Synthesis of novel mono- and bis-pyrazolylthiazole derivatives as anti-liver cancer agents through EGFR/HER2 target inhibition

3-Bromoacetyl-4-(2-naphthoyl)-1-phenyl-1H-pyrazole (6) was synthesized from 2-acetylnaphthalene and was used as a new key building block for constructing the title targets. Thus, the reaction of 6 with the thiosemicarbazones 7a–d and 9–11 afforded the corresponding simple naphthoyl-(3-pyrazolyl)thiazole hybrids 8a–d and 12 ~ 14. The symmetric bis-(2-naphthoyl-pyrazol-3-yl)thiazol-2-yl)hydrazono)methyl)phenoxy)alkanes 18a-c and 21a-c were similarly synthesized from reaction of 6 with the appropriate bis-thiosemicarbazones 17a-c and 19a-c, respectively. The synthesized two series of simple and symmetrical bis-molecular hybrid merging naphthalene, thiazole, and pyrazole were evaluated for their cytotoxicity. Compounds 18b,c and 21a showed the most potent cytotoxicity (IC(50) = 0.97–3.57 µM) compared to Lapatinib (IC(50) = 7.45 µM). Additionally, they were safe (non-cytotoxic) against the THLE2 cells with higher IC(50) values. Compounds 18c exhibited promising EGFR and HER-2 inhibitory activities with IC(50) = 4.98 and 9.85 nM, respectively, compared to Lapatinib (IC(50) = 6.1 and 17.2 nM). Apoptosis investigation revealed that 18c significantly activated apoptotic cell death in HepG2 cells, increasing the death rate by 63.6-fold and arresting cell proliferation at the S-phase. Compound 18c upregulated P53 by 8.6-fold, Bax by 8.9-fold, caspase-3,8,9 by 9, 2.3, and 7.6-fold, while it inhibited the Bcl-2 expression by 0.34-fold. Thereby, compound 18c exhibited promising cytotoxicity against EGFR/HER2 inhibition against liver cancer. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13065-023-00921-6.