Brine shrimp lethality assay ‘an effective prescreen’: Microwave-assisted synthesis, BSL toxicity and 3DQSAR studies-based designing, docking and antitumor evaluation of potent chalcones

Figures & data

Figure 1. Fitting centers used for overlapping chalcones.

Table 1. The brine shrimp cytotoxicity of the synthesized chalcones. .

No.	Ring A	Ring B	LC50 (µM)	No.	Ring A	Ring B	LC50 (µM)
1	Ph	Ph	0.14	18	4′-NH2C6H4	3-OHC6H4	7.1
2	Ph	2-OHC6H4	84.73	19	4′-NH2C6H4	2-OCH3C6H4	2.72
3	Ph	2-OCH3C6H4	0.29	20	4′-NH2C6H4	3-OCH3C6H4	3.79
4	Ph	3-OCH3C6H4	2.6	21	4′-NH2C6H4	4-OCH3C6H4	0.24
5	Ph	4-OCH3C6H4	1.05	22	4′-NH2C6H4	2-NO2C6H4	160.6
6	Ph	2-NO2C6H4	261.58	23	4′-NH2C6H4	3-NO2C6H4	557
7	Ph	3-NO2C6H4	214.23	24	4′-NH2C6H4	4-NO2C6H4	130.56
8	Ph	4-NO2C6H4	364.03	25	4′-NH2C6H4	2-ClC6H4	16.2
9	Ph	2-ClC6H4	167.85	26	4′-NH2C6H4	3-ClC6H4	52.3
10	Ph	3-ClC6H4	0.248	27	4′-NH2C6H4	4-ClC6H4	14.6
11	Ph	4-ClC6H4	4.25	28	4′-NH2C6H4	2-BrC6H4	8.3
12	Ph	2-BrC6H4	1.46	29	4′-NH2C6H4	4-CH3C6H4	150.1
13	Ph	3-BrC6H4	0.21	30	2′-OHC6H4	2-OHC6H4	0.083
14	Ph	4-CH3C6H4	1.05	31	2′,3′,4′-(OCH3)3 C6H2	2-OHC6H4	0.79
15	Ph	3,4-(OCH3)2C6H3	834.63	32	3′,4′,5′-(OCH3)3 C6H2	2-OHC6H4	0.34
16	4′-NH2C6H4	Ph	6.68	33	2′,4′-(Br)2C6H3	2-OHC6H4	54.61
17	4′-NH2C6H4	2-OHC6H4	46.5

Table 2. Observed and predicted pLC₅₀ of the training set compounds.

Chalcones	Observed	Predicted	Residual	Chalcones	Observed	Predicted	Residual
1	6.85	7.10	−0.25	17	4.33	4.39	−0.06
3	6.54	6.63	−0.09	18	5.15	5.00	0.15
4	5.59	5.66	−0.07	20	5.42	5.51	−0.09
5	5.98	6.03	−0.05	21	6.62	6.70	−0.08
6	3.58	3.59	−0.01	24	3.88	4.08	−0.20
7	3.67	4.12	−0.45	26	4.28	4.53	−0.25
8	3.44	3.23	0.20	27	4.84	4.93	−0.09
10	6.61	6.15	0.46	28	5.08	4.59	0.49
12	5.84	6.14	−0.30	30	7.08	6.87	0.21
13	6.68	6.26	0.42	31	6.10	6.11	−0.01
14	5.73	5.81	−0.08	32	6.47	6.44	0.03
16	5.18	5.45	−0.28	33	4.26	4.47	−0.21

Table 3. Observed and predicted pLC₅₀ of the test set compounds.

Chalcones	Observed	Predicted	Residual	Chalcones	Observed	Predicted	Residual
2	4.07	4.22	−0.14	22	3.79	3.43	0.36
9	3.78	4.32	−0.54	23	3.25	2.94	0.31
11	5.37	5.22	0.15	25	4.79	4.51	0.28
15	3.08	2.86	0.22	29	3.82	4.16	−0.34
19	5.57	5.64	−0.08

Figure 2. Calculated versus observed activity of the training set compounds.

Figure 3. Calculated versus observed activity of the test set compounds.

Figure 4. Stereoview of the CoMFA map for the electronic and steric contributions favoring activity.

Figure 5. Favorable electronic and steric regions for enhanced potency in cytotoxic chalcones.

Table 4. Predicted pLC₅₀ of the designed chalcones.

Chalcones	R′	R	pLC50 calcd
34	H	4-F	7.20
35	H	3-OH,4-OCH3	6.31
36	H	4-N(CH3)2	5.95
37	4′-NH2	3-Br	4.64
38	4′-NH2	4-N(CH3)2	5.46

Figure 6. Chalcone 34 bound into the binding pocket of tubulin active site.

Table 5. The energy scores (kCal mol⁻¹) of designed inhibitors.

	Ecomplex	Elig	Eres	G
34	−24.8	−73 808	6630	−80
35	−10.6	−72 803	6630	−79
36	−12.0	−68 374	6630	−75
37	−15.2	−66 316	6630	−72
38	−15.9	−67 705	6630	−74

Table 6. The predicted and observed pLC₅₀ values of the designed chalcone analogues.

Chalcones	R′	R	pLC50 calc.	LD50	pLC50 obs.	Error
34	–	4-F	7.20	0.04	7.36	0.16
35	–	3-OH,4-OCH3	6.31	0.43	6.37	0.06
36	–	4-N(CH3)2	5.95	0.92	6.04	0.09
37	4′-NH2	3-Br	4.64	83.71	4.08	−0.56
38	4′-NH2	4-N(CH3)2	5.46	2.59	5.59	0.13

Figure 7. Cytotoxicity of chalcones 34–38 against human squamous cell carcinoma (H157), malignant melanoma of skin (HT144), breast cancer (MCF7), colon cancer (SKCO1), liver cancer (HepG2) and lung carcinoma (H1299).

Figure 8. Tubulin polymerization activity of 5 μM of each of designed chalcones 34–38 on tubulin polymerization. Taxol and colchicine (5 μM) used as reference compounds whereas DMSO was used as control. The activity was assessed by turbidity change using UV-VIS spectrophotometry.