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Synthetic and natural spiroxindoles are important anti-inflammatory, antibacterial, antileishmanial, and anticancer agents. In this study, we prepared a spiroxindole derivative and evaluated the preliminary results of its biological activity including anti-inflammatory, antileishmanial, and cytotoxic activity against 3T3 and Hela cell lines. By adopting the 1,3-dipolar cycloaddition reaction, we were able to successfully combine olefin, isatin, and an amino acid to form the desired spiroxindole analog 4 (yield, up to 94%). To elucidate the chemical structure of 4, the X-ray single crystal diffraction technique was employed, and the electronic and NMR spectra of 4 were calculated using the B3LYP/6-311G(d,p) method. The calculated 1H and 13C NMR chemical shifts aligned well with the experimental data. Compound 4 was then evaluated for its anti-inflammatory, antileishmanial, and cytotoxic activity against 3T3 and Hela cell lines. This spiroxindole pyrothiazole (IC50 = 65.9 ± 6.6 μM) showed weak anti-inflammatory activity compared to the test standard, ibuprofen (IC50 = 11.2 ± 1.9 μM), and moderate anticancer activity against Hela cell lines compared to doxorubicin (IC50 = 1.2 ± 0.4 μM vs IC50 = 11.2 ± 0.3 μM for 4). Compound 4 also appeared as an effective antileishmanial agent (IC50 = 39.8 ± 0.43 μM) when tested in vitro.

A green, simple and efficient protocol for the synthesis of the two new barbituric acid derivatives; 4 and 5 is described. One pot fashion of 2 mol of barbituric acid derivatives with 3-fluorobenzaldehyde in green solvent (H2O) providing compound 4. Reaction of equimolar of barbituric acid derivatives, dimedone and 4-(trifluoromethyl)benzaldehyde gave compound 5. Using the density functional theory at the B3LYP level and 6-311G(d,p) as basis set, the molecular structures of the studied compounds were optimized. The minimum energy structures have geometrical parameters correlated well with the experimental data. 4 has two barbituric acid moieties more deviated from the planarity than the barbiturate ring in 5. The latter exists in the enol form and it is stabilized by strong intramolecular hydrogen bonding interactions. The NBO analysis revealed the presence of significant π-π* intramolecular charge transfer in this ring, while this effect is absent in 4. The electronic spectra of the studied compounds were investigated experimentally and theoretically using the TD-DFT method. The compound which has one more conjugated ring (5) has one more band at longer wavelength of 318 nm (calc. 313.5 nm) which is assigned to H→L (93%) excitation. The anti-oxidant activity as reactive oxygen scavenger was examined in this research. The NO and DPPH radical scavenger assays were carried out. The results clearly demonstrated that compounds 4 and 5 possess a significant effect as reactive oxygen scavenger compared with the standard drugs. The ligand efficiency (LE) metrics as LE value and ligand lipophilic efficiency (LLE) were calculated and they showed that compound 4 has better character as drug likeness candidate rather than compound 5. The docking study of the compounds showed that compound 4 docked with the receptor (PDB ID: 3JSW) through lipophilic-lipophilic interaction. Interestingly, compound 5 represent dissimilarity from compound 4.

Ferrocene-based anti-inflammatory drug discovery has become an important area in medicinal chemistry. Utilizing the condensation of isatin or ferrocene carbaldehyde with nucleophile, such as oxamic acid hydrazide, the desired isatin 1, and ferrocene 2 oxamohydrazide derivatives were smoothly synthesized in high purity and yield. The structures of the isatin, and ferrocene oxamohydrazides were elucidated using single crystal X-ray diffraction technique, and DFT calculations. Hirshfeld analysis sheds the light on the importance of the O⋯H hydrogen bonds in the molecular packing in both compounds. The oxamohydrazides were examined for anti-inflammatory, and anti-leishmanial activities. The ferrocene oxamohydrazide analogue 2, (IC50 = 5.7 ± 0.3 μM) exhibited a potent anti-inflammatory effect, and was two times more active than the tested ibuprofen as control (IC50 = 11.2 ± 1.9 μM).