Topological descriptors in modelling antimalarial activity: N¹-(7-chloro-4-quinolyl)-1,4-bis(3-aminopropyl)piperazine as prototype

Figures & data

Figure 1.  General structures of (a) bisquinoline (b) N¹-(7-chloro-4-quinolyl)-1,4-bis(3-aminopropyl)piperazine amide derivatives and (c) N¹-(7-chloro-4-quinolyl)-1,4-bis(3-aminopropyl)piperazine amine derivatives as antimalarial agents against the chloroquine-resistant P. falciparum FcB1.

Table I.  Observed and modeled in vitro antimalarial activity of N¹-(7-chloro-4-quinolyl)1,4-bis(3-aminoprpyl)piperazine- amide derivatives (Figure 1b) against the FcB1R strain of P. falciparum.

		− logIC50
Comp No	R	Obs.^*	Equation 1^†	Set 1^‡	Set 2^‡	Equation 2	Set 1	Set 2	Equation 3	Set 1	Set 2
1	4-quinolinyl	7.70	7.32	7.41	7.29	7.08	7.11	7.09	7.32	7.35	6.99
2	1-naphthyl	6.81	7.12	7.18	7.04	7.18	7.25	7.17	7.10	7.13	6.98
3	Phenyl	7.09	7.21	7.22	7.11	7.15	7.17	7.10	7.16	7.06	7.05
4	3-thiophenyl	6.95	6.93	6.99	6.80	6.90	6.95	6.84	6.90	6.92	6.81
5	3-phenoxyphenyl	7.68	7.96	7.90	7.98	7.82	7.80	7.77	7.83	7.78	7.51
6	4-chlorophenyl	7.78	8.44	8.38	8.57	7.30	7.42	7.13	7.90	7.84	7.77
7	4-methoxyphenyl	7.70	7.56	7.54	7.53	7.66	7.73	7.61	7.60	7.69	7.59
8	4-fluorophenyl	7.31	7.11	7.14	7.01	7.31	7.26	7.27	7.20	7.32	7.21
9	4-nitrophenyl	7.91	7.88	8.06	7.83	8.34	7.94	8.37	8.03	8.07	8.02
10	4-hydroxyphenyl	6.38	6.92	6.93	6.88	6.95	6.96	6.94	6.87	7.09	6.72
11	Benzyl	7.17	6.96	6.98	6.93	7.10	7.10	7.06	7.01	6.98	6.96
12	phenethyl	7.09	7.43	7.42	7.42	7.54	7.52	7.52	7.40	7.38	7.31
13	cyclohexyl	6.67	6.97	7.01	6.93	6.90	6.90	6.89	6.90	6.85	6.86
14	cyclopropyl	6.54	6.66	6.71	6.59	6.64	6.63	6.61	6.62	6.85	6.67
15	Hexyl	7.46	7.43	7.39	7.41	7.31	7.22	7.31	7.37	7.21	7.21
16	Propyl	7.13	6.60	6.63	6.49	6.61	6.58	6.54	6.62	6.66	6.62
17	Ethyl	6.56	6.64	6.69	6.56	6.72	6.74	6.69	6.64	6.73	6.59
18	methyl	6.40	6.31	6.42	6.23	6.45	6.54	6.40	6.35	6.47	6.28
19	tert-butyl	6.79	6.61	6.67	6.56	6.89	6.98	6.83	6.71	6.64	6.59
20	isopropyl	6.83	6.64	6.71	6.58	6.77	6.81	6.73	6.68	6.74	6.63
21	N-Boc-Gly	6.41	6.71	6.53	6.86	6.71	6.47	6.87	6.66	6.79	6.63
22	N-Boc-L-Pro	6.37	6.57	6.48	6.60	6.59	6.35	6.64	6.56	6.37	6.27
23	N-Boc-(R)-1,2,3,4-tetrahydro-3-isoquinolinyl	6.41	6.44	6.34	6.53	6.62	6.41	6.80	6.50	6.53	6.28
24	N-Boc-(S)-1,2,3,4-tetrahydro-3-isoquinolinyl	6.40	6.45	6.28	6.50	6.62	6.42	6.66	6.50	6.53	6.60
25	Gly	6.50	6.38	6.64	6.41	6.54	6.64	6.50	6.46	6.70	6.87
26	L-Pro	6.44	6.75	6.99	6.77	6.57	6.62	6.54	6.66	6.77	6.80
27	(R)-1,2,3,4-tetrahydro-3-isoquinolinyl	7.72	7.23	7.33	7.18	7.37	7.39	7.29	7.37	7.43	7.47
28	(S)-1,2,3,4-tetrahydro-3-isoquinolinyl	7.56	7.27	7.38	7.25	7.39	7.42	7.33	7.37	7.43	7.47
29	1,2,3,4-tetrahydro-3-isoquinolinyl	7.42	7.30	7.28	7.26	7.48	7.46	7.43	7.36	7.40	7.34
30^¶	1-propanol carbonyl	6.76	6.77	6.81	6.70	6.59	6.61	6.53	6.68	6.64	6.35
31^¶	1-propanoic acid carbonyl	5.86	5.86	5.68	5.90	5.92	5.67	6.10	5.84	6.49	5.96
32^¶	1-propanamide carbonyl	ND^§	5.90			5.90			5.90
33^¶	N-Boc ethyl amine carbonyl	7.47	6.82	6.83	6.78	6.43	6.41	6.41	6.85	7.25	7.40
34^¶	ethyl amine carbonyl	6.40	6.59	6.74	6.52	6.35	6.39	6.32	6.49	6.56	6.54
	Training r^2			0.82	0.78		0.80	0.70		0.81	0.84
	Test r^2			0.73	0.83		0.66	0.81		0.57	0.74

