Modelling the cytotoxic activity of pyrazolo-triazole hybrids using descriptors calculated from the open source tool “PaDEL-descriptor”

Peer review under responsibility of Taibah University.

Figures & data

Table 1 Antiproliferative activities (IC₅₀-μM) of the (1-benzyl-1H-1,2,3-triazol-4-yl)(1,3-diphenyl-1H-pyrazol-4-yl)methanone derivatives (1–30).

No^a		R	IC50 (μM)
			U87MG	A549	PC-3	HT-29
1		F	6.45	7.07	>50	22.4
2		Cl	>50	>50	>50	>50
3		CF3	>50	>50	>50	>50
4		OCH3	8.87	7.21	4.21	5.71
5		3,4 OCH3	3.37	4.69	2.69	2.92
6		3,4,5 OCH3	7.85	5.56	6.81	4.63
7		F	4.76	5.92	17.87	14.48
8		Cl	9.43	8.5	16.04	15.92
9		CF3	24.76	>50	>50	>50
10		OCH3	3.76	2.13	5.87	2.54
11		3,4 OCH3	1.14	2.3	3.34	2.48
12		3,4,5 OCH3	5.3	3.8	4.4	3.09
13		F	8.91	4.98	>50	12.59
14		Cl	4.24	6.04	11.05	9.92
15		CF3	6.54	5.72	13.4	12.9
16		OCH3	3.3	5.3	6.3	1.78
17		3,4 OCH3	0.86	1.93	3.71	2.42
18		3,4,5 OCH3	3.95	2.42	5.62	3.5
19		F	15.5	13.7	9.7	14.7
20		Cl	5.89	11.21	>50	7.22
21		CF3	4.24	14.5	>50	29.11
22		OCH3	3.63	4.84	7.84	6.99
23		3,4 OCH3	0.97	2.24	3.52	1.78
24		3,4,5 OCH3	1.15	5.32	5.65	4.4
25		F	18.9	>50	>50	28.6
26		Cl	26.7	>50	>50	24.1
27		CF3	8.25	>50	>50	14.72
28		OCH3	2.47	5.5	>50	4.39
29		3,4 OCH3	3.61	3.47	2.32	2.6
30		3,4,5 OCH3	3.81	6.45	5.6	3.89

a Compound number.

Fig. 1 General structure of pyrazolo-triazole hybrids (1-benzyl-1H-1,2,3-triazol-4-yl)(1,3-diphenyl-1H-pyrazol-4-yl) methanone.

Table 2 VIF, t-value and p-value for Models (1)–(4).

Parameter	t-value	p-value	VIF
Model (1)
Intercept	−2.395	0.029	–
ATSC6e	5.055	0.000	1.057
VE1_Dt	−4.391	0.000	1.390
PetitjeanNumber	2.898	0.010	1.115
SpMin1_Bhs	2.539	0.021	1.326
Model (2)
Intercept	5.227	0.000	–
MATS8c	−6.401	0.000	1.456
JGI10	3.996	0.001	1.422
VR3_Dzp	2.883	0.012	1.543
VE3_Dzv	2.507	0.026	1.630
Model (3)
Intercept	6.539	0.000	–
AATS6e	−8.937	0.000	1.999
ASP-7	−3.046	0.012	2.189
SpMin6_Bhi	−2.911	0.015	1.655
Model (4)
Intercept	−2.166	0.045	–
AATSC8c	−11.275	0.000	1.992
VE1_Dzv	8.717	0.000	1.571
SpMin3_Bhs	2.376	0.030	1.499

Fig. 2 Graphical representation of Observed (Obs) versus LOO-predicted (Pred) activities of training set compounds for (a) Model (1), (b) Model (2), (c) Model (3), (d) Model (4).

Table 3 Important statistical parameters of Models (1)–(4).

Model	nTrain	R	$R_A^2$	SEE	Q^2	PRESS	rm^2(LOO)	nTest	$R_{pred}^2$	$r_{m(test)}^2$	rm^2(overall)	cR^2p
1	21	0.873	0.703	0.212	0.554	1.353	0.510	7	0.866	0.723	0.566	0.638
2	18	0.879	0.703	0.118	0.637	0.290	0.590	6	0.858	0.637	0.697	0.687
3	14	0.953	0.880	0.078	0.850	0.0993	0.822	5	0.796	0.657	0.787	0.833
4	20	0.962	0.912	0.118	0.891	0.326	0.879	7	0.707	0.488	0.769	0.827

Table 4 Golbraikh and Tropsha acceptable model criteria of Models (1)–(4).

Sl. No.	Parameter	Threshold value	Model (1)	Model (2)	Model (3)	Model (4)
(i)	Q^2	Q^2 > 0.5	0.55422	0.63712	0.85033	0.8912
(ii)	r^2	r^2 > 0.6	0.90963	0.94474	0.84756	0.82154
(iii)	$|r_0^2-r_{0^{\prime }}^2|$	$|r_0^2-r_{0^{\prime }}^2|<0.3$	0.04583	0.21287	0.2568	0.08512
(iv)	k	0.85 < k < 1.15	1.00128	0.99564	1.00085	1.01793
(v)	k′	0.85 < k′ < 1.15	0.99798	1.00391	0.99842	0.98127

(i) Q² is the cross-validated correlation coefficient, (ii) Parameter r² is the squared correlation coefficient between the observed vs predicted response values of the test set compounds, (iii) $r_0^2$ and $r_{0^{\prime }}^2$ represent the corresponding values for regression through the origin (observed vs. predicted and predicted vs. observed, respectively), (iv) The slopes of the regression lines through the origin are assigned by k and k′.

Fig. 3 Structural requirements of pyrazolo-triazole hybrids for anti-cancer activity.