. 2024 Aug 31;17(9):1154.

doi: 10.3390/ph17091154.

Synthesis of New Thiazole-Privileged Chalcones as Tubulin Polymerization Inhibitors with Potential Anticancer Activities

Hamada Hashem¹, Abdelfattah Hassan^{2

3}, Walid M Abdelmagid⁴, Ahmed G K Habib⁵, Mohamed A A Abdel-Aal⁶, Ali M Elshamsy⁷, Amr El Zawily^{8

9}, Ibrahim Taha Radwan¹⁰, Stefan Bräse¹¹, Ahmed S Abdel-Samea¹², Safwat M Rabea^{13

14}

Affiliations

¹ Pharmaceutical Chemistry Department, Faculty of Pharmacy, Sohag University, Sohag 82524, Egypt.
² Medicinal Chemistry Department, Faculty of Pharmacy, South Valley University, Qena 52242, Egypt.
³ Medicinal Chemistry Department, Clinical Pharmacy Program, South Valley National University, Qena 52242, Egypt.
⁴ Medicinal Chemistry and Drug Discovery Research Centre, Swenam College, 210-6125 Sussex Avenue, Burnaby, BC V5H 4G1, Canada.
⁵ Department of Biotechnology and Life Sciences, Faculty of Postgraduate Studies for Advanced Sciences, Beni-Suef University, Beni-Suef 62521, Egypt.
⁶ Pharmaceutical Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71524, Egypt.
⁷ Medicinal Chemistry Department, Faculty of Pharmacy, Deraya University, New Minia 61768, Egypt.
⁸ Department of Plant and Microbiology, Faculty of Science, Damanhour University, Damanhour 22511, Egypt.
⁹ Division of Pharmaceutics and Translation Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA 52242, USA.
¹⁰ Supplementary General Sciences Department, Faculty of Oral and Dental Medicine, Future University in Egypt, Cairo 11835, Egypt.
¹¹ Institute of Biological and Chemical Systems-Functional Molecular Systems (IBCS-FMS), Karlsruhe Institute of Technology (KIT), Kaiserstrasse 12, 76131 Karlsruhe, Germany.
¹² Pharmacology and Toxicology Department, Faculty of Pharmacy, Deraya University, New Minia 61768, Egypt.
¹³ Medicinal Chemistry Department, Faculty of Pharmacy, Minia University, Minia 61519, Egypt.
¹⁴ Apogee Pharmaceuticals Inc., 4475 Wayburne Dr., Suite 105, Burnaby, BC V6V2H8, Canada.

PMID: 39338317
PMCID: PMC11435058
DOI: 10.3390/ph17091154

Synthesis of New Thiazole-Privileged Chalcones as Tubulin Polymerization Inhibitors with Potential Anticancer Activities

Hamada Hashem et al. Pharmaceuticals (Basel). 2024.

. 2024 Aug 31;17(9):1154.

doi: 10.3390/ph17091154.

Authors

Affiliations

¹ Pharmaceutical Chemistry Department, Faculty of Pharmacy, Sohag University, Sohag 82524, Egypt.
² Medicinal Chemistry Department, Faculty of Pharmacy, South Valley University, Qena 52242, Egypt.
³ Medicinal Chemistry Department, Clinical Pharmacy Program, South Valley National University, Qena 52242, Egypt.
⁴ Medicinal Chemistry and Drug Discovery Research Centre, Swenam College, 210-6125 Sussex Avenue, Burnaby, BC V5H 4G1, Canada.
⁵ Department of Biotechnology and Life Sciences, Faculty of Postgraduate Studies for Advanced Sciences, Beni-Suef University, Beni-Suef 62521, Egypt.
⁶ Pharmaceutical Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71524, Egypt.
⁷ Medicinal Chemistry Department, Faculty of Pharmacy, Deraya University, New Minia 61768, Egypt.
⁸ Department of Plant and Microbiology, Faculty of Science, Damanhour University, Damanhour 22511, Egypt.
⁹ Division of Pharmaceutics and Translation Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA 52242, USA.
¹⁰ Supplementary General Sciences Department, Faculty of Oral and Dental Medicine, Future University in Egypt, Cairo 11835, Egypt.
¹¹ Institute of Biological and Chemical Systems-Functional Molecular Systems (IBCS-FMS), Karlsruhe Institute of Technology (KIT), Kaiserstrasse 12, 76131 Karlsruhe, Germany.
¹² Pharmacology and Toxicology Department, Faculty of Pharmacy, Deraya University, New Minia 61768, Egypt.
¹³ Medicinal Chemistry Department, Faculty of Pharmacy, Minia University, Minia 61519, Egypt.
¹⁴ Apogee Pharmaceuticals Inc., 4475 Wayburne Dr., Suite 105, Burnaby, BC V6V2H8, Canada.

