Anti-proliferative and ADMET screening of novel 3-(1H-indol-3-yl)-1, 3-diphenylpropan-1-one derivatives

Figures & data

Table 1. Standardization of reaction condition for the synthesis of title compounds

SI. No.	Solvent	Acid catalyst	M mol conc. (%)	Time (hrs)	Yield (%)^a
1	Ethanol	CH3COOH	5	8	0
2	Ethanol	CH3COOH	10	8–10	0
3	Methanol	CH3COOH	10	8	30
4	Ethanol	HCl	10	8	85
5	Ethanol	HCl	5	8	90
6	Acetic acid (CH3COOH)Both solvent and catalyst		100(Neat reaction)	8–12	20

^a Yield after column chromatography.

Table 2. Synthesis of target compounds 3(a–j) via two component one pot reaction of indole with different α, β-unsaturated ketones

Entry code	R^1	R^2	R^3	Molecular formula	Yield (%)	M.P (°C)
3a	H	H	H	C23H19NO	87	93–94
3b	Cl	H	H	C23H18ClNO	83	115–117
3c	F	H	H	C23H18FNO	73	107–109
3d	H	Cl	H	C23H18ClNO	90	119–121
3e	H	Cl	Cl	C23H17Cl2NO	70	220–223
3f	Cl	H	Cl	C23H17Cl2NO	72	221–222
3g	F	H	Cl	C23H17ClNO	79	70–73
3h	H	Cl	F	C23H17ClFNO	54	224–225
3i	Cl	H	F	C23H17ClFNO	63	220–221
3j	F	H	F	C23H17F2NO	85	118–120

Table 3. ADME and pharmacological parameters prediction for the ligands 3-(1H-indol-3-yl)-1, 3 diphenylpropan-1-ones 3(a–j) using ADMET SAR toolbox

Ligand	PlogBB^a	logHIA^c	PCaco^b	logpGI (substrate)^d	logpGI (non-inhibitor)^e	PlogS^f	logpapp^g
3a	0.9968	1.0000	0.5299	0.7383	0.8610	−3.7842	1.2765
3b	0.9971	1.0000	0.5794	0.7521	0.8754	−4.6896	1.3566
3c	0.9981	1.0000	0.5624	0.7348	0.7616	−4.0313	1.3373
3d	0.9971	1.0000	0.5794	0.7521	0.8754	−4.6896	1.3566
3e	0.9971	1.0000	0.5794	0.7521	0.8754	4.6896	1.3566
3f	0.9971	1.0000	0.5794	0.7521	0.8754	4.6896	1.3566
3g	0.9979	1.0000	0.5699	0.7516	0.8114	−4.3761	1.3375
3h	0.9979	1.0000	0.5699	0.7516	0.8114	−4.3761	1.3375
3i	0.9979	1.0000	0.5699	0.7516	0.8114	−4.3761	1.3375
3j	0.9981	1.0000	0.5624	0.7348	0.7616	−4.0313	1.3373
Indomethacin	0.9381	0.9509	0.5857	0.6360	0.9313	−4.6825	0.6287
Camptothecin	0.6345	0.8410	0.5555	0.6039	0.7852	−3.0369	1.1839
Tetracycline	0.9841	0.8006	0.7439	0.7910	0.8025	−3.0575	0.7655
Tretinoin	0.9311	0.9925	0.7603	0.6144	0.8912	−3.0895	1.7734
Levostatin	0.9287	0.9452	0.5484	0.7861	0.7046	−5.9475	0.8127
Metronidazole	0.9297	0.9805	0.5365	0.5141	0.8954	−1.3229	0.8033

^a Predicted blood/brain barrier partition coefficient (1-high penetration, 2- medium penetration and 3- Low penetration).

^b Predicted Caco-2 cell permeability in nm/s (acceptable range: −1 is poor, 1is great).

^c Predicted human intestinal absorption in nm/s (acceptable range: 0 poor,>1 great).

^d Predicted P-glycoprotein substrate in nm/s (acceptable range of −5 is poor, 1 is great).

^e Predicted P-glycoprotein inhibitor in nm/s (accepted range: 0–1).

^f Predicted aqueous solubility, (Concern value is 0–2 highly soluble).

^g Predicted probability of Caco-2 cell permeability in cm/s (Concern value is −1 to 1).

