Synthesis and Biological Studies of Some Isatins-3-Hydrazones Imines and Their Metal Chelates

Abstract

The main focus of this thesis is on the synthesis and biological studies of some novel isatin-derived hydrazones, imines and their metal chelates/complexes. Thus, initially, three series of target potential biologically active hydrazones and imines i.e. (47-54), (55-93) and (94-100) were prepared and evaluated for selected biological activities in the present study. The synthesized hydrazones (47-54) were screened for their in vitro antibacterial, antifungal and cytotoxicity potential. Of these, (50), (51) and (54) showed significant antibacterial activity against P. aeruginosa. Similarly, in antifungal assay, compounds (49-52) displayed significant activity against T. longifusus. Also, compounds (49), (51) and (52) proved to be active in a brine shrimp (Artemia salina) lethality bioassay, exhibiting a high degree of cytotoxic activity with LD50 values 3.82×10-5, 2.34×10-5 and 1.53×10-5 M, respectively. The synthetic hydrazones (55-93) were evaluated for their antibacterial, antifungal, phytotoxic, cytotoxic and urease inhibitory effects. In antibacterial assay, none of these was found to be active against any of the tested bacteria. On the contrary, in antifungal assay, twenty six compounds i.e. (55-59), (62-64), (66), (69-70), (72), (78), (80-85) and (87-93) were found to be active, exhibiting weak or non-significant activity (10-30%) against one, two, or three tested fungi. Similarly, in phytotoxicity assay, six compounds i.e. (63), (76), (77), (79), (86) and (91) demonstrated weak or non-significant activity (5-30%) at the highest tested concentration (500μg/mL). To the contrary, in the brine shrimp assay, all the compounds gave LD50 values >1.62 x 10-4 – 2.16 x 10-4 M and, therefore, considered to be almost inactive. However, in urease inhibition assay, they proved to be potent inhibitors of the enzyme, showing IC50 values ranging from 3.70 ± 0.62 to 849 ± 2.26 μM. Compounds (57), (61-63), (65), (68), (70), (71), (77), (79), (80), (82-84), (88), (92) and (93) were found to be relatively more potent, displaying antiurease activity (IC50 = 3.70 ± 0.62 – 20.9 ± 0.57 μM) even better than the reference inhibitor, thiourea (IC50 = 22.3 ± 1.12 μM). Molecular docking studies were also carried out for the hydrazones (55-93) to elucidate their relationship with the binding pockets of the enzyme. Like compounds (55-93), the synthesized bis-imines (94-100) were screened for their in vitro antibacterial, antifungal, phytotoxic, anticancer and antiurease influences. All the compounds were found to be active in antibacterial assay, demonstrating weak to moderate activity against one or more bacterial stains. Similarly, in antifungal assay, all except (100) proved to be active, displaying weak to significant activity against one or more fungi. Furthermore, all the imines also appeared to be active in phytotoxicity assay, showing varied degree of plant growth inhibition (5-100%) at the highest tested concentration (500μg/mL) but much inferior to the reference compound, paraquat, which shows 100 % growth inhibition at 0.015 μg/mL concentration. In sulphorhodamine B (SRB) assay, however, they were found to possess good anticancer activity (IC50 = 2.32 ± 0.11 − 3.88 ± 0.34 μM) against lung carcinoma (H157) cells and low cytotoxicity at Vero cells. Also, in urease inhibition assay, they proved to be potent inhibitors of the enzyme, exhibiting IC50 values in the range 0.04 ± 0.004 – 25.2 ± 1.34 μM. The synthetic bis-imines or Schiff bases (94-100) were used as ligands for synthesizing their Cu(II) complexes (101-107), which were evaluated for their antibacterial, antifungal, anticancer and antiurease potential. All the compounds except (107) were found to be active in antibacterial assay, exhibiting weak to moderate activity against one or more bacterial stains. Similarly, in antifungal assay, all except (102) and (107) displayed weak to good antifungal activity against one or two fungal strains. In anticancer (SRB) assay, coordination/chelation of the Schiff base ligands (94-100) to metal ion was found to cause significant enhancement of activity in all the cases. However, in urease inhibition bioassay, it was found to cause reduction in the enzymatic activity of all the compounds except (105).