DESIGN, SYNTHESIS, BIOLOGICAL EVALUATION AND MOLECULAR DOCKING STUDIES OF NOVEL QUINAZOLINE DERIVATIVES AS GSK-3Β INHIBITORS - PDF

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WRLD JURAL F PHARMACY AD PHARMACEUTICAL SCIECES Srinivas S et al. Volume 2, Issue 6, Research Article ISS DESIG, SYTHESIS, BILGICAL EVALUATI AD MLECULAR DCKIG STUDIES F VEL QUIAZLIE

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WRLD JURAL F PHARMACY AD PHARMACEUTICAL SCIECES Srinivas S et al. Volume 2, Issue 6, Research Article ISS DESIG, SYTHESIS, BILGICAL EVALUATI AD MLECULAR DCKIG STUDIES F VEL QUIAZLIE DERIVATIVES AS GSK-3Β IHIBITRS Srinivas S *, Aparna V. Department of Pharmaceutical Chemistry Ganga Pharmacy College, izamabad , A.P, India. Article Received on 20 August 2013, Revised on 21 Sept 2013, Accepted on 17 ovember 2013 *Correspondence for Author: * Srinivas S, Department of Pharmaceutical Chemistry Ganga Pharmacy College, izamabad , India. ABSTRACT A novel serial of 3-[2-(methyl amino) methyl]-5-{[(2- phenylquinazolin-4-yl)oxy]methyl}-1,3,4-oxadiazole-2(3h)-thione and -4(substituted phenyl)-5-{[(2-phenylquinazolin-4-yl)-oxy]-methyl}- 1, 3, 4-thiadiazol-2-amine derivatives were synthesized, evaluated for their hypoglycemic activity and molecular docking studies were performed against X-ray crystal structure of GSK-3β, are shown their role in the hypoglycemic activity. The molecules are the high potency of compound 6a, 6g, 8a, 8b, and 8e based on glide score and binding poses of the molecules. Key words: GSK-3β inhibitors, quinazolinyl oxadiazoles and kinase inhibitors. ITRDUCTI (Glycogen synthase kinase (GSK) is ser/ thr kinase, originally identified as the enzyme responsible for the inactivating phosphorylation of glycogen synthase 1. The two isoforms GSK-3α (51 KDa) GSK-3β (47KDa) are known and there is high homology (90%) in their kinase domine 2. GSK-3β plays a crucial role in glucose homeostasis, Central ervous system (CS) function (via protein tau and β-catenin) and cancer (via angiogenesis, apoptosis and tumor genesis) 2. Introduction of gsk-dependent phosphorylation should activate insulin dependent glycogen synthesis; there by mimicking the action of insulin to lower plasma glucose 3, thus inhibitors of GSK-3β would afford a novel mode of treating type-ii diabeties 4, 5842 along with type-ii diabetes gsk-3β inhibitors have therapeutic potential for treating neurodegeneration disease, bipolar disorder, strock, cancer, chronic inflammatory disease and alzemer, s disease, huntingtone, s disease, cardiac ischemia and age related loss of bone 4. Keeping in view of this fact, the design and synthesis of newer GSK-3β inhibitors are of immense significance and continue to attract the attention of numerous medicinal chemist and in this present study a novel serice of quinazolinyl oxadiazoles and quinazolinyl thiadiazoles derivatives were synthesized (Scheme-1) and recrystalised by dimethyl formamide as solvent and all synthesized compounds were characterized by IR, H 1 MR, a molecular docking studies were performed against X-ray crystal structure of GSK-3β (pdb code; 1q3d). All these molecules were docked in to the ATP binding site of GSK-3β and their docking score represented in table no.1 and evaluated for their hypoglycemic activity. MATERIALS AD METHD Melting points were recorded on melting apparatus and are uncorrected. IR spectra were recorded on a perkin-elmer FT-IR 240-c spectrophotometer using KBr optic. H 1 MR spectra were recorded on Bruker (Bruker BioScience, USA) AV300 MHz in CDCl 3 using TMS as an internal standard. All reactions were monitored by thinlayer chromatography (TLC) on precoated silicagel 60F254 (mesh); spots were visualized with UVlight. The compound (3):(2-phenyl-4-Quinazolinyl)-oxy-acetate were