Regioselective Synthesis, Structural Characterization, and Antiproliferative Activity of Novel Tetra-Substituted Phenylaminopyrazole Derivatives

• Published in: Molecules (Basel, Switzerland) Switzerland), 2022-09, Vol.27 (18), p.5814
• Main Authors: Lusardi, Matteo, Profumo, Aldo, Rotolo, Chiara, Iervasi, Erika, Rosano, Camillo, Spallarossa, Andrea, Ponassi, Marco
• Format: Article
• Language: English
• Subjects: Analgesics; antiproliferative activity; Chemical properties; computational simulations; Cyclin-dependent kinases; Cytotoxicity; Hydrazine; Hydrazines; Isomers; Kinases; Mass spectrometry; Mass spectroscopy; Methods; NMR; Nuclear magnetic resonance; Nuclear magnetic resonance spectroscopy; Pharmaceutical research; Prototypes; Pyrazole; Pyrazoles; Reagents; Scientific imaging; Selectivity; Structural analysis; Substitutes; tetra-substituted pyrazoles; Tumor cell lines
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules27185814

A small library of highly functionalized phenylaminopyrazoles, bearing different substituents at position 1, 3, and 4 of the pyrazole ring, was prepared by the one-pot condensation of active methylene reagents, phenylisothiocyanate, and substituted hydrazine (namely, methyl- and benzyl-hydrazine). The identified reaction conditions proved to be versatile and efficient. Furthermore, the evaluation of alternative stepwise protocols affected the chemo- and regio-selectivity outcome of the one-pot procedure. The chemical identities of two N-methyl pyrazole isomers, selected as prototypes of the whole series, were unambiguously identified by means of NMR and mass spectrometry studies. Additionally, semiempirical calculations provided a structural rationale for the different chromatographic behavior of the two isomers. The prepared tetra-substituted phenylaminopyrazoles were tested in cell-based assays on a panel of cancer and normal cell lines. The tested compounds did not show any cytotoxic effect on the selected cell lines, thus supporting their pharmaceutical potentials.