* Observed activity; ref. [9a] for compounds 1-29 and ref. [9b] for compounds 30–34

^† For all equations ‘set 1’ corresponds to MACCS cluster and ‘set 2’ corresponds to random selection; unless otherwise stated, all predicted activities are from LOO cross-validation

^‡ Test set compounds are identified in italics and their activities are predicted with the corresponding model developed using the remaining compounds as the training group

^¶ For Compounds 30–34, amide ‘H’ is replaced by methylene cyclopropane

^§ ND - not determined, see ref. [9b].

Table II.  Observed and modeled in vitro antimalarial activity of N¹-(7-chloro-4-quinolyl)1,4-bis(3-aminoprpyl)piperazine-amine derivatives (Figure 1c) against the FcB1R strain of P. falciparum.

		− logIC50
Comp.No^*	R	Obs ^†	Equation 4 ^‡	Set 1 ^¶	Set 2 ^¶	Eq.5	Set 1	Set 2	Eq.6	Set 1	Set 2
35	4-quinolinyl	7.13	7.39	7.42	7.38	7.44	7.43	7.45	7.31	7.34	7.35
36	1-naphthyl	7.58	7.36	7.38	7.35	7.45	7.42	7.48	7.34	7.35	7.36
37	Phenyl	7.78	7.57	7.58	7.52	7.78	7.80	7.73	7.62	7.58	7.58
38	3-thiophenyl	7.94	7.61	7.62	7.58	7.56	7.55	7.53	7.56	7.61	7.51
39	3-phenoxyphenyl	7.70	7.12	7.18	7.14	7.54	7.54	7.58	7.28	7.11	7.36
40	4-chlorophenyl	7.78	7.97	8.06	7.91	7.86	7.84	7.85	7.91	7.96	7.91
41	4-methoxyphenyl	7.71	7.96	8.05	7.93	7.99	7.99	8.01	7.98	7.93	7.98
42	4-fluorophenyl	7.73	7.90	7.95	7.87	7.86	7.83	7.86	7.88	7.94	7.88
43	4-nitrophenyl	8.23	7.78	7.82	7.81	7.98	7.92	8.04	7.91	7.87	7.95
44	4-hydroxyphenyl	7.26	7.56	7.61	7.50	7.36	7.30	7.33	7.43	7.55	7.40
45	Benzyl	7.73	7.42	7.41	7.37	7.58	7.56	7.53	7.46	7.41	7.42
46	Phenethyl	7.59	7.49	7.51	7.45	7.67	7.65	7.61	7.57	7.43	7.53
47	Cyclohexyl	7.37	7.57	7.60	7.51	7.59	7.65	7.48	7.56	7.51	7.46
48	Cyclopropyl	7.99	7.70	7.72	7.61	7.48	7.48	7.33	7.65	7.69	7.54
49	Hexyl	8.02	7.60	7.64	7.54	7.76	7.81	7.70	7.72	7.55	7.63
50	Propyl	7.61	7.69	7.72	7.59	7.76	7.76	7.65	7.70	7.71	7.61
51	Ethyl	7.44	7.75	7.76	7.64	7.82	7.78	7.71	7.75	7.79	7.65
52	Methyl	7.24	7.67	7.72	7.56	7.75	7.77	7.64	7.64	7.74	7.52
53	tert-butyl	8.01	7.85	7.89	7.75	8.11	8.06	8.04	7.93	7.98	7.88
54	Isopropyl	7.73	7.79	7.83	7.68	7.97	7.95	7.88	7.84	7.87	7.76
55	4-quinolinyl	6.85	6.93	6.84	7.12	6.65	6.55	6.90	6.80	6.85	6.94
56	1-naphthyl	6.67	6.84	6.71	7.04	6.87	6.70	7.14	6.74	6.74	6.88
57	Phenyl	7.26	7.58	7.55	7.59	7.71	7.71	7.71	7.56	7.53	7.60
58	3-thiophenyl	7.20	7.45	7.39	7.46	7.36	7.30	7.38	7.34	7.33	7.34
59	3-phenoxyphenyl	6.58	6.67	6.53	6.85	6.86	6.69	7.02	6.73	6.61	6.96
60	4-chlorophenyl	ND^§	7.90			7.59			7.82
61	4-methoxyphenyl	8.02	7.73	7.69	7.71	7.66	7.49	7.75	7.83	7.77	7.92
62	4-fluorophenyl	ND^§	7.74			7.68			7.76
63	4-nitrophenyl	7.34	7.53	7.54	7.60	7.38	7.28	7.52	7.53	7.55	7.66
64	4-hydroxyphenyl	7.34	7.06	7.20	6.99	6.61	6.67	6.66	7.01	7.17	7.06
65	Benzyl	7.58	7.28	7.19	7.33	7.51	7.46	7.56	7.35	7.28	7.40
66	Phenethyl	7.40	7.44	7.37	7.48	7.36	7.29	7.41	7.47	7.33	7.50
67	Cyclohexyl	7.80	7.75	7.71	7.77	7.64	7.69	7.63	7.70	7.68	7.67
68	Cyclopropyl	8.06	8.56	8.52	8.55	8.10	8.17	8.03	8.36	8.49	8.29
69	Hexyl	7.42	7.75	7.71	7.71	7.88	7.98	7.89	7.80	7.58	7.75
70	propyl	8.13	8.09	8.09	8.05	8.28	8.31	8.23	8.14	8.14	8.11
71	Ethyl	8.66	8.31	8.36	8.27	8.28	8.33	8.66	8.37	8.40	8.31
72	methyl	8.30	7.93	7.84	7.75	7.94	7.79	7.78	8.05	8.06	7.96
73	tert-butyl	ND^§	9.56			9.59			9.51
74	isopropyl	9.05	8.80	8.93	8.70	8.86	8.97	8.83	8.91	9.07	8.93
75	hydrogen	7.99	7.72	7.75	7.65	7.56	7.57	7.49	7.68	7.75	7.57
76	1-pentane nitrile	8.00	8.23	8.25	8.19	7.78	7.78	7.75	8.11	8.11	8.07
77	N-Boc propyl amine carbonyl	7.90	7.89	7.89	7.89	7.97	7.88	8.01	7.99	7.84	8.04
78	propyl amine carbonyl	6.82	7.40	7.38	7.35	7.18	7.08	7.12	7.16	7.32	7.09
79	pyrrolidinyl	7.71	7.88	7.85	7.80	7.84	7.86	7.73	7.86	7.89	7.75
80	piperidinyl	7.94	7.87	7.83	7.80	7.79	7.79	7.72	7.87	7.86	7.76
81	azepaninyl	7.87	7.87	7.84	7.78	7.71	7.72	7.57	7.85	7.83	7.74
	Training r^2			0.79	0.73		0.76	0.77		0.79	0.79
	Test r^2			0.57	0.67		0.69	0.62		0.53	0.65