PMID: 39338317
PMCID: PMC11435058
DOI: 10.3390/ph17091154

Abstract

A series of novel thiazole-based chalcones were evaluated for their anticancer activity as potential tubulin polymerization inhibitors. In vitro anticancer screening for the thiazole derivatives 2a-2p exhibited broad-spectrum antitumor activity against various cancer cell lines particularly Ovar-3 and MDA-MB-468 cells with a GI₅₀ range from 1.55 to 2.95 μΜ, respectively. Compound 2e demonstrated significant inhibition of tubulin polymerization, with an IC₅₀ value of 7.78 μM compared to Combretastatin-A4 (CA-4), with an IC₅₀ value of 4.93 μM. Molecular docking studies of compounds 2e, 2g, and 2h into tubulin further supported these findings, revealing that they bind effectively to the colchicine binding site, mirroring key interactions exhibited by CA-4. Computational predictions suggested favorable oral bioavailability and drug-likeness for these compounds, highlighting their potential for further development as chemotherapeutic agents.

Keywords: anticancer; colchicine binding site; thiazole chalcones; tubulin inhibitors.

PubMed Disclaimer

Conflict of interest statement

The authors declare that this study received No funding from Apogee Pharmaceuticals Inc. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication.

Figures

**Figure 1**
Some reported heterocyclic-chalcones and thiazole derivatives targeting colchicine binding site on tubulin.

**Figure 2**
Design of novel thiazole-chalcones targeting colchicine binding site.

**Scheme 1**
Synthesis of thiazole-based chalcones 2a–2p. **Reagents and conditions**: (i) ethanol, 20 °C, 6 h.; (ii) appropriate aromatic aldehyde, 60% NaOH, ethanol, 0 °C, 18 h.

**Figure 3**
The inhibitory activity of thiazole derivatives 2e, 2g, 2h, 2j, 2q, and **CA-4** on tubulin polymerization.

**Figure 4**
The superimposition of the redocked (orange) and co-crystallized (green) poses of colchicine (RMSD = 1.0090 Å).

**Figure 5**
Interactions of CA-4 with colchicine binding site: (A) the 2D binding interactions; (B) the 3D binding interactions.

**Figure 6**
Interactions of 2e with colchicine binding site: (A) the 2D binding interactions; (B) the 3D binding interactions.

**Figure 7**
Interactions of 2g with colchicine binding site: (A) the 2D binding interactions; (B) the 3D binding interactions.

**Figure 8**
Interactions of 2h with colchicine binding site: (A) the 2D binding interactions; (B) the 3D binding interactions.

**Figure 9**
BOILED Egg plot of target compounds 2a–2p and CA-4.

**Figure 10**
Rader model for target compounds 2a–2p and Combretastatin A4.

**Figure 11**
Structure–activity relationship of thiazole–chalcone derivatives.

See this image and copyright information in PMC

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Synthesis of New Thiazole-Privileged Chalcones as Tubulin Polymerization Inhibitors with Potential Anticancer Activities

Affiliations

Synthesis of New Thiazole-Privileged Chalcones as Tubulin Polymerization Inhibitors with Potential Anticancer Activities

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