Novel pyrazole–pyrazoline hybrids endowed with thioamide as antimalarial agents: their synthesis and 3D-QSAR studies

Figures & data

Figure 1. Commercially available drugs bearing pyrazole nucleus.

Figure 2. Title compounds bearing the structural motifs.

Table 1. IC₅₀ and SI values of the synthesised compounds.

	Substitution		IC50^a
Compound No.	R1	R2	µg/mL	µM	SI^b	Activity pIC50	Predicted activity pIC50	Fitness
29^∧	H	H	26.036	61.47	ND	4.584	4.47	2.93
30^∧	H	Cl	30.101	65.73	ND	4.521	4.63	2.94
31^∧∧	H	4-CH3	15.209	31.17	ND	4.818	4.82	2.48
32^∧∧	H	4-OCH3	5.883	12.06	ND	5.230	5.26	2.91
33^∧∧	H	4-NH2	1.508	3.22	33	5.822	5.62	2.94
34^∧	4-Cl	H	32.768	66.54	ND	4.485	4.68	2.96
35*^∧	4-Cl	Cl	35.643	77.83	ND	4.448	4.85	2.97
36^∧∧	4-Cl	4-CH3	8.905	19.63	ND	5.050	5.07	2.51
37*^∧∧	4-Cl	4-OCH3	3.559	7.86	ND	5.449	5.47	2.49
38*^∧∧	4-Cl	4-NH2	0.977	2.09	22	6.010	5.86	2.96
39^∧	4-CH3	H	24.845	52.53	ND	4.605	4.73	2.96
40^∧∧	4-CH3	Cl	12.043	27.46	ND	4.919	4.90	2.97
41^∧∧	4-CH3	4-CH3	7.721	16.36	ND	5.112	5.02	2.97
42^∧∧	4-CH3	4-OCH3	2.772	6.14	ND	5.557	5.47	2.95
43^∧∧	4-CH3	4-NH2	0.715	1.53	16	6.146	6.18	2.96
44*^∧	4-OCH3	H	20.713	43.88	ND	4.684	5.00	2.99
45*^∧∧	4-OCH3	Cl	10.091	23.06	ND	4.996	5.18	3.00
46^∧∧	4-OCH3	4-CH3	4.642	10.61	ND	5.333	5.20	3.00
47^∧∧	4-OCH3	4-OCH3	1.904	4.20	40	5.720	5.70	2.98
48^∧∧	4-OCH3	4-NH2	0.546	1.13	12	6.263	6.43	2.98

^aCalculated using HN-NonLin V1.1 Software.

^bSI: IC₅₀ values of cytotoxic activity/IC₅₀ values of antimalarial activity.

*Compounds used as test.

^∧Ligands of the inactive set.

^∧∧Ligands of the active set.

Figure 3. Active alignment of the data set.

Figure 4. Title compounds showing AMX pattern and the different rings.

Scheme 1. Reagents and conditions: (i) Phenyl hydrazine, GAA, methanol, reflux; (ii) DMF, POCL₃; (iii) Aromatic ketone, NaOH, methanol, reflux; (iv) Thiosemicarbazide, ethanol, reflux.

Table 2. Statistical parameters of the best model.

Hypothesis	SD	r^2	RMSE	q^2	Pearson-r
ADHRR.9	0.1299	0.9612	0.2507	0.7982	0.9992

SD: standard deviation, r²: determination coefficient on the training set, RMSE: root mean squared error on the test set, q²: determination coefficient on the test set, r-Pearson: Pearson's correlation coefficient on the test set.

Figure 5. Fitness plot of the model.

Figure 6. Electron withdrawing, Hydrogen bond donor and hydrophobic characteristics of the hypothesis ADHRR.9.