synthesized by reported method 5 General procedure for synthesis of (2-phenyl-4-Quinazolinyl)-oxy-acetyl hydrazine (4): Compound 3 (0.01 mol) and hydrazine hydrate (0.01 mol) were taken up in absolute ethanol (15ml) and heated on a water bath at reflux for period of 6hrs. The solid that precipitated on cooling were filtered, dried and purified by column chromatography. The physical data of synthesized compound were represented in table no. 2. IR (KBr, cm -1 ): 1290(C--C), 1616 (C=), 1762(C=), 3056, 2918(C-H); H 1 MR (CDCl 3, ppm) δ: 4.2(s, 2H, CH 2 ), 4.4 (s, 2H, H 2 ), (m, 9H, Ar-H), 9.3(s, 1H, -H). General procedure for synthesis of 5{(2-phenyl quinazolin-4yl)-oxy- methyl}-1, 3, 4 oxadiazole-2(3h)-thione (5): Compound 4 (0.01mol) and carbon disulphide (0.03) were taken in ethanolic solution of KH (0.1mol) 15 ml, and heated at reflux on a water bath for 20 hrs. Completion of the reaction is monitored by TLC, the solvent was evaporated under reduced pressure and the residue was triturated with cold water, neutralization of the solution with acetic acid yielded a 5843 precipitate which was filtered, dried and purified using column chromatography. The physical data of synthesized compound were represented in table no. 2. IR (KBr, cm -1 ): 3448 (-H), 1204 (C=S), 1632 (C=), 3051, 2851 (C-H); H 1 MR (CDCl 3, ppm) δ: 4.3 (s, 2H, CH 2 ) 7.3(s, 1H, H), (m, 4H, Ar-H), (t, 2H, Ar-H), (t, 2H, Ar-H), 8.5(s, 1H, Ar-H). Synthesis of 3-[2-(methyl amino) methyl]-5-{[(2-phenylquinazolin-4-yl)-oxy]-methyl}-1,3,4- oxadiazole-2(3h)-thione(6a-): To a boiling solution of compound 5 (0.01mol) in ethanol (25ml) containing aqueous formaldehyde (40% 1ml) and -alkyl amines (0.01mol) was added with stirring and the solution heated for 30 mints and left over night. The solid separated was filtered under reduced pressure, washed with pet. ether and recrystalised from ethyl acetate and purified using column chromatography. Similarly the compounds 6b to 6i were synthesized by using different -alkyl amines and the physical data of synthesized compound were represented in table no. 2. IR (KBr, cm -1 ): 3063, 2359 (C-H), 2925 (-H) 1622, 1606 (C=), 1208 (C=S); H 1 MR (CDCl 3, ppm) δ: (m, 9H, Ar-H), 4.0 (s, 2H, CH 2 ), (m 5H CH 2 CH 3 ), 2.0 (s, 1H, -H). Synthesis of 1-2-phenyl-1,3-quinazolin-4-(yl-oxymethyl)- 4 -p-(substituted phenyl)- thiosemicarbazide(7): To a boiling solution of compound 4 (0.001mol) in absolute ethanol (25ml) p-substituted phenyl isothiocynate (0.001mol) was added and the solution heated on reflux about 30mints, complete the reaction was monitored by TLC. The solid separated was filtered, recrystalised from DMF and purified using column chromatography. The physical data of synthesized compound were represented in table no. 2. Synthesis of -phenyl-5-{[(2-phenylquinazolin-4-yl)-oxy]-methyl}-1, 3, 4-thiadiazol-2- amine (8a): To the chilled H 2 S 4 (AR, 25ml) compound 7 (0.001 mol) was added gradually with constant stirring, after the addition was over, poured on crushed ice (100g) with water, recrystalised from (DMF) di methyl formamide and purified using column chromatography. Similarly the compounds 8b to 8e were synthesized and the physical data of synthesized compound were represented in table no. 2. IR (KBr, cm -1 ): 3195 (-H), 3061 (C-H), 1627 (C=); H 1 MR (CDCl 3, ppm) δ: (s, 1H, -H), (m 13H, Ar-H), 5.20 (s, 2H, CH 2 ), 1.90 (m, 3H, CH 3 ) 3-[2- (ethyl amino) methyl]-5-{[(2-phenylquinazolin-4-yl)-oxy]-methyl}-1,3,4-oxadiazole- 2(3H)-thione (6b): H 1 MR (CDCl 3, ppm) δ: (m, 9H, Ar-H), 4.0 (s, 2H, CH 2 ), 2.0 (s, 1H, -H), (m 5H CH 2 CH 3 ), 3.91 (s, 2H, CH 2 ). 3-[2- (propyl amino) methyl]-5-{[(2-phenylquinazolin-4-yl)-oxy]-methyl}-1,3,4-oxadiazole- 2(3H)-thione (6c): H 1 MR (CDCl 3, ppm) δ: (m, 9H, Ar-H), 4.0 (s, 2H, CH 2 ), 2.0 (s, 1H, -H), (m 5H CH 2 CH 3 ), 3.91 (s, 2H, CH 2 ), (m 5H CH 2 CH 3 ). 