DOI: 10.6084/m9.figshare.26250870
title: Thiazolation of phenylthiosemicarbazone to access new thiazoles: anticancer activity and molecular docking

description: <b>Aim:</b> Novel thiazole hybrids were synthesized via thiazolation of 4-phenylthiosemicarbazone (<b>4</b>). <b>Materials & methods:</b> The anticancer activity against the NCI 60 cancer cell line panel. <b>Results:</b> Methyl 2-(2-((1-(naphthalen-2-yl)ethylidene)hydrazineylidene)-4-oxo-3-phenylthiazolidin-5-ylidene)acetate (<b>6a</b>) 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 IC<sub>50</sub> of 1.569 ± 0.06 μM. Compound <b>6a</b> inhibited PI3Kα with IC<sub>50</sub> = 0.225 ± 0.01 μM. Moreover, compound <b>6a</b> revealed a decrease of Akt and mTOR phosphorylation in OVCAR-4 cells. In addition, antibacterial activity showed that compounds <b>11</b> and <b>12</b> were the most active against <i>Staphylococcus aureus</i>. <b>Conclusion:</b> Compound <b>6a</b> is a promising molecule that could be a lead candidate for further studies. Novel naphthalene-azine-thiazole hybrids <b>5-12</b> were synthesized via late-stage thiazolation of the corresponding 4-phenylthiosemicarbazone <b>4</b>. Compound <b>6a</b> showed significant anticancer activity at single-dose screening and yielded excellent inhibitory activity with a mean GI of 51.18%. Compound <b>6a</b> showed the highest cytotoxic activity against OVCAR-4 with an IC<sub>50</sub> of 1.569 ± 0.06 μM. Moreover, compound <b>6a</b> exhibited an IC<sub>50</sub> of 31.89 ± 1.19 μM against normal ovarian cell line (OCE1) and a selectivity index of 19.1. Compound <b>6a</b> inhibited PI3Kα with IC<sub>50</sub> = 0.225 ± 0.01 μM compared with alpelisib (IC<sub>50</sub> = 0.061 ± 0.003 μM). Moreover, compound <b>6a</b> revealed a powerful decrease of Akt and mTOR phosphorylation in the OVCAR-4 cell line. The cell cycle analysis showed that compound <b>6a</b> 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 <b>11</b> and <b>12</b> were the most active derivatives, with MIC value of 256 μg/ml against <i>Staphylococcus aureus</i>. Molecular docking was done and showed that <b>6a</b> 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, <b>6a</b> is the most promising molecule that could be a lead candidate for further studies. A series of naphthalene-azine-thiazole derivatives were synthesized and evaluated for their anticancer and antibacterial activity. These findings propose that compound <b>6a</b> has cytotoxic properties and is a starting structure for a new generation of PI3Kα kinase inhibitors. 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 <b>11</b> and the coumarin-containing derivative <b>12</b> showed the highest antibacterial activity with MIC value of 256 μg/ml against <i>S. aureus</i>. Compound <b>6a</b> showed the highest activity against the ovarian cancer cell line OVCAR-4 with an IC<sub>50</sub> of 1.569 ± 0.06 μM. Compound <b>6a</b> inhibited PI3Kα with IC<sub>50</sub> = 0.225 ± 0.01 μM compared with alpelisib (IC<sub>50</sub> = 0.061 ± 0.003 μM). Compound <b>6a</b> inhibited the growth of OVCAR-4 cells during the G2/M phase and increased total apoptosis by 26.8-fold. Compound <b>6a</b> 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).