Design, Synthesis, Antitumor Activities and Molecular Docking of N-Isopimaroyl-N'-aroyl Thiosemicarbazide Derivatives

doi:10.6023/cjoc202503022

Abstract

Using the natural product isopimaric acid as a starting material, nine N-isopimaroyl-N'-aryl acylamino thiourea derivatives were designed and synthesized through functional group assembly strategy. The tetrazolium salt (MTT) assay was used to evaluate the inhibitory activity of these compounds against four human cancer cells of HepG-2, K562, MCF-7 and PC-3. The results showed that these compounds exhibited moderate to significant inhibitory effects on four tumor cell lines. Among them N-isopimaroyl-N'-(4-hydroxybenzamido)thiourea (3d) demonstrated the strongest activity with IC₅₀ values of (8.3±2.2) and (9.1±1.5) μmol/L for MCF-7 and PC-3 cells, respectively. Structure-activity relationship analysis revealed that the introduction of methyl and bromine atom in the meta-position of phenyl was not conducive to the enhancement of anticancer activity, while the introduction of hydroxyl group in the para position was helpful to enhance the activity. When the phenyl was replaced by heterocyclic aromatic group, the anti-proliferative activity of the compound against MCF-7 and PC-3 decreased. Further molecular docking studies indicated that, except for N-isopimaroyl-N'-(2-furanylamino)thiourea (3i), all other compounds formed stable protein-ligand complexes with the target protein PARP-1 through hydrogen bonding and hydrophobic interactions. Compound 3d exhibited multiple interactions with PARP-1, and the hydrogen bond formed with the TYR907 residue was likely a key factor contributing to its significant antitumor activity.

Key words: isopimaric acid, aroyl thiosemicarbazide, antitumor activity, molecular docking

Cite this article

Juanjuan Liu, Ya Gao, Guoyong Luo, Shaoping Yang. Design, Synthesis, Antitumor Activities and Molecular Docking of N-Isopimaroyl-N'-aroyl Thiosemicarbazide Derivatives[J]. Chinese Journal of Organic Chemistry, 2025, 45(12): 4497-4504.

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Compound	IC₅₀/(μmol•L^－1)
Compound	HepG2	K562	MCF-7	PC-3	LO2
3a	34.5±2.7	67.3±2.6	10.4±2.1	16.2±1.6	63.37±2.3
3b	54.4±1.6	42.1±2.2	38.8±2.5	36.4±2.3	109.24±1.2
3c	62.3±1.3	54.2 ±1.7	20.1±1.6	17.5±2.4	80.84±3.1
3d	26.1±2.2	40.5±1.2	8.3±2.2	9.1±1.5	73.48±1.7
3e	30.7±1.8	76.7±2.6	41.5±2.4	38.3±1.8	93.86±1.4
3f	43.5±2.3	33.4±2.4	23.2±3.0	23.2±3.4	39.46 ±2.8
3g	36.4±1.5	27.2±1.5	26.4±1.9	32.6±1.2	71.51±1.3
3h	35.2±1.2	43.7±3.2	23.5±2.4	27.3±1.4	102.38±2.2
3i	32.8±2.7	35.3±3.4	44.2±1.7	37.8±3.4	86.43±2.7
P1	NT	NT	NT	67.65±2.5	48.73±2.3
P2	NT	NT	NT	33.67±1.9	96.82±1.7
5-FU	31.4±1.3	26.3±2.1	32.2±1.4	36.3±1.7	68.01±1.4

Compound	IC₅₀/(μmol•L^－1)
Compound	HepG2	K562	MCF-7	PC-3	LO2
3a	34.5±2.7	67.3±2.6	10.4±2.1	16.2±1.6	63.37±2.3
3b	54.4±1.6	42.1±2.2	38.8±2.5	36.4±2.3	109.24±1.2
3c	62.3±1.3	54.2 ±1.7	20.1±1.6	17.5±2.4	80.84±3.1
3d	26.1±2.2	40.5±1.2	8.3±2.2	9.1±1.5	73.48±1.7
3e	30.7±1.8	76.7±2.6	41.5±2.4	38.3±1.8	93.86±1.4
3f	43.5±2.3	33.4±2.4	23.2±3.0	23.2±3.4	39.46 ±2.8
3g	36.4±1.5	27.2±1.5	26.4±1.9	32.6±1.2	71.51±1.3
3h	35.2±1.2	43.7±3.2	23.5±2.4	27.3±1.4	102.38±2.2
3i	32.8±2.7	35.3±3.4	44.2±1.7	37.8±3.4	86.43±2.7
P1	NT	NT	NT	67.65±2.5	48.73±2.3
P2	NT	NT	NT	33.67±1.9	96.82±1.7
5-FU	31.4±1.3	26.3±2.1	32.2±1.4	36.3±1.7	68.01±1.4

Compd.	Docking score	Hydrogen bond	Hydrophobic interaction	Π-stacking
3a	－43.5	GLY863	LEU877, TYR889, ILE895, TYR896, TYR907	—
3b	－40.6	—	LEU877, ALA880, TYR896, ALA898, TYR907	TYR907
3c	－39.7	GLY863	LEU877, ALA880, TYR889, TYR896, TYR907, GLU988	—
3d	－39.3	GLY863, TYR907	ALA880, TYR889, TYR896, TYR907	TYR907
3e	－37.2	—	LEU877, ALA880, TYR896, TYR907	—
3f	－33.9	ALA880, TYR889	TYR896, TYR907	—
3g	－37.7	GLY863	TYR896, TYR896, TYR907	TYR907
3h	－33.1	HIS862, SER864, ASN868	LEU877, TYR889, TYR896, TYR907	—
3i	－32.2	ASN868	LEU877, ALA880, TYR889, ILE895, TYR896, TYR907	—
P1	－32.6	GLY888	TYR889, TYR896, TYR907	—
P2	－34.3	GLY888, TYP889	LEU877, TYR889, MET890, TYR896	—

Compd.	Docking score	Hydrogen bond	Hydrophobic interaction	Π-stacking
3a	－43.5	GLY863	LEU877, TYR889, ILE895, TYR896, TYR907	—
3b	－40.6	—	LEU877, ALA880, TYR896, ALA898, TYR907	TYR907
3c	－39.7	GLY863	LEU877, ALA880, TYR889, TYR896, TYR907, GLU988	—
3d	－39.3	GLY863, TYR907	ALA880, TYR889, TYR896, TYR907	TYR907
3e	－37.2	—	LEU877, ALA880, TYR896, TYR907	—
3f	－33.9	ALA880, TYR889	TYR896, TYR907	—
3g	－37.7	GLY863	TYR896, TYR896, TYR907	TYR907
3h	－33.1	HIS862, SER864, ASN868	LEU877, TYR889, TYR896, TYR907	—
3i	－32.2	ASN868	LEU877, ALA880, TYR889, ILE895, TYR896, TYR907	—
P1	－32.6	GLY888	TYR889, TYR896, TYR907	—
P2	－34.3	GLY888, TYP889	LEU877, TYR889, MET890, TYR896	—

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