Synthesis, X-ray Structure, Hirshfeld, DFT Conformational, Cytotoxic, and Anti-Toxoplasma Studies of New Indole-Hydrazone Derivatives

Abstract

The hydrazones <b>3a</b>-<b>c</b>, were synthesized from the reaction of indole-3-carbaldehyde and nicotinic acid hydrazide, isonicotinic acid hydrazide, and benzoic acid hydrazide, respectively. Their structures were confirmed using FTIR, ¹HNMR, and ¹³CNMR spectroscopic techniques. Exclusively, hydrazones <b>3b</b> and <b>3c</b> were confirmed using single crystal X-ray crystallography to exist in the <b><i>Eanti</i></b> form. With the aid of DFT calculations, the most stable configuration of the hydrazones <b>3a</b>-<b>c</b> in gas phase and in nonpolar solvents (CCl₄ and cyclohexane) is the <b><i>ESyn</i></b> form. Interestingly, the DFT calculations indicated the extrastability of the <b><i>EAnti</i></b> in polar aprotic (DMSO) and polar protic (ethanol) solvents. Hirshfeld topology analysis revealed the importance of the N…H, O…H, H…C, and π…π intermolecular interactions in the molecular packing of the studied systems. Distribution of the atomic charges for the hydrazones <b>3a</b>-<b>c</b> was presented. The hydrazones <b>3a</b>-<b>c</b> showed a polar character where <b>3b</b> has the highest polarity of 5.7234 Debye compared to the <b>3a</b> (4.0533 Debye) and <b>3c</b> (5.3099 Debye). Regarding the anti-toxoplasma activity, all the detected results verified that <b>3c</b> had a powerful activity against chronic toxoplasma infection. Compound <b>3c</b> showed a considerable significant reduction percent of cyst burden in brain homogenates of toxoplasma infected mice representing 49%.