Synthesis, Biological Evaluation, and Quantitative Structure−Activity Relationship Analysis of New Schiff Bases of Hydroxysemicarbazide as Potential Antitumor Agents

Abstract

Thirty Schiff bases of hydroxysemicarbazide (Ar-CH=NNHCONHOH) have been synthesized and tested against L1210 murine leukemia cells. The IC(50) values were found to be in a range from 2.7 x 10(-6) to 9.4 x 10(-4) M. A total of 17 out of the 30 compounds had higher inhibitory activities than hydroxyurea (an anticancer drug currently used for the treatment of melanoma, leukemia, and ovarian cancer) against L1210 cells. Six compounds with IC(50) values in micromolar range were 11- to 30-fold more potent than hydroxyurea (IC(50) = 8.2 x 10(-5) M). The partition coefficient (log P) and ionization constants (pK(a)) of a model compound [1-(3-trifluoromethylbenzylidene)-4-hydroxysemicarbazide, 1] were measured by the shake-flask method, and the measured log P was used to derive Hansch-Fujita pi constant of -CH=NNHCONHOH. On the basis of the newly derived pi and those of other moieties, the partition coefficients (SlogP) of the other 29 compounds were calculated by the summation of pi values. Quantitative structure-activity relationship (QSAR) analysis showed that, besides the essential pharmacophore (-NHCONHOH), hydrophobicity (SlogP), molecular size/polarizability (calculated molar refractivity), and the presence of an oxygen-containing group at the ortho position (I) were important determinants for the antitumor activities. In conclusion, the results obtained in this study show that several Schiff bases of hydroxysemicarbazide are potent inhibitors of tumor cells and warrant further investigation as cancer chemotherapeutic agents.

Crystal structure of 3,5-dihydroxy-N'-(1-naphthylmethyl)- benzohydrazide monohydrate, C18H14N2O3 · H2O

“…Some of the complexes derived from Schiff bases have been found to have pharmacological and antitumor properties [1][2][3][4]. The asymmetric unit of the title crystal structure consists of a hydrazone molecule and awater molecule of crystallization.…”

Schiff bases: An emerging potent class of pharmaceuticals

“…The rapid development of these ligands resulted in an enhanced research activity in the field of coordination chemistry leading to very interesting conclusions. Many biologically important schiff bases have been reported in the literature possessing, antibacterial (Biyala et al, 2007;Morad et al 2007;Rajavel et al 2008;Chohan et al, 2007) , antifungal (Rajendran et al, 2002), antimicrobial (Mishra et al, 2008), anticonvulsant (Sridhar et al, 2002), anti HIV , anti-inflammatory ) and antitumor activities (Desai et al, 2001;Ren et al, 2002) Schiff bases derived from a large number of carbonyl compounds and amines are an important class of ligands that coordinate to metal ions via azomethine nitrogen and have been studied extensively (Tumer et al, 1998). Schiff base complexes derived from 4-hydroxysalicylaldehyde and amines have strong anticancer activity e.g.…”

“…Bioinorganic and biomimetics, containinga C=N bond, are widely represented (Biyala et al, 2008). Schiff bases have been intensively investigated recently owing to their strong coordination capability and diverse biological activities, such as antibacterial and antitumor activities (Ren et al, 2002). The tuberculostatic activity of isonicotinic acid hydrazide and its aroylhydrazones containing azomethine nitrogen is attributed to their ability to form stable complexes with d-and f-block metal ions (Pal, 2002).…”

Preparation, Characterization and Biological Activity Studies for Some Mixed Ligands Complexes of 1, 10- Phenanthroline and Schiff Base Ligand with Metal Ions

“…The geometrical construction appears often in the π-system of a Schiff's base and thermo chemically characterizes of Schiff's as well, impacts the electronic composition have attracted much investigator notice in view of their capability to chalet metal ions, appearing as bidentate ligands in metal coordinates including (N,N,O,O) donor atom positions [13,14]. The Schiff …”