3-[2- (butyl amino) methyl]-5-{[(2-phenylquinazolin-4-yl)oxy]methyl}-1,3,4-oxadiazole- 2(3H)-thione (6d): H 1 MR (CDCl 3, ppm) δ : (m, 9H, Ar-H), 4.0 (s, 2H, CH 2 ), 2.0 (s, 1H, -H), 3.91 (s, 2H, CH 2 ), (m, 5H, CH 2 CH 3 ). 3-[2- (morpholinyl amino) methyl]-5-{[(2-phenylquinazolin-4-yl)-oxy]-methyl}-1,3,4- oxadiazole-2(3h)-thione (6e): H 1 MR (CDCl 3, ppm) δ: (m, 9H, Ar-H), 4.0 (s, 2H, CH 2 ), 2.0 (s, 1H, -H), 4.01 (s, 2H, CH 2 ), 2.9 (m, 4H, CH 2 CH 2 ), 3.65 (m, 4H, CH 2 CH 2 ). 3-[2- (piperzinyl amino) methyl]-5-{[(2-phenylquinazolin-4-yl)oxy]methyl}-1,3,4- oxadiazole-2(3h)-thione (6f): H 1 MR (CDCl 3, ppm) δ: (m, 9H, Ar-H), 4.0 (s, 2H, CH 2 ), 2.0 (s, 1H, -H), 4.01 (s, 2H, CH 2 ), 2.67 (m, 4H, piperidine). -(4-methylphenyl)-5-{[(2-phenylquinazolin-4-yl) oxy]-methyl}-1, 3, 4-thiadiazol-2-amine (8b): H 1 MR (CDCl 3, ppm) δ: (s, 1H, -H), (m 13H, Ar-H), 5.20 (s, 2H, CH 2 ), 1.90 (m, 3H, CH 3 ). -(4-methoxy phenyl)-5-{[(2-phenylquinazolin-4-yl) oxy]-methyl}-1, 3, 4-thiadiazol-2- amine (8c): H 1 MR (CDCl 3, ppm) δ: (s, 1H, -H), (m 13H, Ar-H), 5.20 (s, 2H, CH 2 ), 3.80 (s, 3H, CH 3 ). -(2-methoxy phenyl)-5-{[(2-phenylquinazolin-4-yl) oxy]-methyl}-1, 3, 4-thiadiazol-2- amine (8d): H 1 MR (CDCl 3, ppm) δ: (s, 1H, -H), (m 13H, Ar-H), 5.20 (s, 2H, CH 2 ), 3.80 (s, 3H, CH 3 ). -(2-nitro phenyl)-5-{[(2-phenylquinazolin-4-yl) oxy]-methyl}-1, 3, 4-thiadiazol-2-amine (8e): H 1 MR (CDCl 3, ppm) δ: (s, 1H, -H), (m 13H, Ar-H), 5.20 (s, 2H, CH 2 ) MLECULAR DCKIG STUDIES All the derivatives of quinazolinyl oxadiazoles and quinazolinyl thiadiazoles were selected for their molecular docking studies on selected X-ray crystal structure of GSK-3β (pdb code; 1q3d)(3) using glid ( Schrodinger, PLS-2005 software), the possible binding mode of a GSK-3β inhibitors illustrate in fig.no.1. The compounds (14) were docked in to ATP binding site of GSK. The key interaction for this complex includes hydrogen bonding between portion of amide hydrogen and back bone of carbonyl group with Val135, Asp 200, and Asp 186 respectively. The substituted functional group on phenyl ring to forms another hydrogen bonding with Gln 185, Lys85 and electrostatic interaction of phenyl ring with Tyro140, pyridine nitrogen to forms electrostatic interaction withtyr134, the interaction image of compound 8 with in to ATP binding site of GSK were illustrate in fig.no.2. The docking score calculated by glid score and their docking score of all molecules were shown in table no.1. PHARMACLGY All the compounds were screened on albino rats for their hypoglycemic activity following the method of agarwal (6). A group of albino rats were selected randomly assigned into three groups (1-3) of five rats (n=5) each as follows, group 1 received vehicle (Distilled water) and served as control group, group 2 received standard drug (Tolbutamide) and served as standard group. Group 3 received test compounds (100 mg/kg) and served as test- group. All these animals kept on fast for 12 hrs, the fasting blood sugar sample were drawn from the tail veins of the rats and their glucose content was measured. The compounds to be tested were emulsified with 5% gum tragacanth and administered orally at single dose of 100 mg/kg body weight. The blood sample were again drawn from the tail vein at intervals of 1, 2 and 4 hrs and their glucose content were again determined and the percentage Change of glucose level were calculated and results shown in table 2. RESULTS AD DISCUSSI The synthesis of quinazoline oxadiazoles and quinazoline thiadiazole derivatives was achieved following the steps outlined in scheme 1.The antranilic acid underwent cyclization with benzoyl chloride in pyridine at 0-5 o C to give 2-phenyl-4(H)-3,1 benzoxazin4-one (1) by benzylation followed