Synthesis and Antitumor Activity of New Metronidazole-Linked Thiophene or Pyrazole Analogues

A series of metronidazole hybridized with various substituted thiophene and/or pyrazole derivatives was synthesized, and their structure was identified by using spectroscopic methods, including IR, MS, ¹H NMR, and ¹³C NMR. The created metronidazole-thiophene and metronidazole-pyrazole hybrids were investigated toward dissimilar cell lines, HCT-116, PC3, HepG2, and MCF-7, as well as the WI38 standard cell line, and the results showed a good effectiveness toward the MCF-7 cell line in comparison to Dox. as a control. Meanwhile, metronidazole hybrids 14a-d containing an amino-pyrazole moiety demonstrated strong anticancer activity against MCF-7 with IC₅₀ ranging from 5.18 ± 0.39 to 11.51 ± 0.33 μM while Dox exhibited an IC₅₀ of 1.36 ± 0.18 μM. The structure–activity relationship of synthesized metronidazole hybrids was examined, and an intriguing remark was observed in terms of anticancer activity, particularly against the MCF-7 cell line. The molecular docking method was employed to analyze how the target protein (PdB: 3U9W, human leukotriene A-4 hydrolase, LA4H) interacts with the synthesized molecules.