Vol. 30, No. 10 (2018)
Quinazolinone Platinum Metal Complexes: in silico Design, Synthesis and Evaluation of Anticancer Activity 2165
contains a 2,4-diaminopteridine ring and N,N-dimethyl-p-
aminobenzoic acid residue linked with glutamic acid by a
peptide bond. In aqueous solution, it exists in fully protonated
form as a H3L ligand [11]. The main objectives for drug design
were to achieve relative safety, circumvention of resistance
and improvement on the spectrum of activity of the proposed
metal complexes. in silico screening of compounds was carried
out usingVlife MDS 4.3 software. Quinazoline metal complex
derivatives were synthesized through bromination, esterifi-
cation, ring formation by formamide at 120 °C, Schiff base
synthesis and finally, lead molecules were synthesized by co-
ordination metal complex formation. These compounds were
characterized by IR, NMR, XRD, FESEM studies. in vitro
cytotoxicity study was performed on 10 human cell lines in
ACTREC, Navi Mumbai with adiramycin as standard drug
for comparison.
this point was reached, the mixture was converted into thick
mass of white glistening crystals of hydro bromides of the
bromo anthranilic acids. The product was filtered, washed with
benzene and dried. It was then boiled with dilute hydrochloric
acid and filtered while hot under suction. The insoluble residue
was extracted twice with boiling water. The filtrate, upon
cooling yielded an abundant precipitate of the bromo anthra-
nilic-acid (2).
Antranilic acid/bromo anthanilic acid (2) (1 eq) 1 g 0.007
mol was dissolved in pyridine and reaction was maintained at
0 °C. Then benzoyl chloride (1 eq) (0.84 mL, 0.007) mol was
added drop wise. The reaction mixture was stirred for 3-4 h.
While ice cold water was added, white precipitate of 2-phenyl-
4H-benzo[d][1,3]oxazin-4-one (3) was obtained, filtered and
washed with cool water to remove pyridine.
A suspension of ethyl 2-amino-5-bromobenzoate (2)
(0.500 g, 2.048 mmol) in formamide (1.225 mL, 30.7 mmol)
was refluxed at 120 °C for 4 h. Reaction was monitored by
TLC using 50 % ethyl acetate in petrolium ether as mobile
phase. After the complete conversion of starting material,
reaction mixture was cooled to room temperature to form crys-
talline precipitate. Reaction mixture was poured on ice-cold
water and then solid formed was filtered out as 6-bromoquina-
zolin-4(3H)-one (3) (0.218 g), 0.969 mmol.
Antranilic acid/bromoanthanilic acid (2) (1.08 g) was
dissolved in DMSO (3 mL). Then KOH (1.5 eq) and CS2
(0.5mL) was added [18]. The reaction mixture was refluxed
at 110 °C for 3-4 h with continuous stirring. Reaction mixture
was then neutralized with dil. sulphuric acid to form product
3. The product was separated by vacuum filtration.
2-Phenyl-4H-benzo[d][1,3]oxazin-4-one (1 eq) 2.5 g,
0.015 mol was dissolved in pyridine, then hydrazine hydrate
(2 eq) 1.5 mL, 0.031 mol was added. The reaction mixture
was refluxed for 3-4 h and reaction was monitored by TLC.
Ice cold water was added to precipitate out white solid product
4. It was filtered and washed with cool water to remove pyridine.
Synthesis of 3-(2-substituted benzylideneamino)-2-
phenylquinazolin-4(3H)-one: To hot ethanolic solution of 2-
amino 3-phenyl quinazolin 4-one (4) 0.5 g (0.002 mol) (1 eq),
hot ethanolic solution of substitued benzaldehyde (1 eq) was
added and 2-3 drops of H2SO4 were subsequently added. The
reaction mixture was then refluxed with stirring for 1 h to form
solid mass 5. The product was separated by vacuum filtration.
Synthesis of 3-(2-substituted benzylideneamino)-2-
phenylquinazolin-4(3H)-one platinum metal complex [19]:
Calculated amount of quinazolinone Schiff base 5 (1.2 eq)
was dissolved in hot ethanol. To this solution; calculated
amount of metal salt (1.1 eq) [(PtCl2·2H2O) was added with
continuous stirring. The reaction mixture was refluxed with
continuous stirring for 2-3 h. On cooling, complex 6 was preci-
pitated out (Scheme-I). It was then washed with aqueous ethanol
and dried under vacuum. The details of 12 Schiff bases and
synthesized metal complexes are given in Tables 2 and 3, respec-
tively.
EXPERIMENTAL
Docking simulation: Computer-assisted simulated docking
experiments were carried out inV-life MDS 4.3 for prioritized
molecules. Validation of protein subunit was done by the online
server [12].Protein data bank (PDB: 1S3V) contains structural
information of the macromolecules determined by X-ray
crystallography and NMR spectroscopy [13]. Two dimensional
structures of ligand were prepared in ChemDraw or Marvin
sketch and converted to 3D by Vlife sciences MDS 4.3. The
3D structures were energetically minimized using Merck
Molecular Force Field (MMFF). Conformers of the compounds
were generated by Monte Carlo method. All the Conformers
were then energetically minimized up to the RMS gradient of
0.01. MMFF was used for optimizing molecules. Parameters
used were MMFF, Gasteiger Marsili charge and dielectric
properties were kept constant. Library of ligands containing
40 molecules were designed as shown in Table-1.
All chemicals were purchased from Sigma Aldrich,
Merck, Spectrochem and Research Laboratory of laboratory
grade and analytical grade. Column chromatography was
performed for purification of compounds on Spectrochem
silica gel (60-120 mesh). TLCs were carried out on pre-coated
silica gel, GF254 aluminium sheets (Merck 5554). Melting
points were determined in open capillary on Veego (India)
electronic apparatus and are uncorrected. FT-IR spectra were
recorded on Shimadzu FTIR Affinity-1 instrument with disk
1
pellet method using potassium bromide. The H NMR (300
MHz) spectra were recorded on a Bruker 500 MHz; Model:
Advance III HD, in CDCl3 and DMSO in CIF Center, Savitribai
Phule University, Pune. FESEM- EDS were performed on
Bruker XFlash 6I30 and element detection range from 4Be to
95Am. This method basically used for quantification analysis
of metals in synthesized complex from CIF, Savitribai Phule
University of Pune, Pune, India.
Synthesis of Schiff bases
Synthesis of 3-(2-substituted benzylideneamino)-2-
substituted quinazolin-4(3H)-one (3) [14-17]: Anthranilic
acid (1) (12 g, 0.1 mol) was dissolved in glacial acetic acid
and cooled at 0 °C. Then bromine in acetic acid was added,
till the reddish-brown colour of the bromine persisted. Before
in vitro Cytotoxicity assay: in vitro cytotoxicity of the
synthesized compounds were performed at ACTREC, Navi
Mumbai, against 10 Human Cancer Cell lines i.e.A549 (lungs),
K562 (lukemia), MCF7 (breast), SiHa (cervix), KB (nesophayn-
Sawant, Sanjay D.