* for compounds 55–74, R = R₁; for compounds 75–81, R₁ is cyclopropyl methyl

^† observed activity; ref. [9a] for compounds 35–74 and ref. [9b] for compounds 75–81

^‡ see the corresponding footnote ‘b’ and ‘c’ in Table I

^¶ ND - not determined, see ref.[9a].

Figure 2.  Plots of training (▴) and test (ο) sets predicted activities versus observed activity corresponding to Equations (1)(a, b) and (2) (c, d)Equations (1)(a, b) and (2) (c, d). Number of compounds in training set is 21 and in test set is 12.

Figure 3.  Plot of fraction contribution of MLR-like PLS coefficients (normalized) of the 6 descriptors from Equations (1) and (2) to the activity. The serial numbers 1 to 6 on the horizontal axis refer to the descriptors nDB, ICR, T(n..Cl), GATS1e, GATS2p, and nHDon, respectively.

Figure 4.  Plots of training (▴) and test (ο) sets predicted activities versus observed activity corresponding to Equations (4) (a, b) and (5) (c, d). Number of compounds in training set is 30 and in test set is 14.

Figure  5.  Plot of fraction contribution of MLR-like PLS coefficients (normalized) of the 7 descriptors from Equations (4) and (5) to the activity. The serial numbers 1 to 7 on the horizontal axis refer to the descriptors GMTIV, S0K, ICR, IVDE, MATS8m, MATS6e and Hy, respectively.

A Ryckebusch, R Deprez-Poulain, L Maes, MA Debreu-Fontaine, E Mouray, P Grellier, and C Sergheraert. (2003). Synthesis and in Vitro and in Vivo antimalarial activity of N1-(7-chloro-4-quinolyl)-1,4-bis(3-aminopropyl)piperazine derivatives. J Med Chem 46:542–557. (b) A Ryckebusch, MA Debreu-Fontaine, E Mouray, P Grellier, C Sergheraert, P Melnyk.Bioorg Med Chem Lett 2005;15:297–302.

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