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A new series of thirty nine 5-trifluoromethoxy/fluoro/chloro-isatin 3-hydrazonothiazolines 5a–n, 6a–o and 7a–j were synthesized by cyclization of the corresponding intermediate N4-aryl-substituted isatin-3-thiosemicarbazones 3 (prepared by condensation of appropriate isatin 1 with appropriate N4-aryl-substituted 3-thiosemicarbazides 2) with 4-chlorophenacyl bromide 4 in absolute ethanol or ethanol–benzene mixture and screened for their cytotoxicity, phytotoxicity, antifungal and urease inhibitory potential. All the synthesized compounds were found to be almost inactive in a brine shrimp (Artemia salina) bioassay, demonstrating IC50 values > 1.62 × 10−4 to 2.17 × 10−4 M. In a phytotoxicity assay, out of thirty-nine compounds tested, six i.e. 5i, 6h, 6i, 6k, 7c and 7h proved to be active, showing weak or non-significant (5–30%) activity at the highest tested concentration (500 μg mL−1). Similarly, in antifungal assay, twenty-six compounds i.e. 5a, 5b, 5d–f, 5h–j, 5m, 6a, 6b, 6d, 6j, 6l–o, 7a, 7b and 7d–j were found to be active against one, two, or three selected fungal strains, exhibiting weak or non-significant inhibition (10–30%). Of these, 6d and 6o displayed a relatively better activity profile in terms of the number of organisms inhibited. On the other hand, in a urease inhibition bioassay, all the synthesized hydrazonothiazolines proved to be potent enzyme inhibitors, demonstrating inhibitory activity with IC50 values ranging from 3.70 ± 0.62 to 849 ± 2.26 μM. Compounds 5c, 5g–i, 5k, 5n, 6b, 6c, 6i, 6k, 6l, 6n, 6o, 7a, 7e, 7i and 7j were, however, found to be relatively very potent, displaying outstanding enzymatic activity (IC50 = 3.70 ± 0.62 to 20.9 ± 0.57 μM), even better than the reference inhibitor thiourea (IC50 = 22.3 ± 1.12 μM), and may thus act as valid leads for further studies. Molecular docking studies of the synthesized isatin–thiazolines 5a–n, 6a–o and 7a–j were also carried out to elucidate their relationship with the binding pockets of the enzyme. This study offers the first example of exhibition of urease inhibitory potential by isatin–thiazolines and as such provides a solid basis for further research on these compounds to develop more potent antiurease compounds of medicinal/agricultural interest.

Several isatin-3-thiosemicarbazones (a class of Schiff bases) from our earlier studies have been validated as promising cytotoxic agents and urease inhibitors. Also, a number of isatin-derived imines (Schiff bases) and their Cu(II) complexes have been reported in the literature to exhibit potential cytotoxic activity towards different cells. In view of this, a series of seven new 5-(un)-substituted isatin-derived bis-Schiff bases/ligands 3a–g and their Cu(II) complexes 5a–g were synthesized and evaluated for their cytotoxic and urease inhibitory activities. All the Schiff base ligands 3a–g proved to be active in sulforhodamine B (SRB) bioassay, displaying promising cytotoxic activity against lung carcinoma (H157) cells. Compound 3b was found to be the most potent inhibitor of H157 cells, exhibiting an IC50 value of 2.32 ± 0.11 μM. Similarly, all the metal complexes 5a–g proved to be active in this assay, demonstrating enhanced cytotoxic activity in each case, occurring as a result of coordination of the Schiff base ligands to the metal ion. Compound 5d proved to be the most potent inhibitor of H157 cells, showing cytotoxic activity comparable to that of the standard drug, vincristine (VCN) (IC50 = 1.29 ± 0.06 vs. 1.03 ± 0.04 μM). In the urease inhibition assay, all the synthesized Schiff base ligands except 3f proved to be highly potent enzyme inhibitors, displaying inhibitory activity even better than that of the reference inhibitor, thiourea (IC50 = 0.04 ± 0.004–5.86 ± 0.09 vs. 22.3 ± 1.12 μM), and thus may act as promising lead molecules for further studies. Molecular docking studies were also carried out for bis-Schiff bases 3a–g to elucidate their relationship with the binding pockets of the enzyme.

Activated nitro derivatives of pyridinium salts have been shown to mediate in the highly selective ortho nitration of phenol in high yield.