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. 2025 Apr 16:13:1565699.
doi: 10.3389/fchem.2025.1565699. eCollection 2025.

Design, synthesis, in silico studies, and apoptotic antiproliferative activity of novel thiazole-2-acetamide derivatives as tubulin polymerization inhibitors

Lamya H Al-Wahaibi  1 , Ali M Elshamsy  2 , Taha F S Ali  3 , Bahaa G M Youssif  4 , Stefan Bräse  5 , Mohamed Abdel-Aziz  3 , Nawal A El-Koussi  2   6
Affiliations

Design, synthesis, in silico studies, and apoptotic antiproliferative activity of novel thiazole-2-acetamide derivatives as tubulin polymerization inhibitors

Lamya H Al-Wahaibi et al. Front Chem. .

Abstract

Introduction: Tubulin polymerization inhibitors have emerged as interesting anticancer therapies. We present the design, synthesis, and structural elucidation of novel thiazole-based derivatives to identify novel tubulin inhibitors with potent antiproliferative efficacy and strong inhibition of tubulin polymerization.

Methods: The novel compounds consist of two scaffolds. Scaffold A compounds 10a-e and scaffold B compounds 13a-e. the structures of the newly synthesized compounds 10a-e and 13a-e were validated using 1H NMR, 13C NMR, and elemental analysis.

Results and discussion: The most effective antitubulin derivative was 10a, exhibiting an IC50 value of 2.69 μM. Subsequently, 10o and 13d exhibited IC50 values of 3.62 μM and 3.68 μM, respectively. These compounds exhibited more potency than the reference combretastatin A-4, which displayed an IC50 value of 8.33 μM. These compounds had no cytotoxic effects on normal cells, preserving over 85% cell viability at 50 μM. The antiproliferative experiment demonstrated that compounds 10a, 10o, and 13d displayed significant activity against four cancer cell lines, with average GI50 values of 6, 7, and 8 μM, equivalent to the reference's doxorubicin and sorafenib. Compounds 10a, 10o, and 13d were demonstrated to activate caspases 3, 9, and Bax, while down-regulating the anti-apoptotic protein Bcl2. Molecular docking studies demonstrated superior binding affinities for 10a (-7.3 kcal/mol) at the colchicine binding site of tubulin, forming key hydrophobic and hydrogen bonding interactions that enhance its activity. ADMET analysis confirmed favorable drug-like properties, establishing these compounds as promising candidates for further development as anticancer agents targeting tubulin polymerization.

Keywords: CA-4; antiproliferative; cell viability; colchicine; docking; tubulin.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Structures of Dasatinib, thia-netropsin, and Alpelisib.
FIGURE 2
FIGURE 2
Structures of compound IV and CA-4 (V).
FIGURE 3
FIGURE 3
Structures of previously reported compound IV and new compounds 10a-o and 13a-e.
SCHEME 1
SCHEME 1
Synthesis of the chalcone intermediates 5a–e. Reagents and Reaction conditions: (i) SO2Cl2, toluene, 0°C, 12 h; (ii) NH3, CS2, EtOH, RT, 6 h; (iii) appropriate aromatic aldehyde, 60% NaOH, EtOH, 0°C, 18 h.
SCHEME 2
SCHEME 2
Synthesis of the key intermediates 9a-c. Reagents and Reaction conditions: (iv) NBS, PTSA. H2O, acetonitrile, reflux, 10 h; (v) thiourea, Na2CO3, EtOH, reflux, 5 h; (vi) Chloroacetyl chloride, DCM, Na2CO3, H2O, 0°C, 12 h.
SCHEME 3
SCHEME 3
Synthesis of the target compounds 10a-o and 13a-e. Reagents and Reaction conditions: (vi) Chloroacetyl chloride, DCM, Na2CO3, H2O, 0°C, 12 h; (vii) Na2CO3, NaI, acetone, RT, 6 h.
FIGURE 4
FIGURE 4
Superimposition of redocked (brown) and co-crystallized (green) poses of CA-4 in the colchicine binding site (RMSD = 0.4994 Å).
FIGURE 5
FIGURE 5
(A) 2D interaction diagram and (B) 3D binding mode of CA‐4 within the colchicine binding site.
FIGURE 6
FIGURE 6
(A) 2D interaction diagram and (B) 3D binding mode of 10a within the colchicine binding site.
FIGURE 7
FIGURE 7
(A) 2D interaction diagram and (B) 3D binding mode of 13d within the colchicine binding site.
FIGURE 8
FIGURE 8
Bioavailability radar of 10a as retrieved from SwissADME server.
See this image and copyright information in PMC

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