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

The hydrazones 3a-c, 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 3b and 3c were confirmed using single crystal X-ray crystallography to exist in the Eanti form. With the aid of DFT calculations, the most stable configuration of the hydrazones 3a-c in gas phase and in nonpolar solvents (CCl4 and cyclohexane) is the ESyn form. Interestingly, the DFT calculations indicated the extrastability of the EAnti 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 3a-c was presented. The hydrazones 3a-c showed a polar character where 3b has the highest polarity of 5.7234 Debye compared to the 3a (4.0533 Debye) and 3c (5.3099 Debye). Regarding the anti-toxoplasma activity, all the detected results verified that 3c had a powerful activity against chronic toxoplasma infection. Compound 3c showed a considerable significant reduction percent of cyst burden in brain homogenates of toxoplasma infected mice representing 49%.

Synthesis of AZT analogues: 7-(3-azido-2-hydroxypropyl)-, 7-(3-amino-2-hydroxypropyl)-,7-(3-triazolyl-2-hydroxypropyl)theophylline.

Nucleophilic displacement of the tosyloxy group in 7-(2-hydroxy-3-p-toluenesulfonyloxypropyl)theophylline (1) with azide anion afforded 7-(3-azido-2-hydroxypropyl)theophylline (2). Reduction of the 3-azido group in 2 with Ph3P/Py/NH4OH afforded the 3-amino derivative 4, alternatively obtained by regioselective amination of 7-(2,3-epoxypropyl)theophylline (3). Selective acetylation of 4 gave the N-acetyl derivative 5. 1,3-Dipolar cycloaddition of the azide group in 2 with N1-propargyl thymine (6) afforded the regioisomeric triazole 7.