by dehydration. Compound 1 up on reaction with foramide results in the more stable 2-phenyl-4(3H)-quinazolinone (2), up on alkylation Compound 2 with ethylchloroacetate in dry acetone over anhydrous potassium carbonate yielded its -alkylated 5846 product; ethyl-[(2-phenyl-4-quinazolinyl)-oxy]-acetate (3). Compound 3 was reacted further with hydrazine hydrate (80%) in absolute alcohol to get the corresponding 2-phenyl-4- quinazolinyloxy acetyl hydrazide (4). The compound 4 was reacting further with carbon disulphide (CS 2 ) and KH and p- substituted phenyl isothiocynate yielded 2 1 thia oxadiazoles (5) and 2phenyl-1, 3 quinazolin-4-oxymethyl--p (substituted phenyl) thiosemicarbazide (7). The compound 5 reacts further with formaldehyde 40% and different alkyl amines yields -methyl 5-(2-phenyl-1, 3 quinazolin 4-yl oxy methyl)-2 thio- 1, 3, 4 oxadiazole(6).the compound 7 undergoes cyclization with H 2 S 4 (AR) yielded a 2phenyl (1, 3-quinazolin 4-yl oxy methyl)--p-(substituted phenyl) 1, 3, 4-thiadiazole derivatives (8). All the synthesized compounds were characterized based on the physical and spectral data; the physical data of all compounds were given in table no.2. The molecular docking studies were performed against crystal structure of GSK-3β and the respective docking scoring functions were given in table no.1. The 6a, 6b, 6c, 6f, 6d, 6g of oxadiazoles and 8a, 8c, 8f, 8b of thiadiazole derivatives are shown to be exhibit good binding its ATP binding sites of GSK-3β by interacting with Val135, Asp186, Asp200 and lys85, the docking results were given in table no.1. All the synthesized compound were evaluated for their hypoglycemic activity on rats and percentage reduction of blood glucose level were calculated, results were given in table no.2. The substituted phenyl on thiazolo- quinazoline is exhibit greater hypoglycemic activity than alkyl substituted oxadiazolo-quinazoline. The compounds 8c, 8b, 8a and 6i, 6f, 6a are shown to be exhibits good hypoglycemic activity. Table. o. 1 Molecular docking studies of all synthesized compounds S.o class Entry ID R 1 R 2 docking score XP GScore XP HBond 1 6a 277 H CH b 278 H C 2 H c 279 H propyl d 280 H butyl e 281 H morpholine f 282 H piperidine g 283 H p-tolylene h 284 H Phenyl piperidine i 285 H p-methoxy piperidine 10 8a 293 H b 294 CH c 295 p- CH d CH e CH a b H c H 2 I II CC 2 H 5 CHH 2 d III g IV e H CHHCSH R 1 S VII V F R 1 h S H S R 2 VIII R 1 VI Scheme: 1 Synthesis of quinazolinyl oxadiazoles & quinazolinyl thiadiazoles Reagents conditions: a) Benzoyl chloride & pyridine, b) HCH 2, c) Ethyl chloroacetate and dry acetone d) HH 2.H 2 / ethanol, e) CS 2 /KH, f) HCH, -alkyl amine, g) p- substituted phenyl isothiocynate, h)h 2 S 4 (AR) Table. o. 2 Physical data and hypoglycemic activity of all synthesized compounds S.no. R 1 R 2 m.p. o c %Yield Hypoglycemic activity(%reduction blood sugar) 6a H CH b H C 2 H c H propyl d H butyl e H morpholine f H piperidine g H p-tolylene h H Phenyl piperidine i H p-methoxy piperidine a H b CH c p-ch d - CH e Fig.1 Docking image of compound 8 in an X-ray crystal structure of GSK-3β (pdb code; 1q3d) 5849 Fig.2 Binding interaction of compound 8 with ATP binding site of GSK-3β CCLUSI Gsk3β represented a promising target and designing gsk3β inhibitors would offer a novel approach to develop potent inhibitors in this class. In the present study we were synthesized quinazolinyl oxadiazoles and quinazolinyl thiadiazoles and molecular docking study were performed against crystal structure of gsk3β and this study results helpful in further detailed study for developing a potential gsk3β inhibitors. ACKWLEDGMET Authors are thankful to the Ganga Educational Society for providing the facilities. REFERECES 1. 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