Table 4. LD₅₀ and probability of health effects of 3-(1H-indol-3-yl)-1, 3 diphenylpropan-1-one 3(a–j) using ACD/I-Lab 2.0

ADME-TOX Parameters	Intra-peritoneal^a	Oral^a	Intravenous^a	Subcutaneous^a	Blood effect^b	Cardio-vascular system effect^b	Gastro-intestinal effect^b	Kidney effect^B	Liver effect^b	Lung effect^B
3a	422 (0.5)	640 (0.46)	32 (0.56)	240 (0.54)	0.6	0.96	0.89	0.73	0.53	0.43
3b	410 (0.5)	600 (0.45)	34 (0.57)	220 (0.55)	0.68	0.97	0.89	0.8	0.52	0.41
3c	500 (0.3)	520 (0.45)	36 (0.51)	260 (0.53)	0.7	0.96	0.71	0.76	0.55	0.45
3d	410 (0.5)	600 (0.45)	34 (0.57)	220 (0.55)	0.68	0.97	0.89	0.8	0.52	0.41
3e	410 (0.5)	600 (0.45)	34 (0.57)	220 (0.55)	0.75	0.97	0.9	0.89	0.52	0.42
3f	400 (0.4)	570 (0.4)	32 (0.55)	190 (0.51)	0.75	0.96	0.9	0.89	0.52	0.42
3g	460 (0.4)	480 (0.45)	35 (0.53)	220 (0.52)	0.77	0.96	0.73	0.79	0.55	0.43
3h	460 (0.4)	480 (0.45)	35 (0.53)	220 (0.52)	0.77	0.96	0.73	0.79	0.55	0.43
3i	460 (0.4)	480 (0.45)	35 (0.53)	220 (0.52)	0.77	0.96	0.73	0.79	0.55	0.43
3j	220 (0.4)	400 (0.39)	40 (0.52)	350 (0.5)	0.68	0.97	0.89	0.79	0.57	0.46

^a Estimated LD₅₀-mouse value in mg/kg after intra peritoneal, oral, intravenous and subcutaneous administration.

^b Estimated probability of blood, gastrointestinal system, kidney, liver and lung effect at therapeutic dose range of compounds 3a–j. The drugs with moderate effect on reliability index (>0.5). The drugs with border line effect on reliability index (>0.3, <0.5).

Figure 1. The antiproliferative screening results of the synthesized compounds 3(a–j).

Table 5. Anti-proliferative study of different derivatives of 3-(1H-indol-3-yl)-1, 3- diphenylpropan-1-one

Cancer cell lines		3a	3c	3d	3e	3f	3g	3j	Dox
K-562	Avg% inhibition	7.57	13.63	7.57	16.88	14.39	13.20	21.32	95.57
	SD	1.64	1.98	1.96	1.86	0.98	2.09	1.96	2.22
MCF-7	Avg% inhibition	21.09	17.22	19.87	27.40	19.26	22.21	23.23	97.61
	SD	1.36	0.52	3.18	2.65	3.313	4.06	3.76	2.18
HeLa	Avg% inhibition	33.33	31.72	35.67	33.40	26.16	29.75	25.43	97.16
	SD	3.71	3.23	0.71	2.50	3.21	5.17	1.61	2.27
Colo205	Avg% inhibition	18.63	16.03	17.76	19.10	17.92	13.20	17.29	91.55
	SD	2.27	1.436	2.19	4.376	2.61	1.60	2.39	1.87
HepG-2	Avg% inhibition	29.57	31.63	38.84	36.34	34.13	33.22	32.50	92.35
	SD	2.58	3.93	1.26	2.16	2.03	3.75	2.87	1.56

Notes: Average % inhibition of the samples was tested at a concentration of 10 μ mol.

SD: Standard deviation.

Dox: Doxorubucin was employed as positive control against differ.

Cell lines tested: K562 (Chronic myelogenous leukaemia), MCF-7 (Breast Cancer), HeLa (Cervical cancer), Colo205 (Colorectal adenocarcinoma), HepG2 (Hepatocellular carcinoma).

Scheme 1. Synthesis of 3-(1H-indol-3-yl)-1, 3-diphenylpropan- 1- ones derivatives 3(a–j).