99
5x	17.22	0.74	16.91	0.71	4.76	0.98
5y	1.29	0.88	6.34	0.92	1.81	0.99
6a	5.97	0.87	10.62	0.91	13.09	0.86
6b	25.8	0.98	NI	0.83	NI	0.67
6c	10.81	0.66	NI	–	13.75	0.91
6d	6.20	0.86	11.47	0.89	14.98	0.84
6e	9.95	0.93	4.94	0.82	8.85	0.98
6f	22.59	0.81	23.00	0.59	12.68	0.89
6g	8.10	0.93	14.80	0.88	13.91	0.79
5-FU	30.66	0.98	3.51	0.96	18.67	0.98
CPT	0.15	0.89	<0.1	0.87	<0.1	0.91

(*): Compounds active above 100 µM concentration were considered to have no inhibition.

Table 3. GI₅₀ (µM) values of some carboxamide and thioamide derivatives for detailed discussion of SAR.

Samples	X	R1	R2	R3	HUH-7	MCF-7	HCT-116
5c	O	- H	- H	Isopropyl	–	–	–
5m	O	- F	- F	Isopropyl	36.57	45.23	20.94
5s	O	- Cl	- H	Isopropyl	15.36	13.16	17.12
6d	S	- Cl	- H	Isopropyl	6.20	11.47	14.98
5e	O	- H	- H	2,6-Dichlorophenyl	–	–	–
5u	O	- Cl	- H	2,6-Dichlorophenyl	6.44	6.14	8.93
5f	O	- H	- H	2-Benzylphenyl	–	–	–
5x	O	- Cl	- H	2-Benzylphenyl	17.22	16.91	4.76
5h	O	- H	- H	Allyl	–	10.91	–
5t	O	- Cl	- H	Allyl	16.29	9.12	10.14
6e	S	- Cl	- H	Allyl	9.95	4.94	8.85

Table 4. MCF-7 (breast cancer cell line) and MCF-12A (normal-like breast epithelial cell line) cytotoxicity comparison of compound 6e (µM).

Compound	MCF-7	R^2	MCF-12A	R^2
6e	4.94	0.8	8.5	0.9
CPT	<0.1	0.9	<0.1	0.8