Spectral, structural, and pharmacological studies of perillaldehyde and myrtenal based benzohydrazides

Abstract

N-Acylhydrazones have been an interesting scaffold due to their diverse biological activities toward different therapeutic targets. We synthesized seven new N'‐[(E)‐[(4S)‐4‐(prop‐1‐en‐2‐yl)cyclohex‐1‐en‐1‐yl]methylidene]benzohydrazides as well as seven new N'-[(E)-{6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl}methylidene]benzohydrazides. The structure of synthesized hydrazides has been studied by using X-ray analysis, FT-IR, NMR, and HRMS spectra. Derivatives containing fluorine atoms in position 2 of the phenyl ring display versatile structures in solution and the solid state. The 1H NMR spectra of 3c and 5c measured in DMSO-d6 display at ambient temperature two unequally populated sets of signals. These facts confirm the existence of the two conformers of 3c and 5c of different stability which interconvert by rotation about their C―N bond slowly enough to lead to discrete sets of signals in 1H NMR spectra at room temperature. The kinetics of the conformational interconversion of derivatives 3c and 5c in DMSO-d6 were studied by two-dimensional exchange spectroscopy (2D EXSY). In 1H NMR spectra of 3c and 5c measured in CDCl3 and acetone-d6 was observed the strong splitting of the H-2 signal into a doublet because of H-bond formation between organic fluorine and NH donor. The FT–IR spectra of 3a–g and 5a–g confirmed the presence of the H-bonds N–H···O=C and N–H···N. Hydrazones 3f, 5a, and 5c crystallize in the P1 space group and the asymmetric units contain two pairs of pseudo-centrosymmetric molecules. Hydrazone 5b crystallizes in the P41 space group and the asymmetric units contain only one molecule. In the crystal, the molecules in 3f, 5a and 5b are linked through N―H···O hydrogen bonds, in 5c also N―H···N hydrogen bonds are present. In contrast to the NMR, the X-ray and IR spectra did not give unambiguous evidence of the F···H−N H-bond. The synthesized hydrazones 3c and 3g exhibited excellent antiproliferative effects in Jurkat cells with IC50 values of 3.8 and 4.2 μM, respectively. Our findings indicate that these compounds are promising antitumor agents.