Design, Synthesis, Cytotoxicity, and Computational Screening of Pyrazole-Based Benzamide Derivatives

A group of novel 4-(1,3-dimethyl-1H-pyrazol-5-yl)-3,5-dimethoxy-N-(substituted) benzamide derivatives were developed through a sequence of Suzuki–Miyuara coupling, hydrolysis, and amine acylation reactions. They underwent evaluations for their in vitro cytotoxic effects on human breast (MCF-7), lung (A-549), and liver (HepG2) cell lines, using doxorubicin as a control. Naphthalene derivative 6g exhibited remarkable efficacy across all three cell lines, showing IC50 values of 9.47 ± 0.22, 9.52 ± 0.25, and 9.97 ± 0.35 µM against MCF-7, A-549, and HepG2, respectively, in comparison with the standard. Another compound 6e featuring m-cyano and o-methyl groups demonstrated notable activity across all three cell lines, with IC50 values of 10.17 ± 0.41 µM for MCF-7, 10.97 ± 0.49 µM for A-549, and 11.05 ± 0.51 µM for HepG2. The selectivity index of these compounds indicated a greater preference for targeting cancer cells and less toxic to normal cells. Molecular docking of potent ligands against FGFR1 yielded optimal docking scores, characterized by hydrogen bonding and hydrophobic interactions. The anticipated pharmacokinetics led to augmented drug-like properties.