Design, synthesis, cytotoxic evaluation, and QSAR study of some 6H-indolo[2,3-b]quinoxaline derivatives

Figures & data

Scheme 1.  Synthesis of 6H-indolo[2,3-b]quinoxaline derivatives. A: Conc. HCl, sodium sulfate, hydroxylamine HCl, reflux for 15 min; B: PPA/H₂SO₄, 56°C for 6 h/120°C for 6 h; C, D: o-phenylenediamine or diaminobenzoic acid, acetic acid/HCOOH, reflux for 1–7 h; E: CDI, dry DMF, stir at room temperature for 4 h, DCM, MgSO₄; F: dry DMF, 120°C, 30 min–2 h; G: K₂CO₃, dry DMF, 85–100°C for 12–16 h.

Table 1.  Structural variations and cytotoxicity of 6H-indolo[2,3-b]quinoxaline derivatives.

Compound code	R1	R2	R3	R4	Cytotoxicity (IC50, µM)
IDQ-1	H	H	H	H	92
IDQ-2	-COOH	H	H	H	75
IDQ-3	H	H	-COOH	H	93
IDQ-4	H	H	H	-COOH	141
IDQ-5	-CON(CH3)2	H	H	H	27
IDQ-6	H	-C2H5	H	H	38
IDQ-7	H	H	H	-Br	118
IDQ-8	H	-C2H5	H	-Br	64
IDQ-9	-COOH	H	H	-Br	112
IDQ-10	H	H	H	-N(CH3)2	22
IDQ-11	H	H	H	-N(C2H5)2	33
IDQ-12	H	H	H		58
IDQ-13	H	H	H		47
IDQ-14	H	H	H		38
Standard				Cisplatin	7
Standard				5-FU	266

Table 2.  Molecular descriptors used for modeling cytotoxicity of 6H-indolo[2,3-b]quinoxaline derivatives.

–LogIC50	Mp	nCIC	RBF	nCp	nCOOHPh
4.0362	0.74	4	0	0	0
4.1249	0.73	4	0.03	0	1
4.0315	0.73	4	0.03	0	1
3.8508	0.73	4	0.03	0	1
4.5686	0.7	4	0.08	2	0
4.4202	0.71	4	0.06	1	0
3.9281	0.79	4	0	0	0
4.1938	0.75	4	0.06	1	0
3.9508	0.78	4	0.03	0	1
4.6576	0.7	4	0.08	2	0
4.4815	0.68	4	0.12	2	0
4.2366	0.69	5	0	0	0
4.3279	0.69	5	0	0	0
4.4202	0.68	5	0.02	1	0

Table 3.  Physicochemical characteristic of 6H-indolo[2,3-b]quinoxaline derivatives.

Compound code	Molecular formula	Molecular weight		Melting point^b	Solubility	Rf value	λmax	Yield
		Calcd.	Found^a
IDQ-1	C14H9N3	219.24	219	215–218°C	Methanol	0.89	306, 356	85%
IDQ-2	C15H9N3O2	263.25	263	180–182°C	DMSO, methanol	0.82	395.5, 280	77%
IDQ-3	C15H9N3O2	263.25	263	320–323°C	DMSO, methanol	0.20	356, 281	65%
IDQ-4	C15H9N3O2	263.25	263	170–172°C	Methanol	0.60	333.5	62%
IDQ-5	C17H14N4O	290.32	290	217–220°C	DMSO, methanol	0.42	265.5, 370	56%
IDQ-6	C16H13N3	247.29	247	248–251°C	DMSO	0.75	346.5, 394.5	72%
IDQ-7	C14H8BrN3	298.14	297	275–277°C	DMF, acetone	0.92	356	90%
IDQ-8	C16H12BrN3	326.19	326	229–230°C	DMF, acetone	0.44	355.5, 265.5	64%
IDQ-9	C15H8BrN3O2	342.15	342	320–323°C	DMSO, DMF	0.56	355.5, 265.5	60%
IDQ-10	C16H14N4	262.31	262	280–282°C	DMF, acetone	0.80	280, 357	75%
IDQ-11	C18H18N4	290.36	290	310–312°C	DMSO, acetone	0.48	355, 306.5, 263	80%
IDQ-12	C18H16N4O	304.35	304	350–352°C	DMF, acetone	0.51	268, 329	70%
IDQ-13	C19H18N4	302.37	302	326–330°C	DMSO, DMF	0.51	279, 354	72%
IDQ-14	C19H19N5	317.39	317	>360°C	DMF, acetone	0.63	281, 355	67%

^aMW found by mass spectrometry.

