Thiazolation of phenylthiosemicarbazone to access new thiazoles: anticancer activity and molecular docking

Abstract

Aim: Novel thiazole hybrids were synthesized via thiazolation of 4-phenylthiosemicarbazone (4). Materials & methods: The anticancer activity against the NCI 60 cancer cell line panel. Results: Methyl 2-(2-((1-(naphthalen-2-yl)ethylidene)hydrazineylidene)-4-oxo-3-phenylthiazolidin-5-ylidene)acetate (6a) showed significant anticancer activity at 10 μM with a mean growth inhibition (GI) of 51.18%. It showed the highest cytotoxic activity against the ovarian cancer OVCAR-4 with an IC₅₀ of 1.569 ± 0.06 μM. Compound 6a inhibited PI3Kα with IC₅₀ = 0.225 ± 0.01 μM. Moreover, compound 6a revealed a decrease of Akt and mTOR phosphorylation in OVCAR-4 cells. In addition, antibacterial activity showed that compounds 11 and 12 were the most active against Staphylococcus aureus. Conclusion: Compound 6a is a promising molecule that could be a lead candidate for further studies.

Plain language summary

Novel naphthalene-azine-thiazole hybrids 5-12 were synthesized via late-stage thiazolation of the corresponding 4-phenylthiosemicarbazone 4. Compound 6a showed significant anticancer activity at single-dose screening and yielded excellent inhibitory activity with a mean GI of 51.18%. Compound 6a showed the highest cytotoxic activity against OVCAR-4 with an IC₅₀ of 1.569 ± 0.06 μM. Moreover, compound 6a exhibited an IC₅₀ of 31.89 ± 1.19 μM against normal ovarian cell line (OCE1) and a selectivity index of 19.1. Compound 6a inhibited PI3Kα with IC₅₀ = 0.225 ± 0.01 μM compared with alpelisib (IC₅₀ = 0.061 ± 0.003 μM). Moreover, compound 6a revealed a powerful decrease of Akt and mTOR phosphorylation in the OVCAR-4 cell line. The cell cycle analysis showed that compound 6a caused an arrest at the G2/M phase. The compound also increased the total apoptosis by 26.8-fold and raised the level of caspase-3 by 4.34 times in OVCAR-4. In addition, antibacterial activity was estimated against Gram-positive and Gram-negative bacterial strains. Compounds 11 and 12 were the most active derivatives, with MIC value of 256 μg/ml against Staphylococcus aureus. Molecular docking was done and showed that 6a interlocked and fitted well into the ATP binding site of PI3Kα kinase (Protein Data Bank ID: 4JPS) with a fitness value (-119.153 kcal/mol) and forms the key H-bonds with Val851 and Ser854 like the marketed PI3Kα inhibitor alpelisib. Consequently, 6a is the most promising molecule that could be a lead candidate for further studies.

TWEETABLE ABSTRACT

A series of naphthalene-azine-thiazole derivatives were synthesized and evaluated for their anticancer and antibacterial activity. These findings propose that compound 6a has cytotoxic properties and is a starting structure for a new generation of PI3Kα kinase inhibitors.

GRAPHICAL ABSTRACT

Summary points

• A series of naphthalene–azine–thiazole derivatives were synthesized.

• The characterization of all the synthesized compounds was carried out using several analytical and spectroscopic techniques.

• The synthesized compounds were tested against various cancer cell lines and antibacterial.

• Benzenesulfonamide derivative 11 and the coumarin-containing derivative 12 showed the highest antibacterial activity with MIC value of 256 μg/ml against S. aureus.

• Compound 6a showed the highest activity against the ovarian cancer cell line OVCAR-4 with an IC₅₀ of 1.569 ± 0.06 μM.

• Compound 6a inhibited PI3Kα with IC₅₀ = 0.225 ± 0.01 μM compared with alpelisib (IC₅₀ = 0.061 ± 0.003 μM).

• Compound 6a inhibited the growth of OVCAR-4 cells during the G2/M phase and increased total apoptosis by 26.8-fold.

• Compound 6a interlocked and fitted well into the ATP binding site of PI3Kα kinase (Protein Data Bank ID: 4JPS) with a fitness value (-119,153 kcal/mol).

Keywords: :

• 4-phenylthiosemicarbazide
• alpelisib (NVP-BYL719)
• antibacterial
• anticancer
• azine
• molecular docking
• naphthalene
• PI3Kα inhibition
• thiazolation
• thiazole

Supplemental material

Supplemental data for this article can be accessed at https://doi.org/10.1080/17568919.2024.2342668

Acknowledgments

The authors value the contribution of the associates of the National Institute of Health, USA, for antiproliferative screening. Several thanks are owed to Chemistry Department, Faculty of Science, Al-Azhar University, Egypt for providing equipment and chemicals. Dr. Shimaa M. Abd El-Gilil is grateful to the Pharmaceutical Organic Chemistry Department, Faculty of pharmacy (Girls), Al-Azhar University, Egypt for its consistent support.

Financial disclosure

The authors have no financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.