Synthesis, X-ray structure, Hirshfeld, cytotoxicity and anticancer studies of pyrazole and pyridazin-4(H)-one derivatives

In this study, 2-(1-benzoyl-5-hydroxy-3-phenyl-4,5-dihydro-1H-pyrazol-5-yl)-1-phenylethan-1-one (3) and 3benzyl-6-phenylpyridazin-4(1H)-one (4) were synthesized, characterized and their anti-cancer activities were evaluated. The structures of both compounds were confirmed from their FTIR, 1H, 13C, 1H1H- COSY, 1H13C- HMQC NMR spectra and microanalysis. The structure of 4 is further confirmed using X-ray single crystal diffraction. The structure is not perfectly planar showing different degrees of twisting between the aromatic ring systems. Hirshfeld calculations revealed the importance of the O...H (7.8%), N...H (4.9%) and C...O (1.8%) short contacts in the supramolecular structure of 4. The two newly synthesized derivatives were first screened for cytotoxic activities on normal skin fibroblasts (HSF) for evaluating their safety profiles. More investigations were conducted by evaluating their anticancer activities against two human tumors (MDA-MB 231 and HCT). Both compounds were found more active than the reference 5-fluorouracil against MDA-MB231 showing IC50 values of 8.02 mu M and 6.205 mu M for 3 and 4, respectively, however, 68.155 mu M and 71.8 mu M on treating of HCT cells. Finally, both compounds were subjected for molecular docking studies into the binding site of the Aldehyde Dehydrogenase 1A (ALDH1A) enzyme based on findings of the earlier in vitro biological evaluation to get a better understanding of potential intermolecular interactions and look into the possibility of a binding pattern that may be responsible for the compounds inhibitory activities.