^bMP, open capillary method, uncorrected.

Table 4.  Lipinski parameters of the compounds.

Compound code	MW	LogP	HBD	HBA
IDQ-1	219.26	2.95	1	2
IDQ-2	263.27	2.53	1	4
IDQ-3	263.27	2.53	1	4
IDQ-4	263.27	2.53	1	4
IDQ-5	290.35	2.28	1	3
IDQ-6	247.32	3.59	0	2
IDQ-7	298.15	3.71	1	2
IDQ-8	326.21	4.35	0	2
IDQ-9	342.16	3.29	1	4
IDQ-10	262.34	3.01	1	2
IDQ-11	290.40	3.90	1	2
IDQ-12	304.38	2.23	1	3
IDQ-13	302.41	3.96	1	2
IDQ-14	317.43	2.13	1	2
Cisplatin	247.2	0.00	2	0
5-fluorouracil	130.09	–0.69	2	2

Note. MW, molecular weight; HBD, hydrogen bond donor; HBA, hydrogen bond acceptor.

Figure 1.  Position of the metabolites of 6H-indolo[2,3-b]quinoxaline derivatives (A), cisplatin (B), and 5-fluorouracil (C).

Table 5.  Correlation matrix for descriptors in QSAR models of series I.

	–LogIC50	Mp	nCIC	RBF	nCp	nCOOHPh
–LogIC50	1.000	–0.755	0.208	0.618	0.851	–0.621
Mp		1.000	–0.537	0.339	–0.503	0.395
nCIC			1.000	–0.470	–0.199	–0.330
RBF				1.000	0.877	–0.153
nCp					1.000	–0.501
nCOOHPh						1.000

Table 6.  Variance inflation factor (VIF) and t-values of descriptors in the QSAR models derived for series I.

Model	Effect	VIF	t-Value
Model 1	Constant	—	10.768
	nCP	1.041	8.438
	nCIC	1.041	3.566
Model 2	Constant	—	8.614
	Mp	1.307	–3.225
	RBF	1.129	2.949
	nCOOHPh	1.184	–2.677

Table 7.  Experimental and predicted activity values of 6H-indolo [2,3-b]quinoxaline derivatives.

Experimental result	Model 1		Model 2
	Predicted activity	Calculated activity	Predicted activity	Calculated activity
4.0362	3.99286	3.99939	4.14079	4.1175
4.1249	3.97713	3.99939	3.99945	4.03241
4.0315	3.9937	3.99939	4.03274	4.03241
3.8508	4.02576	3.99939	4.09715	4.03241
4.5686	4.55959	4.56206	4.45679	4.47745
4.4202	4.26535	4.28073	4.38303	4.38746
3.9281	4.01204	3.99939	3.96796	3.94584
4.1938	4.29031	4.28073	4.27018	4.25013
3.9508	4.00802	3.99939	3.80898	3.86076
4.6576	4.52601	4.56206	4.43662	4.47745
4.4815	4.59246	4.56206	4.81092	4.65742
4.2366	4.23332	4.23446	4.31165	4.28916
4.3279	4.18504	4.23446	4.27258	4.28916
4.4202	4.57527	4.51579	4.36528	4.37914

Figure 2.  Graph showing correlation between experimental activity and predicted activity of model 1.

Figure 3.  Graph showing correlation between experimental activity and calculated activity of model 1.

Figure 4.  Graph showing correlation between experimental activity and predicted activity of model 2.

Figure 5.  Graph showing correlation between experimental activity and calculated activity of model 2.